A borrowing hydrogen methodology: Palladium-catalyzed dehydrative: N -benzylation of 2-aminopyridines in water

Article abstract of DOI:10.1039/c8gc01028e

We demonstrate a greener borrowing hydrogen methodology using the π-benzylpalladium system, which offers an efficient and environmentally friendly dehydrative N-monobenzylation of 2-aminopyridines with benzylic alcohols in the absence of base. The crossover experiment using benzyl-α,α-d₂ alcohol and 3-methylbenzyl alcohol afforded H/D scrambled products, suggesting that the dehydrative N-benzylation in our catalytic system involves a borrowing hydrogen pathway. KIE experiments show that C-H bond cleavage at the benzylic position of benzyl alcohol is involved in the rate-determining step (KIE = 2.9). This simple base-free protocol can be achieved under mild conditions in an atom-economic process, affording the desired products in moderate to excellent yields.

Full text of DOI:10.1039/c8gc01028e

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A borrowing hydrogen methodology: palladium-catalyzed
dehydrative N-benzylation of 2-aminopyridines in water
Received 00th January 20xx,
Accepted 00th January 20xx
Hidemasa Hikawa,* Hirokazu Imamura, Shoko Kikkawa, and Isao Azumaya*
We demonstrate a greener borrowing hydrogen methodology using the π-benzylpalladium system, which offers an
efficient and environmentally friendly dehydrative N-monobenzylation of 2-aminopyridines with benzylic alcohols in the
absence of base. The crossover experiment using benzyl-α,α-d2 alcohol and 3-methylbenzyl alcohol afforded H/D
scrambled products, suggesting that the dehydrative N-benzylation in our catalytic system involves a borrowing hydrogen
pathway. KIE experiments show that C-H bond cleavage at the benzylic position of benzyl alcohol is involved in the rate-
determining step (KIE = 2.9). This simple base-free protocol can be achieved under mild conditions in an atom-economic
process, affording the desired products in moderate to excellent yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
other transition-metal-catalyzed in situ oxidation of the
alcohol generates the aldehyde; 2) the aldehyde reacts with an
amine to form the corresponding imine; and 3) the imine is
Introduction
2-Aminopyridines are valuable targets as structural
constituents of many pharmacophores of biologically
interesting compounds in modern drug discovery. They are
found in drugs such as tripelennamine (antihistamine),
reduced by the metal hydride complex to give the N-alkylated
amine. Advantageously, this protocol can be performed
without the addition of an external hydrogen source.
Therefore, an attractive salt-free and atom-economic process
affords the desired products along with water as the sole co-
product. However, the classical borrowing hydrogen methods
suffer from disadvantages such as the use of strong bases
(tBuOK or KOH) and moisture sensitive hazardous organic
solvents.8 Therefore, a greener protocol expresses the goal to
minimize the environmental impact in chemical production.9 In
2011, Fujita and Yamaguchi et al. developed an
environmentally benign amination of alcohols catalyzed by a
water-soluble Cp*Iridium complex in water without a base.9b
mirtazapine
(antidepressant),
piroxicam
(NSAID),
salazosulfapyridine (antirheumatoid arthritis), palbociclib
(antitumor agent) and rosiglitazone (antidiabetic) (Figure 1).
Therefore, efficient methods for the direct introduction of
diverse functionalities on 2-aminopyridines have been
developed.1 The alkylation of amines is one of the most useful
transformations, which involves treating amines with
alkylhalides (Scheme 1A).2 However, these multistep and
hazardous processes should be improved due to their low
atom economy and the production of stoichiometric amounts
of waste. Furthermore, this approach often requires harsh
conditions due to the low nucleophilicity of the amines3 and
multiple steps such as protection/deprotection4 to prevent
over-alkylation.5
Me
N
O
O
S
Me
Ph
N
N
N
N
H
N
N
N
O
O
N
Me
Me
Recently, the borrowing hydrogen (or hydrogen
autotransfer) methodology has gained increasing interest as
an alternative synthetic pathway for straightforward and
sustainable C-N bond formation, since this method can be
performed using stable, available, and non-toxic alcohols
instead of halides or aldehydes (Scheme 1B).6 This work was
pioneered by Watanabe and Grigg in 1981.7 The mechanism
for N-alkylation proceeds as follows: 1) the Ru(II)-, Ir(III)- or
tripelennamine
(antihistamine)
mirtazapine
(antidepressant)
piroxicam
(NSAID)
O
O
S
H
N
N
N
N
N
N
O
O
H
HO2C
N
N
N
Me
N
HO
HN
Me
salazosulfapyridine
(antirheumatoid arthritis)
palbociclib
(antitumor agent)
O
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi,
Chiba 274-8510, Japan. E-mail: hidemasa.hikawa@phar.toho-u.ac.jp and
isao.azumaya@phar.toho-u.ac.jp
Me
NH
N
N
S
O
Electronic Supplementary Information (ESI) available: [Copies of 1H and 13C NMR
spectra for all compounds.]. See DOI: 10.1039/x0xx00000x
O
rosiglitazone
(antidiabetic drug)
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Figure 1. Representative biologically active 2-aminopyridines.
occurred when using a Brønsted acid such as TsOH
・H2O
(entry 4), excluding an SN2 type reaction mechanism in the
formation of 3a. With regard to the palladium catalysts, PdCl2,
PdBr2, Pd(OTf)2 and zero-valent palladium, Pd2(dba)3, also
resulted in excellent yields (92-95%, entries 5-8). In contrast,
no reaction occurred in the absence of phosphine (entries 9
and 10). Other salts such as Ir(III), Ni(II), Co(II), Fe(II) and Cu(II)
were less effective than Pd(II) (entries 11-15). Replacing water
with polar organic solvents such as EtOH, DMSO, 1,4-dioxane
and cyclopentyl methyl ether (CPME)13 resulted in no reaction
(entries 16-19).
We have developed a unique strategy for dehydrative
benzylation by the π
-benzylpalladium(II) species A10 generated
from Pd(0)/sodium diphenylphosphinobenzene-3-sulfonate
(TPPMS) and benzyl alcohol in water.11 We recently described
for the first time
methodology for N-benzylation of 2-aminobenzonitriles.12 As
an extension of our investigation on the -benzylpalladium(II)
a new greener borrowing hydrogen
π
system, we herein present the dehydrative N-benzylation of
poor nucleophilic amines such as 2-aminopyridines in water
(Scheme 1C). This simple base-free protocol can achieve the
dehydrogenation of benzyl alcohols under mild conditions,
whereas strong bases are essential in general hydrogen-
transfer strategies. To the best of our knowledge, the
application of the borrowing hydrogen method without the
need for strong bases and hazardous organic solvents has
remained elusive to date. This greener method has reduced
waste generation, uses safer solvents and reaction conditions,
and increases energy efficiency, all of which contribute to the
Table 1. Effects of catalysts and solvents.a
Catalyst (5 mol%)
TPPMS (10 mol%)
N
N
Ph
Ph
OH
+
NH2
solvent
100-120 oC, 16 h
N
N
N
Ph
2a
(2-5 equiv)
H
1a
3a
Ph
not obtained
sealed tube, air
T. (oC)
Yield (%)b
Entry Catalyst
2a (equiv)
Solvent
H2O
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
TsOH·H2O
PdCl2
2
120
72
97 (90) c
efficiency of
a chemical transformation. Therefore, our
2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
H2O
120
100
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
catalytic strategy has emerged as an attractive alternative to
traditional synthetic methods.
3
H2O
80 (0) f
4
H2O
0
5
H2O
93
92
93
95
0
6
PdBr2
H2O
7
Pd(OTf)2
H2O
d
8
Pd2(dba)3
H2O
e
9
Pd(OAc)2
Pd2(dba)3
H2O
d,e
10
11
12
13
14
15
16
17
18
19
H2O
0
IrCl3·xH2O
NiCl2·6H2O
CoCl2·6H2O
FeCl2·4H2O
CuCl2
H2O
Trace
18
0
H2O
H2O
H2O
Trace
0
H2O
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
EtOH
DMSO
dioxane
CPME
0
0
0
Scheme 1. N-Benzylation of 2-aminopyridines.
0
a Reaction conditions: 2-aminopyridine 1a (1 mmol), catalyst (5 mol%), TPPMS (10
mol%), benzyl alcohol 2a (2-5 equiv), solvent (4 mL), 100-120 oC, 16 h in a sealed tube
under air. b The conversion was determined by 1H NMR analysis of the crude product
using 1,3,5-trimethoxybenzene as an internal standard. c Isolated yield. d 2.5 mol%. e
Results and discussion
Effects of catalysts and solvents.
without TPPMS. f at 80 o
C
Initially, 2-aminopyridine (1a) and benzyl alcohol (2a) were
chosen as the model compounds to optimize the dehydrative
N-benzylation. The reaction of amine 1a with alcohol 2a (2
equiv) using Pd(OAc)2 (5 mol%) and TPPMS (10 mol%) in water
Reaction scope.
With the optimized conditions in hand, we examined the
substrate scope of the dehydrative N-benzylation (Scheme 2).
Both an electron-donating methyl group and electron-
withdrawing fluoro, alkoxycarbonyl, trifluoromethyl, cyano
and amido groups on the benzene ring of substituted 2-
o
at 120 C for 16 h gave the desired N-monobenzylated 3a in
72% yield selectively despite the possibility of forming the
corresponding N,N-dibenzylated product (Table 1, entry 1).
The yield of 3a was increased to 97% by using 5 equiv of
alcohol 2a (entry 2). Lowering the reaction temperature
resulted in decreased yield (80%, entry 3). No reaction
aminopyridines
corresponding N-benzylated products 3b-i in moderate to
excellent yields. Advantageously, an amine containing
1 were tolerated well to produce the
a
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sensitive reducible cyano group led to desired 3h in 85% yield. 1b occurs (path A), alcohol 2c would be converted into N-
Furthermore, we explored different heteroaromatic amines benzylated 3o, which is not labelled with deuterium. In
such as 3-aminopyridine and 2-aminopyrimidine, which contrast, a hydrogen and deuterium transfer pathway leads to
afforded the corresponding products 3j-k in good to excellent the H/D scrambling product 3o-d along with 3o (path B).
yields. The scope of alcohols
2
was examined next with 2- Therefore, deuterium incorporation into 3o would rule out the
nucleophilic substitution pathway. As expected, the crossover
aminopyridine (1a) or 5-(trifluoromethyl)pyridin-2-amine (1b
)
as the coupling partner. The use of benzyl alcohols with experiment afforded a mixture of deuterated 3o-d with 3o in
electron-donating methyl and alkoxy groups resulted in good 35% isolated yield along with a mixture of 3g-d and 3g-d2 in
yields (3l-q). A sterically demanding methyl group at the ortho 40% isolated yield. The deuterium incorporation into 3o was
position was tolerated in the direct substitution (3n, 80%). The indicated by 1H and 13C NMR spectra as well as the mass
α
-alkyl benzyl alcohol, 1-(4-methoxyphenyl)ethan-1-ol (2b), spectrum. In the 13C NMR spectrum, the methylene carbon is a
afforded the desired product 3r in 61% yield in spite of the 1:1:1 triplet at 45.8 ppm for 3o-d but a singlet at 46.1 ppm for
possible formation of
elimination from the
a
vinylarene through
β
-hydride 3o (Figure 2). In the 1H NMR spectrum, the ratio of the
α
-substituted -benzylpalladium(II) integration values of the methylene doublet at 4.5 ppm to the
π
intermediate.14 The dehydrative substitution of 2- doublet at 6.4 ppm is 1.5:1.0, suggesting that an almost
naphthalenemethanol also led to the desired 3s in 75% yield. equimolar mixture of 3o and 3o-d is formed (Figure 2). The
Legros et al. reported that the loss of resonance energy for the FAB mass spectrum shows two lines as pseudomolecular ion
formation of the
intermediate is less important than for the
benzyl)palladium(II) intermediate.15 In contrast, the use of a
substrate with a strong electron-withdrawing nitro group and
2-phenylethyl alcohol resulted in no reaction.
(
η3-naphthalenemethyl)palladium(II) peaks (M+H+) at m/z 267 for 3o and 268 for 3o-d (see SI).
( -
η3
Scheme 3. Crossover experiment. Reaction conditions: amine 1b (1 mmol),
Pd(OAc)2 (5 mol%), TPPMS (10 mol%), alcohols 2a-d2 (5 mmol) and 2c (5 mmol),
H2O (4 mL), 120 oC, 16 h in a sealed tube under air.
48.2 48.0
47.8
47.6
47.4
47.2
47.0
46.8
46.6
46.4
46.2
46.0
45.8
45.6
45.4
45.2
45.0
44.8
44.6
44.4
44.2
44.0
43.8
X : parts per Million : Carbon13
Scheme 2. Scope of anilines
1
and benzyl alcohols 2. Reaction conditions: 1 (1
(5 equiv), H2O (4 mL), 120 oC, 16
mmol), Pd(OAc)2 (5 mol%), TPPMS (10 mol%),
2
6.5
6.4
6.3
6.2
6.1
6.0
5.9
5.8
5.7
5.6
5.5
5.4
5.3
5.2
5.1
5.0
4.9
4.8
4.7
4.6
4.5
4.4
h in a sealed tube under air. Yield of isolated products. a No reaction occurred in
the absence of Pd catalyst.
X : parts per Million : Proton
Figure 2. 13C and 1H NMR spectra for mixture of 3o and 3o-d
.
Crossover experiment.
To gain insight into the mechanism of the borrowing
hydrogen methodology, we carried out a crossover experiment
using different benzyl alcohols (Scheme 3). If the direct
nucleophilic substitution of 3-methylbenzyl alcohol (2c) with
Kinetic isotope effect.
KIE studies were performed to gain further mechanistic
insight into the dehydrogenation step. The intermolecular
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competition between benzyl alcohol 2a and its deuterium-
1
labeled substrate 2a-d7 gave KIE = 2.9 on the basis of H NMR
analysis, suggesting that C-H bond cleavage at the benzylic
position of benzyl alcohol was involved in the rate-determining
step (Scheme 4A). Higashimoto et al. reported that the
photocatalytic oxidation of benzyl alcohol by O2 on TiO2 at 313
K gave KIE = 2.8.16a O’Leary et al. reported a KIE value of 5.8 in
the chromium(VI) oxidation of 2-propanol.16b These papers
Figure 3. Hammett plot for the Pd-catalyzed N-benzylation of 2-aminopyridines
(X = Me, F, CO2Me, and CN) with benzyl alcohol (2a) in water.
1
Mechanistic considerations.
On the basis of these results and our previous report, we
propose a catalytic system for the dehydrative N-benzylation
of 2-aminopyridines (1a) with benzyl alcohol (2a) in water as
illustrated in Scheme 5. First, oxidative addition of 2a to water-
also suggest that α-deprotonation from the alcohol is the rate-
determining step. Additionally, Zhang and Wang et al.
reported that iridium-catalyzed dehydrogenaton of benzyl
amine in water gave KIE = 1.9.16c
soluble Pd(0)/TPPMS catalyst affords the cationic
benzylpalladium(II) complex
(step 1). Water activates the sp3
C-O bond by hydrogen bonds between water and the hydroxyl
group of the alcohol for formation of the -benzylpalladium(II)
complex , and the resulting cationic charge of complex is
π-
A
Next, the rates for dehydrative N-benzylation “in H2O” and
“in D2O” were compared. After 4 h, the reaction rate was
faster “in H2O” than “in D2O” with a kinetic solvent isotope
effect (KSIE) of 2.2 (Scheme 4B). In general, the KSIE for
protonation shows values of 5-7.17 This low value suggests
hydrogen bonding activation by water for the dehydrative N-
benzylation. Additionally, our base-free protocol can achieve
the deprotonation of benzyl alcohols, whereas strong bases
are essential in general hydrogen transfer strategies.
Therefore, the reaction rate of BnOH might be faster than that
of BnOD (generated from BnOH in D2O) with a kinetic isotope
effect of 2.2.
π
A
A
stabilized by water. The KSIE of 2.2 suggests hydrogen bonding
activation in water (see Scheme 4B). Shinokubo and Oshima
reported that an aqueous biphasic reaction system enables the
direct use of allyl alcohol in the Tsuji-Trost reaction, and
theoretical calculations have elucidated the importance of
hydration of the hydroxy group for the smooth generation of
the
should be favored by electron-donating groups on
intermediate , since these will stabilize the positive charge on
π
-allylpalladium species.20 Furthermore, this process
A
A. Competitive deuterium labeling experiment.
Pd(II). Indeed, no reaction occurred using 4-nitrobenzyl alcohol
(see Scheme 2). Additionally, phenethyl alcohol also resulted in
Ph
OH
Pd(OAc)2 (5 mol%)
TPPMS (10 mol%)
H/D
2a (1 mmol)
+
D
D
N
NH2
no reaction since the
be formed. Next, the Pd(II)-catalyzed oxidation of alcohol 2a
generates the aldehyde (step 2). Initially, the π-
π-benzylpalladium(II) species could not
H2O, 120 oC, 16 h
N
N
H
H/D
KIE = 2.9
1a
D5-Ph
OH
(1 mmol)
2a-d7 (1 mmol)
4
B. Deuterium isotope effect for "in H2O" and "in D2O".
Ph OH 2a (5 equiv)
benzylpalladium(II) cation species is coordinated with the
hydroxide of 2a, and then the acetoxy anion acts as a base to
remove the acidic proton of the cationic alcohol-Pd(II)
intermediate, followed by formation of a palladium alkoxide
Pd(OAc)2 (5 mol%)
TPPMS (10 mol%)
100 oC, 4 h
H2O: 13%, D2O: 6%
KSIE = 2.2
N
N
Ph
N
NH2
H
1a
species
under neutral aqueous conditions, whereas the use of strong
bases is essential to form the alkoxide in traditional
affords benzaldehyde ( ) along
-hydride elimination. The KIE
is involved
in the turnover-limiting step (see Scheme 4A). The aldehyde
reacts with amine 1a to form the corresponding imine (step
to
B. Notably, our catalytic system proceeds smoothly
3a
Scheme 4. Kinetic isotope effects.
B
protocols. The intermediate
with palladium(II) hydride
B
4
Hammett study.
C
by β
The electronic effects for the dehydrative N-benzylation
of 2.9 indicates that the C-H cleavage of alkoxide
B
were examined for a number of different 4-substituted 2-
4
aminopyridines
in Figure 3, a small negative Hammett
obtained.18 In contrast, large negative
the Tsuji-Trost type N-benzylation of anilines (
2.8),11a,19 since there is a build-up of positive charge by the
Pd(II) cation species in the transition state (Figure 3A). These
results suggest a hydrogen bonding effect in promoting the
cyclocondensations of 2-aminopyridines with aldehydes
1
(X = Me, F, CO2Me and CN groups). As shown
value of 0.7 was
values are observed in
2.2 to －
6
ρ
－
3), which is reduced by the palladium(II) hydride complex
C
ρ
give N-monobenzylated 3a and regenerate the
π-
ρ
=
－
benzylpalladium(II) species
A (step 4).
A
1
through the borrowing hydrogen pathway (Figure 3B).
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Scheme 5. Proposed mechanism.
Scheme 7. Scale-up experiment.
Control experiments.
Several control experiments were performed to exclude
the possibility of other reaction pathways and support the
proposed mechanism.21 First, in the presence of a radical
scavenger (BHA: 3-tert-butyl-4-hydroxyanisole, 1 equiv) or
under an Ar atmosphere, the yield of the desired product 3a
remained unchanged, suggesting that a radical pathway based
on a single electron transfer (SET) is not included in our
catalytic system, nor is oxygen essential to the oxidation
Conclusions
In summary, we have developed an environmentally
benign borrowing hydrogen methodology for N-
monobenzylation of 2-aminopyridines in water. Notably, the
catalytic protocol consisting of the π-benzylpalladium system
enables the dehydrative N-monobenzylation without the need
for strong bases or other additives, whereas strong bases are
essential in general hydrogen-transfer strategies. Furthermore,
this method can be applied to several substrates even in the
presence of sensitive functional groups.
(dehydrogenation)
disproportionation of benzyl alcohol
(Scheme 6B). If the dehydrogenation of benzyl alcohol (2a) to
benzaldehyde 4a proceeds, toluene should be formed
through -hydride elimination of intermediate , followed by a
step
(Scheme
6A).
Next,
the
(
2a
)
was examined
(
)
β
B
Experimental
reductive elimination cascade. We were delighted to observe
General procedure: A mixture of aminopyridines 1 (1 mmol),
the benzaldehyde (4a: 42%) and toluene (5a: 38%) from 2a in
palladium(II)
acetate
(12 mg,
0.05 mmol),
sodium
the reaction mixture. As expected,
α-alkyl benzyl alcohol 2b
diphenylphosphinobenzene-3-sulfonate (TPPMS, 36 mg, 0.1 mmol)
and benzyl alcohol 2 (5-10 mmol) in H2O (4 mL) was heated for 16 h
in a sealed tube under air. After cooling, the reaction mixture was
poured into water and extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash column chromatography (silica
gel, hexanes/EtOAc) to give desired product 3.
was also converted to the corresponding ketone 4b and
reduced product 5b (Scheme 6C). The reaction of an N-
alkylated substrate such as 2-(methylamino)pyridine (1c) did
not proceed (Scheme 6D). Therefore, our catalytic system is
employed for the selective N-monobenzylation.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number
16K08179.
Notes and references
1
(a) A. Alanthadka, E. S. Devi, A. T. Selvi, S. Nagarajan, V.
Sridharan, C. U Maheswari, Adv. Synth. Catal. 2017, 359
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2017, 19 5790-5793; (c) R. Sakamoto, S. Sakurai, K.
Maruoka, Chem. Comm. 2017, 53, 6484-6487; (d) X. Jie, Y.
Shang, X. Zhang, W. Su, J. Am. Chem. Soc. 2016, 138
5623−5633; (e) T. Mita, K. Michigami, Y. Sato, Chem. Asian J.
2013, , 2970–2973; (f) D. Liang, Y. He, L. Liu, Q. Zhu, Org.
,
,
,
Scheme 6. Control experiments. The conversion was determined by 1H NMR
analysis of the crude product using an internal standard.
8
Lett. 2013, 15, 3476–3479.
J. L. Vrijdag, D. De Ruysscher, W. M. De Borggraeve, Eur. J.
Org. Chem. 2017, 1465–1474;
J. L. Vrijdag, F. Delgado, N. Alonso, W. M. De Borggraeve, N.
Perez-Macias, J. Alcazar, Chem. Commun. 2014, 50, 15094-
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(a) H. Huang, H. Ji, H. Li, Q. Jing, K. J. Labby, P. Martásek, L. J.
Roman, T. L. Poulos, R. B. Silverman, J. Am. Chem. Soc. 2012,
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Laufer, J. Med. Chem. 2008, 51, 5630-5640.
2
3
Scale-up experiment.
Finally, to demonstrate the utility of our catalytic system, a
gram scale reaction of 1b with 2a in the presence of Pd(OAc)2
(5 mol%) and TPPMS (10 mol%) in water was carried out
(Scheme 7). As expected, the desired 3g was obtained
successfully in 72% isolated yield.
4
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DOI: 10.1039/C8GC01028E
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Green Chemistry
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DOI: 10.1039/C8GC01028E
We demonstrate a borrowing hydrogen methodology using the p-benzylpalladium system, which offers
an efficient and environmentally friendly dehydrative N-monobenzylation of 2-aminopyridines with
benzylic alcohols in the absence of base. This simple protocol can be achieved under mild conditions in
an atom-economic process, affording the desired products in moderate to excellent yields.