Palladium catalyzed Suzuki cross-coupling of benzyltrimethylammonium salts via C-N bond cleavage

Article abstract of DOI:10.1039/C7RA02549A

A palladium catalyzed Suzuki cross-coupling for construction of Csp³-Csp² bond via Csp³-N bond activation of benzyltrimethyl-ammonium salt is described. This reaction not only offered a highly efficient approach to diarylmethanes but also paved the way for the application of benzyltrimethylammonium salts in the palladium catalyzed cross coupling reactions.

Full text of DOI:10.1039/C7RA02549A

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PAPER
Palladium catalyzed Suzuki cross-coupling of
benzyltrimethylammonium salts via C–N bond
cleavage†
Cite this: RSC Adv., 2017, 7, 15805
ab
b
b
b
b
ab
Tao Wang, Shuwu Yang, Silin Xu, Chunyu Han, Ge Guo and Junfeng Zhao*
Received 1st March 2017
Accepted 2nd March 2017
3
2
3
A palladium catalyzed Suzuki cross-coupling for construction of Csp –Csp bond via Csp –N bond
activation of benzyltrimethyl-ammonium salt is described. This reaction not only offered a highly
efficient approach to diarylmethanes but also paved the way for the application of
benzyltrimethylammonium salts in the palladium catalyzed cross coupling reactions.
DOI: 10.1039/c7ra02549a
rsc.li/rsc-advances
Palladium catalyzed cross-coupling reactions between various and co-workers reported a palladium catalyzed C–H arylation of
10
electrophiles and nucleophilic metal reagents are highly prac- oxazoles with aryltrimethyl-ammonium salts. Reeves developed
1
tical methodologies for C–C bond formation. They are one of the palladium catalyzed cross-coupling between aryltrimethyl-
11
the signicant accomplishments of last century's chemistry and ammonium salts and Grignard reagents. However, palladium
their signicance has been recognized by the 2010 Nobel Prize catalyzed Suzuki cross-coupling of quaternary ammonium salts
in Chemistry. Among these cross coupling reactions, the Suzuki is still kept untouched. In addition, considering the diversity of
reaction, the coupling between organoborane reagents and palladium catalyzed organic transformations, establishment of
electrophiles, is the most popular one because of the inherent robust palladium catalyst systems for activating the C–N bond of
advantages of organoboron reagents, such as air- and moisture- quaternary ammonium salts would be valuable for exploring
stability, good functional group tolerance, low toxicity and wide their application in organic synthesis. In such context, we herein
2
availability. A variety of electrophiles such as aryl halides, tri- reported the rst palladium catalyzed Suzuki coupling with
3
4
5
6
7

ates, mesylates/tosylates, esters, ethers, and phosphates
benzyltrimethylammoniums as the electrophile partner.
Diarylmethane derivatives have been widely used in phar-
have been developed for this reaction. Very recently, the tran-
sition metal catalyzed Suzuki coupling reactions involving the maceuticals and materials (Fig. 1). Very recently, Rhee dis-
C–N bonds cleavage have attracted much attentions. Quater- closed that the synthesis of diarylmethanes could be
nary ammonium salts are the most important C–N bond con- accomplished by palladium catalyzed Suzuki cross-coupling of
taining electrophiles due to their wide availability and high N,N-ditosylbenzylamines via C–N bond activation. We envi-
reactivity. Macmillan and co-workers reported the rst Ni sioned that palladium catalyzed Suzuki cross-coupling of ben-
catalyzed Suzuki cross-couplings of aryltrimethylammoniums.
12
8
9
13
8i
zylammonium salts with aryl boronic acids would be an
Watson extended this concept to benzyltrimethyl ammoniums effective approach to diarylmethanes. It is initiated by investi-
and realized the stereospecic preparation of enantioenriched gating the crossing coupling of 4-cyanophenyl boronic acid
8j
diarylethanes. However, both cases involved the using of air with benzylammonium salt 1a, which is readily prepared
and moisture sensitive Ni catalysts which limited their practical
application. Compared with Ni catalyzed reactions carried out
under inert atmosphere, palladium catalyzed coupling reac-
tions are relatively easy to handle. However, the palladium
catalyzed cross-coupling reactions involving C–N bond cleavage
of quaternary ammonium salts remained rare. Recent studies
demonstrated that palladium could be used as valid catalyst for
cross-coupling reaction of quaternary ammonium salts. Wang
a
National Research Center for Carbohydrate Synthesis, Key Laboratory of Chemical
Biology, Jiangxi Province, China
b
College of Chemistry & Chemical Engineering, Jiangxi Normal University, 99, Ziyang
Road, Nanchang, Jiangxi, 330022, P. R. China. E-mail: zhaojf@jxnu.edu.cn
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra02549a
1
Fig. 1 Drugs containing diarylmethane motif.
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a
Table 1 Optimization of reaction conditions
donating (3b–f) or -withdrawing (3g–j) groups on the phenyl
ring of benzylammonium salts, good to excellent yields were
obtained. The ortho methyl substituent could be tolerated (3b).
Notably, the C–N bond could be selectively cleaved in the
presence of ether (3e & 3f), uoro (3g) and chloro (3h) groups
albeit bromo and iodo-substituted benzylammonium salts did
not offer the target cross coupling products.
The substrate scope of boronic acids had also been investi-
gated and the results are summarized in Scheme 2. Moderate
electron-withdrawing and -donating groups were tolerated while
their stronger congeners cause slight decrease in yield. Even the
steric demanding 2,6-dimethyl substituents were tolerated (3aa).
It is noted that a series of functional groups such as carbonate
Catalyst
Ligand
b
Entry
(3 mol%)
(10 mol%)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
—
dppf
dppp
Xantphos
Mixture
Mixture
Mixture
Mixture
Mixture
Mixture
Mixture
Mixture
Mixture
Mixture
Mixture
Mixture
PhMe
DMSO
DMF
CH
THF
EtOH
EtOH
EtOH
EtOH
—
—
—
Trace
67(65)
65
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Pd(acac)
Pd (dba)
Pd(TFA)
PdCl (PPh
Pd(PPh
PdCl (dppf)
Pd(OAc)
2
(3ag), aldehyde (3ai) and ester (3aj) were compatible. In addition,
2
3
63
57
55
diarylmethanes containing heterocycles such as pyridine (3ak),
furan (3al) and thiophene (3am) could also be prepared by this
method. Styrylboronic acid also proceeded smoothly to furnish
the cross coupling product in excellent yield (3ao). No evidence
of Heck coupling was observed when (4-vinylphenyl)boronic acid
was employed as the substrate (3an). Interestingly, for some
cases (3a–d, 3f–i), we could get the same products with that of
Scheme 1 from different set of starting materials by employing
the standard reaction conditions. This advantage will be more
prominent when one of the starting material is more expensive
or not available.
2
2
3
)
2
10
11
12
13
14
15
16
17
18
19
20
21
3
)
4
54(50)
50
2
2
2
20
34
18
54
43
32
75
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
2
2
2
3
CN
c
99(98)
97
d
e
A signicant functional group orthogonality to chloride,
96

uoride, ether and amine for benzylammonium salts as well as
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (3 mol%),
ꢀ
boronic acids was observed in this methodology. For example, the
9 : 1. GC yield, isolatedd yield was chloro group was kept intact in both cases (3h) and thus affording
ligand (10 mol%) and Na
Mixture: toluene : DMSO
indicated
2
CO
¼
3
(2 equiv.) in solvent (1 mL) at 100 C.
b
c
parentheses.
EtOH
(3
mL).
Potassium
an opportunity for further functionalization. This feature was
exemplied by sequential Suzuki-cross couplings (Scheme 3).
A plausible reaction mechanism was proposed in Scheme 4.
The oxidative addition of Pd(0) A formed in situ, with
phenyltriuoroborate was used in place of boronic acid.
e
Phenylboronic acid pinacol ester as the boron reagent.
quantitatively via methylation of 4-cyano-N,N-dimethylbenzyl-
amine. As shown in Table 1, the reaction is sensitive to ligand.
Only the monodentate PPh ligand afforded moderate yield of
3
target diarylmethane accompanied by signicant amount of
homo coupling product of boronic acid when PdCl was used as
2
the catalyst. Although further screening of palladium catalysts
did not offer any improvement, a dramatic solvent affect was
observed (Table 1, entries 13–18). In particularly, homo
coupling of boronic acid, the notorious issue of Suzuki cross-
coupling, could be suppressed signicantly by using ethanol
as the solvent. We were delighted to observe that the homo
coupling could be suppressed completely when more ethanol
was used (Table 1, entry 19). In turn, the yield of cross coupling
product was increased up to quantitative. The similar reaction
efficiencies were observed when potassium phenyl-
triuoroborate and phenylboronic acid pinacol ester were used
as the boron reagent (Table 1, entry 20 & 21).
With the optimized reaction conditions in hand, we next set
out to evaluate the generality of benzylammonium salts with 4-
cyanophenyl boronic acid as a model substrate. As shown in
Scheme 1, a broad substrate scope of benzylammonium salts
was observed. It seems that the electronic effect and the steric
effect of the substituents on the benzylammonium salts have
Scheme 1 Palladium-catalyzed reaction of 4-cyanophenyl boronic
acid with various benzylammonium salts. Reaction conditions: 1 (0.2
mmol), 2a (0.4 mmol), PdCl
2
(3 mol%), PPh
3
(10 mol%) and Na
2
CO
3
(0.4
ꢀ
mmol) in ethanol (3 mL) at 100 C for 18–24 h. Isolated yields were
little effect on the reaction efficiency. No matter electron- given.
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Scheme 4 Proposed reaction mechanism.
a new complex D, which upon reductive elimination furnished
the cross coupling product 3.
In summary, we have developed the rst palladium catalyzed
Suzuki cross-coupling reaction of quaternary ammonium salts.
This reaction represented the rst example of palladium cata-
3
2
lyzed Csp –Csp coupling of benzyltrimethylammonium salts
via C–N bond activation. It not only offered an effective
synthetic strategy to diarylmethane derivatives but also paved
the way for the unprecedented palladium catalyzed cross-
coupling of benzyltrimethyl ammonium salts. Further applica-
tion of the catalyst system to other palladium catalyzed cross-
coupling reactions of benzyltrimethyl ammonium salts are
undergoing in our laboratory and the results will be reported in
due course.
Scheme
2 Palladium-catalyzed reaction of 1-(4-cyanophenyl)-
N,N,N-trimethylmethanaminium trifluoromethanesulfonate reaction
Acknowledgements
conditions: 1a (0.2 mmol), 2 (0.4 mmol), PdCl
mol%) and Na CO
2
(3 mol%), PPh
(0.4 mmol) in ethanol (3 mL) at 100 C for 18–24 h.
3
(10
ꢀ
2
3
This work is supported by the National Natural Science Foun-
dation of China (21462023, 21562026) and the Natural Science
Isolated yields were given.
Foundation
of
Jiangxi
Province
(20143ACB20007,
2
0161BAB203085).
benzyltrimethylammonium salt 1 produced C–Pd complex B
with the release of trimethylamine. Followed by a trans-
metalation with boronic acid, the palladium complex B afforded
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