A palladium-catalyzed dehydrative: N -benzylation/C-H benzylation cascade of 2-morpholinoanilines on water

Article abstract of DOI:10.1039/c7gc03780e

A strategy for the palladium-catalyzed dehydrative tandem benzylation of 2-morpholinoanilines with benzyl alcohols has been developed. This cascade reaction is devised as a straightforward and efficient synthetic route for N-(1,2-diphenylethyl)-2-morpholinoanilines in moderate to good yields (50-81%). The dehydrative sp³ C-H bond benzylation proceeds chemoselectively at the benzylic position of N-benzyl-2-morpholinoaniline to form a new C(sp³)-C (sp³) bond. KIE experiments show that C-H bond activation is involved in the rate-determining step (KIE = 2.7). A Hammett study of 2-morpholinoanilines gives a negative ρ value, suggesting that there is a build-up of positive charge in the transition state. A on water protocol, which affords the corresponding desired products with water as the sole co-product, can be achieved under mild reaction conditions without the need for bases or other additives in an atom-economical process.

Full text of DOI:10.1039/c7gc03780e

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: H. Hikawa, R.
Ichinose, S. Kikkawa and I. Azumaya, Green Chem., 2018, DOI: 10.1039/C7GC03780E.
This is an Accepted Manuscript, which has been through the
Volume 18 Number
7 7 April 2016 Pages 1821–2242
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Accepted Manuscripts are published online shortly after
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1463-9262
CRITICAL REVIEW
G. Chatel et al.
Heterogeneous catalytic oxidation for lignin valorization into valuable
chemicals: what results? What limitations? What trends?
rsc.li/green-chem

Please do not adjust margins
Green Chemistry
Page 1 of 10
View Article Online
DOI: 10.1039/C7GC03780E
Journal Name
ARTICLE
Palladium-catalyzed dehydrative N-benzylation/C-H benzylation
cascade of 2-morpholinoanilines on water
Hidemasa Hikawa,* Risa Ichinose, Shoko Kikkawa, and Isao Azumaya*
Received 00th January 20xx,
Accepted 00th January 20xx
A strategy for the palladium-catalyzed dehydrative tandem benzylation of 2-morpholinoanilines with benzyl alcohols has
been developed. This cascade reaction is devised as a straightforward and efficient synthetic route for N-(1,2-
diphenylethyl)-2-morpholinoanilines in moderate to good yields (50-81%). The dehydrative sp3 C-H bond benzylation
proceeds chemoselectively at the benzylic position of N-benzyl-2-morpholinoaniline to form a new C(sp3)-C (sp3) bond. KIE
experiments show that C-H bond activation is involved in the rate-determining step (KIE = 2.7). A Hammett study of the 2-
DOI: 10.1039/x0xx00000x
www.rsc.org/
morpholinoanilines gives a negative
ρ value, suggesting that there is a build-up of positive charge in the transition state.
The “on water” protocol, which affords the corresponding desired products with water as the sole co-product, can be
achieved under mild reaction conditions without the need for base or other additives on the atom-economic process.
Sheldon et al. 10 In 2014, Tunge et al. developed the Tsuji-Trost
type benzylation via retro-Claisen activation of carbon
nucleophiles utilizing benzyl alcohols.11 In 2016, Zhang et al.
Introduction
2-Morpholinoaniline moieties are found in drug candidates
for treatment of cancer,1 Alzheimer's disease,2 wet age-related
macular degeneration (wet AMD)3 and infectious disease4
(Figure 1). However, these compounds are limited to
structures containing an amide moiety. Therefore, efficient
methods for the direct introduction of diverse functionalities
on 2-morpholinoanilines are gaining increasing interest in
medicinal chemistry. For example, the palladium-catalyzed
(hetero)arylation (Buchwald-Hartwig amination) of 2-
morpholinoanilines has recently been reported. 5
reported in situ C-O bond activation by dimethylcarbonate.12
Recently, the scope of -allylpalladium chemistry has been
extended to electrophilic umpolung allylic substitutions via bis-
-allylpalladium intermediates. This work was pioneered by
π
π
Yamamoto et al. in 1996 (Scheme 1A).13 In 2017, Bao and
Yamamoto demonstrated the palladium-catalyzed allylation of
benzyl chlorides with allyl pinacolborates through coupling of
the η1-allyl ligand with the η3-benzyl ligand of η3-allyl-η3
-
benzylpalladium intermediates (Scheme 1B).14 Pincer
complexes have also been employed in the catalytic allylation
of electrophiles, since the allyl moiety is constrained to an η1
Palladium-catalyzed Tsuji-Trost type benzylation has become
one of the most powerful strategies for the formation of
carbon-carbon and carbon-nitrogen bonds.6 Early studies on
-
coordination state required for the nucleophilic reactivity. 15
We have been developing a unique strategy for benzylation
by the -benzylpalladium(II) species from Pd(0)/TPPMS
the generation of π-benzylpalladium(II) complexes used benzyl
π
A
halides. 7 Furthermore, the use of benzyl carbonates, acetates
and phosphonates as activated alcohols has been reported to
be effective under neutral conditions.8 In contrast, the direct
use of benzyl alcohols for benzylation is especially challenging
because of their low reactivity towards Pd(0) compared with
(TPPMS: sodium diphenylphosphinobenzene-3-sulfonate) and
non-activated benzyl alcohol (Scheme 2A).16 Water activates
the sp3 C-O bond by hydrogen bonds between water and the
hydroxyl group of the alcohol to form complex
reported new type of palladium-catalyzed tandem
benzylation of anilines with benzyl alcohols for direct
construction of
N-(1,2-diphenylethyl)anilines.17 These
processes involve the formation of bis- -benzylpalladium
A. We recently
a
benzyl halides. Therefore, the development of
a direct
catalytic substitution of benzyl alcohols as electrophilic
partners, which affords the desired products along with water
as the sole co-product, is highly attractive in synthetic organic
chemistry.9 In this regard, early studies on the Pd-catalyzed
carbonylation of benzyl alcohols have been reported by
π
intermediates followed by the coupling of the η1-benzyl ligand
(nucleophiles) with the η3-benzyl ligand (electrophiles).
Although elegant protocols for the synthesis of N-(1,2-
diphenylethyl)anilines have been establish to date (e.g., the
benzylation
of
imines,18
hydroamination
of
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
alkynes/reduction,19 and reductive amination of ketones),20
these methods require the use of toxic reagents and organic
solvents under anhydrous conditions.
Electronic Supplementary Information (ESI) available: [Copies of 1H and 13C NMR
spectra for new compounds.]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 10
View Article Online
DOI: 10.1039/C7GC03780E
ARTICLE
Journal Name
Notably, the “on water” protocol is essential for achieving this
efficient strategy in our catalytic system.21 This green method
has reduced waste generation, uses safer solvents and
reaction conditions, and increases energy efficiency, all of
which contribute to the efficiency of
transformation.
a
chemical
Scheme 2. Strategy for the tandem benzylation by
π
-benzylPd(II)
A
on water.
Figure 1. Representative biologically active 2-morpholinoanilines.
Scheme 3. Reaction of 1a with benzyl chloride.
Results and discussion
1. Effects of catalysts and solvents. Initially, 2-
morpholinoaniline (1a) and benzyl alcohol (2a) were chosen as
the model compounds to optimize the reaction conditions.
When
diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol%) as
the catalyst, the desired N-(1,2-diphenylethyl)-2-
using
Pd(OAc)2
(5
mol%)
and
sodium
Scheme 1. Reactions of bis-π-allylPd(II) complexes.
morpholinoaniline (3a) was obtained selectively in 75% yield
(Table 1, entry 1). In contrast, no reaction occurred in the
absence of TPPMS (entry 2). With regard to the palladium(II)
catalysts, Pd(OAc)2 gave the best result (entry 1 vs entries 3-7).
As an extension of our investigation of the π-benzylpalladium
system, we herein present the palladium-catalyzed
dehydrative N-benzylation/benzylic C-H benzylation cascade of
2-morpholinoanilines on water (Scheme 2B). The tandem
reaction proceeds smoothly to produce N-(1,2-diphenylethyl)-
2-morpholinoanilines in moderate to good yields, which can
potentially be used for the construction of a diverse chemical
library in drug discovery. The dehydrative sp3 C-H bond
benzylation reaction chemoselectively occurs on the benzylic
position of the N-monobenzylated intermediate to form a new
o
When the reaction was performed at 100 C, the yield of 3a
was increased to 95% (entry 8). Replacing water with organic
solvents such as toluene, heptane, EtOH, 1,4-dioxane or DMF
resulted in no reaction (entries 9-14). Furthermore, low yield
or no reaction occurred with the use of D2O or under the neat
condition, respectively (entries 15-16). These results suggested
that the “on water” accelerated reaction would proceed since
the organic-water interface effect of dangling OH groups could
enhance the reaction rates. The use of zero-valent palladium,
Pd2(dba)3·CHCl3, afforded the product 3a in 81% yield (entry
17).
C(sp3)-C(sp3) bond,
a reaction that cannot proceed by
traditional benzylation protocols such as the use of benzyl
chloride with base (Scheme 3). Therefore, direct catalytic
functionalization of the sp3 C-H bond has emerged as an
attractive alternative to traditional synthetic methods.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 3 of 10
View Article Online
DOI: 10.1039/C7GC03780E
Journal Name
ARTICLE
of 5-7.22 Therefore, these low deuterium isotope values
suggested that hydrogen bonding activation occurred for the
benzylic C-H benzylation on water.
Table 1. Effects of catalysts and solvents.a
O
O
O
Ph
OH 2a (5 equiv)
N
N
N
N
Pd catalyst (5 mol%)
TPPMS (10 mol%)
80-100 oC, 20 h
NH
Ph
NH2
1a
Ph
5
Ph
Ph
3a
not detected
Conv. (%) b
75
Entry
1
Pd catalyst
Pd(OAc)2
T (oC)
Solvent
H2O
80
2 c
3
Pd(OAc)2
80
80
80
80
80
80
100
80
80
80
80
80
80
80
80
120
H2O
0
PdBr2
H2O
0
4
PdCl2
H2O
36
62
47
0
5
PdCl2(CH3CN)2
Pd(OCOCF3)2
[PdCl(allyl)]2
Pd(OAc)2
H2O
6
H2O
7
H2O
8 d
9
H2O
95
0
Pd(OAc)2
toluene
heptane
EtOH
dioxane
DMF
DMF
D2O
10
11
12
13
14
15
16
17 e
Pd(OAc)2
0
Pd(OAc)2
0
Figure 2. Reaction time course for the conversion of 2-morpholinoaniline (1a, 0.5
mmol) with benzyl alcohol (2a, 5 equiv) into desired 3a and N-benzyl-2-
morpholinoaniline (4a).
Pd(OAc)2
0
Pd(OAc)2
0
PdCl2(PPh3)2
Pd(OAc)2
0
44
0
Pd(OAc)2
neat
H2O
Pd2(dba)3·CHCl3
81
a Reaction conditions: aniline 1a (1 mmol), Pd catalysts (5 mol%), TPPMS (10 mol%),
benzyl alcohol 2a (5 equiv), solvent (4 mL), 80 oC, 20 h 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 without TPPMS. d under Ar. e Using 2a (10 equiv).
2. Reaction progress. To gain further understanding of the
reaction progress, the reaction of 2-morpholinoaniline (1a
)
with benzyl alcohol (2a
)
was monitored by 1H NMR
spectroscopy. After 6 h, the reaction of 1a afforded N-benzyl-
2-morpholinoaniline (4a) in 73% yield smoothly. In contrast, N-
(1,2-diphenylethyl)-2-morpholinoaniline
slowly while 4a was reduced (Figure 2). Furthermore, the N-
monobenzylated 4a as starting material afforded
(
3a)
was formed
a
dibenzylated product 3a smoothly (Figure 3). These results
indicated that N-benzylation of 1a with 2a occurred quickly to
Figure 3. Conversion of N-benzyl-2-morpholinoaniline (4a, 0.5 mmol) with benzyl
alcohol (2a, 5 equiv) into desired 3a at different time intervals in the “on water”
reaction.
form mono-N-benzylated product 4a, which then slowly
converted to desired 3a through benzylic C-H benzylation.
4. Control experiments. We conducted competition
experiments to investigate the role of the 2-morpholino group
on the palladium-catalyzed N-benzylation and benzylic C-H
benzylation steps. The N-benzylation of 2-morpholinoaniline
3. Kinetic isotope effect. KIE studies were performed to gain
further mechanistic details of the benzylic C-H activation. The
intermolecular competition between mono-N-benzylated 4a
and its deuterium-labeled substrate 4a-d gave KIE = 2.7 on the
(
(
1a) proceeded smoothly to give 4a in 45% yield, while aniline
) was produced in only 29% yield (Scheme 5A). This result
1
basis of H NMR analysis, suggesting that C-H bond cleavage
7
was involved in the rate-determining step (Scheme 4A). Next,
the rates for Pd-catalyzed benzylic C-H benzylation “on H2O”
and “on D2O” were compared. The reaction rates were faster
“on H2O” than “on D2O” with a primary H/D effect of 1.6
(Scheme 4B). In general, the KIE for protonation shows values
suggested that this process was favored by the electron-
donating 2-morpholino group on aniline. In contrast, the C-H
benzylation of electron-sufficient 4a is slower than that of 8,
suggesting that N-benzylated 4a would act as an electrophile
(Scheme 5B). Next, the reaction of 1a with an electron-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 10
View Article Online
DOI: 10.1039/C7GC03780E
ARTICLE
deficient benzylic alcohol, 4-fluorobenzyl alcohol (2b), did not scope of benzyl alcohols
Journal Name
2
was examined next with 2-
afford the dibenzylated product but gave N-monobenzylated morpholinoaniline (1a) as the coupling partner. The use of
4b in 78% yield (Scheme 5C). No reaction occurred when using benzyl alcohols with electron-donating alkoxy and alkyl groups
4b as a starting material in the palladium-catalyzed reaction, resulted in moderate to good yields
(3f-j). A sterically
indicating the electron-deficient benzyl moiety generated from demanding methoxy group at the ortho position was tolerated
the 4-fluorobenzyl alcohol (2b) could not act as a nucleophile in the benzylic C-H benzylation (3k, 61%). In contrast, the
in the C-H benzylation step.
benzyl alcohol with an electron-withdrawing trifluoromethyl
group resulted in no reaction. Furthermore, replacement of
the morpholino group with a piperazino group on the benzene
ring was tolerated in our catalytic system (3l, 61%).23 In
contrast, 2-dimethylaminoaniline did not react due to the
poisoning of the Pd(II) cation species (morpholine: pKa value of
8.5 vs dimethylamine: pKa value of 10.6).24
Scheme 4. Kinetic isotope effects.
A. N-Benzylation of anilines 1a and 7.
O
O
N
Ph
OH
2a (1 mmol)
N
Pd(OAc)2 (5 mol%)
TPPMS (10 mol%)
NH2
1a (0.25 mmol)
Ph
N
H
Ph
N
Ph
H
100 oC, 2 h, air
4a: 45%
Ph NH2
8: 29%
7 (0.25 mmol)
Dibenzylated products were not obtained.
B. Benzylic C-H benzylation of N-monobenzylated 4a and x.
O
N
O
Ph
OH
N
2a (0.5 mmol)
Pd(OAc)2 (5 mol%)
TPPMS (10 mol%)
N
H
Ph
Ph
Ph
NH
NH
4a (0.25 mmol)
100 oC, 16 h, air
Ph
Ph
Ph
N
Ph
Ph
H
3a: 12%
: 21%
9
8 (0.25 mmol)
C. Reaction of 4-fluorobenzyl alcohol (2b).
OH
O
O
2b (5 equiv)
F
N
N
Pd(OAc)2 (5 mol%)
TPPMS (10 mol%)
N
H
120 oC, 20 h, air
sealed tube
NH2
4b: 78%
1a
F
Dibenzylated product was not obtained.
Scheme 5. Control experiments.
5. Reaction scope. Results for the reactions of several 2-
morpholinoanilines with benzyl alcohols using Pd(OAc)2
Scheme 6. Scope of anilines
anilines (1 mmol), Pd(OAc)2 (5 mol%), TPPMS (10 mol%), benzyl alcohols
equiv), H2O (4 mL), 120 oC, 20 h in a sealed tube. Yield of isolated products.
1
and benzyl alcohols
2
.
Reaction conditions:
1
2
1
2
(5
and TPPMS are summarized in Scheme 6. Both electron-
donating methyl and electron-withdrawing chloro and
trifluoromethyl groups on the benzene ring of substituted 2-
6. Hammett study. To demonstrate the electronic effect of the
tandem benzylation, the relative rates of coupling of 3- and 5-
morpholinoanilines
1 were tolerated well to produce the
substituted 2-morpholinoanilines
1 (X = Me, Cl and CF3 groups)
corresponding products 3b-e in moderate to good yields. The
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 5 of 10
View Article Online
DOI: 10.1039/C7GC03780E
Journal Name
ARTICLE
with benzyl alcohol (2a) were examined. Figure 4 shows good palladium(II)/sulfoxide catalyst to afford
correlation between the log(kX/kH) and the -benzyl palladium(II) intermediate is
values of the intermediates.25 The bis-
respective substituents. The resulting negative -benzyl palladium complex
value of 2.2 converted to the η3 -benzyl/η1
suggests that there is a build-up of positive charge in the by coordination of a ligand such as TPPMS, which would
π-allylpalladium(II)
σ
π
ρ
-π
-σ
I
transition state.
involve the nucleophilic η1
η3 -benzyl ligand. Therefore, the η1
the η3
-benzyl ligand of intermediate
-σ-benzyl ligand and electrophilic
-π
-
σ
I
-benzyl ligand attacks
to form a new C(sp3)-
-π
C(sp3) bond at the benzylic position in the reductive
elimination step (step 4). The reaction of 4-fluorobenzyl
alcohol did not afford the desired product 3, since the
electron-deficient η1
nucleophilic benzylation (see Scheme 5C). Additionally, the
-σ
-benzyl ligand is disadvantageous for
electron-donating groups on the benzene ring of intermediate
stabilize the δ+ charge in the
makes it the more electrophilic position for direct
I
π
-benzyl Pd(II) species, which
intramolecular nucleophilic attack from the
ligand. This δ+ charge is also stabilized by the nitrogen lone
pair.
σ-benzyl anion
Figure 4. Hammett plot for the rate constants of benzylation by various
substituted 2-morpholinoanilines 1.
7. Mechanistic considerations. On the basis of these results
and our previous report,16,17 we propose a catalytic system for
the benzylation of 2-morpholinoaniline
(1a) with benzyl
alcohol (2a) on water as illustrated in Scheme 7. First, oxidative
addition of benzyl alcohol 2a to the water-soluble
Pd(0)/TPPMS species affords the cationic mono-π-
benzylpalladium(II) complex A (step 1). The dangling OH
groups on the water surface activate the sp3 C-O bond of the
alcohol 2a by forming hydrogen bonds, and the resulting
cationic charge of complex
Table 1). This process should be favored by electron-donating
groups on intermediate , since these will stabilize the positive
A is also stabilized by water (see
A
charge on Pd(II). Therefore, the benzylation using 4-
trifluoromethylbenzyl alcohol did not proceed since the
Scheme 7. Proposed mechanism.
alcohol could not form cationic intermediate
In contrast, the N-benzylation of 4-fluorobenzyl alcohol (2b
proceeded due to the weaker electron-withdrawing ability of a
fluoro group than a CF3 group (fluoro group: Hammett p value
of 0.06 vs CF3: Hammett σp value of 0.54). Next, the
nucleophilic substrate 1a attacks intermediate smoothly to
A (see Scheme 6).
)
σ
A
afford the N-monobenzylated product 4a and regenerate Pd(0)
(the dehydrative Tsuji-Trost type benzylation). Indeed, the
reaction rate of electron-sufficient substrate 1a is faster than
that of aniline
(
7
)
(see Scheme 5A). Next, the N-
-benzylpalladium(II)
monobenzylated 4a coordinates with
π
A
to form a cationic N-palladated intermediate, with its positive
charge stabilized by the electron-donating 2-morpholino
group. Hammett studies show that there is a build-up of
positive charge in the transition state. The dehydrative C-H
cleavage at the benzylic position proceeds since the positive
charge of N-palladated complex TS increases the acidity of the
benzylic proton. This is followed by formation of the bis-π-
benzyl palladium(II) intermediate (step 3). The KIE of 2.7
suggests that the C-H cleavage process is involved in the
turnover-limiting step. White and co-workers reported the
electrophilic allylic C-H cleavage of
α-olefins using a
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 6 of 10
View Article Online
DOI: 10.1039/C7GC03780E
ARTICLE
Journal Name
Scheme 8. Possible reaction pathways from the imine and the hydride palladium
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 washed with hexanes, then purified by flash
column chromatography (silica gel, hexanes/EtOAc) to give desired
product 3.
species.
To exclude the possibility of the reaction pathway from
imine
catalyzed reaction of 2-morpholinoaniline (1a),18 benzaldehyde
10), and benzyl alcohol (2a) was investigated (Scheme 8A).
After 1 h, the imine
was detected by 1H NMR analysis of
5 and the hydride palladium species, the palladium-
(
N-(1,2-Diphenylethyl)-2-morpholinoaniline 3a
6
Following the scale-up experiment (see SI), 3a was obtained as a
pale yellow solid. 1.63 g (76%); mp 95-97 °C; IR (KBr) (cm-1) 3320,
2961, 2844, 1601, 1508; 1H-NMR (400 MHz, CDCl3) δ 2.64 (brs, 2H),
2.89 (brs, 2H), 2.96 (dd, J=14.0, 9.6 Hz, 1H), 3.24 (dd, J=14.0, 4.8 Hz,
1H), 3.77 (brs, 4H), 4.55 (brs, 1H), 5.30 (brs, 1H), 6.27 (dd, J=7.6, 1.2
Hz, 1H), 6.60 (td, J=7.2, 1.2 Hz, 1H), 6.81 (td, J=7.6, 1.2 Hz, 1H), 6.94
(dd, J=7.6, 1.2 Hz, 1H), 7.18-7.40 (m, 10H); 13C-NMR (100 MHz,
CDCl3) δ 45.7, 51.7, 59.2, 67.8, 111.6, 116.8, 119.6, 126.2, 126.8,
128.5, 128.6, 129.3, 137.9, 138.5, 142.4, 143.9; MS (FAB): m/z 359
[M+H]+; Anal. Calcd for C24H26N2O: C, 80.41; H, 7.31; N, 7.81. Found:
C, 80.37; H, 7.17; N, 7.78.
reaction mixture. After 7 h, desired product 3a and N-
monobenzylated 4a were formed in 24% and 57% yields,
respectively (Scheme 8B). In contrast, the desired 3a was
obtained in 55% yield when using 4a as the starting material
(see Figure 2). These results suggested that N-
monobenzylated 4a not imine
6 would be the intermediate in
the benzylic C-H benzylation process. Furthermore, the
reaction of 4a was not inhibited by the addition of a radical
scavenger (BHA: 3-tert-butyl-4-hydroxyanisole,
1
equiv)
(Scheme 8C). Therefore, the possibility of a reaction pathway
through the carbon radical addition to the imine via a single
electron transfer process was also excluded.
N-(1,2-Diphenylethyl)-5-methyl-2-morpholinoaniline 3b
Following the general procedure, 3b was obtained as a white solid.
302 mg (81%); mp 135-137 °C; IR (KBr) (cm-1) 3400, 3332, 3060,
3030, 2961, 2856, 2813, 1607, 1582, 1521; 1H-NMR (400 MHz,
CDCl3) δ 2.08 (s, 3H), 2.85 (brs, 4H), 2.96 (dd, J=14.4, 9.2 Hz, 1H),
3.22 (dd, J=14.4, 4.8 Hz, 1H), 3.76 (brs, 4H), 4.55 (ddd, J=9.2, 4.4, 4.4
Hz, 1H), 5.31 (d, J=4.0 Hz, 1H), 6.10 (d, J=1.6 Hz, 1H), 6.40 (dd, J=7.6,
1.2 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.15-7.39 (m, 10H); 13C-NMR (100
MHz, CDCl3) δ 21.4, 45.6, 52.0, 59.1, 67.8, 112.3, 117.2, 119.6,
126.2, 126.7, 126.9, 128.5, 128.6, 129.3, 134.8, 136.2, 138.0, 142.3,
144.0; MS (FAB): m/z 373 [M+H]+; Anal. Calcd for C25H28N2O・
0.1H2O: C, 80.22; H, 7.59; N, 7.48. Found: C, 79.81; H, 7.58; N, 7.41.
8. Scale-up experiment. Finally, we examined the scalability of
our catalytic system (Scheme 9). To demonstrate the utility of
our environmentally benign, efficient and simple protocol, a
gram scale reaction of 1a with 2a in the presence of Pd(OAc)2
(5 mol%) and TPPMS (10 mol%) on water was carried out. The
gram-scale synthesis of desired 3a was achieved successfully in
76% isolated yield.
3-Chloro-N-(1,2-diphenylethyl)-2-morpholinoaniline 3c
Following the general procedure, 3c was obtained as a white solid.
279 mg (71%); mp 120-122 °C; IR (KBr) (cm-1) 3376, 3054, 3023,
2850, 1595, 1584, 1569; 1H-NMR (400 MHz, CDCl3) δ 2.25 (d, J=11.2
Hz 1H), 2.57 (d, J=11.2 Hz 1H), 3.00 (dd, J=14.0, 9.2 Hz 1H), 3.26 (dd,
J=14.0, 4.4 Hz 1H), 3.32 (dd, J=11.2, 2.8 Hz 1H), 3.57 (dd, J=10.8, 2.0
Hz 1H), 3.63-3.79 (m, 3H), 3.90 (d, J=9.2 Hz 1H), 4.61 (dt, J=9.6, 5.2
Hz 1H), 6.00 (d, J=4.4 Hz 1H), 6.16 (d, J=8.0 Hz 1H), 6.49 (dd, J=8.4,
1.6 Hz 1H), 6.76 (t, J=8.4 Hz 1H), 7.17 (d, J=7.2 Hz 2H), 7.19-7.35 (m,
8H); 13C-NMR (100 MHz, CDCl3) δ 45.2, 48.7, 58.5, 68.1, 68.4, 109.7,
118.0, 126.2, 126.9, 127.1, 127.6, 128.6, 128.7, 129.2, 132.2, 133.5,
137.6, 143.4, 146.8; MS (FAB): m/z 393 [M+H]+, 395 [M+H+2]+; Anal.
Calcd for C24H25ClN2O: C, 73.36; H, 6.41; N, 7.13. Found: C, 73.64; H,
6.43; N, 7.14.
Scheme 9. Scale-up experiment.
Conclusions
In summary, we have demonstrated a straightforward and
efficient synthetic route to N-(1,2-diphenylethyl)-2-
morpholinoanilines using the
π-benzylpalladium system on
water. This simple protocol, which affords the corresponding
desired products with water as the sole co-product, can be
achieved under mild conditions without the need for bases or
other additives on the atom-economic process. The
dehydrative C-H benzylation on the benzylic position of N-
benzyl-2-morpholinoanilines is involved in the new C-C bond
formation. Notably, the “on water” protocol is essential for the
success of our catalytic system.
5-Chloro-N-(1,2-diphenylethyl)-2-morpholinoaniline 3d
Following the general procedure, 3d was obtained as a white solid.
196 mg (50%); mp 128-130 °C; IR (KBr) (cm-1) 3326, 2844, 1588,
1501; 1H-NMR (400 MHz, CDCl3) δ 2.59 (brs, 2H), 2.82 (brs, 2H), 2.95
(dd, J=14.4, 9.2 Hz, 1H), 3.24 (dd, J=14.4, 5.2 Hz, 1H), 3.75 (brs, 4H),
4.53 (dt, J=9.2, 4.8 Hz, 1H), 5.35 (d, J=4.4 Hz, 1H), 6.23 (d, J=2.4 Hz,
1H), 6.54 (dd, J=8.4, 2.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 7.17 (dd,
J=6.4, 2.0 Hz, 2H), 7.19-7.38 (m, 8H); 13C-NMR (100 MHz, CDCl3) δ
45.4, 51.8, 58.9, 67.7, 111.3, 116.3, 120.7, 126.1, 126.9, 127.3,
128.6, 128.8, 129.3, 130.7, 137.1, 137.6, 143.1, 143.5; MS (FAB):
m/z 393 [M+H]+, 395 [M+H+2]+; Anal. Calcd for C24H25ClN2O: C,
73.36; H, 6.41; N, 7.13. Found: C, 73.50; H, 6.41; N, 7.13.
Experimental
General procedure:
palladium(II) acetate
A
mixture of anilines
1
(1 mmol),
sodium
(12 mg,
0.05 mmol),
diphenylphosphinobenzene-3-sulfonate (TPPMS, 36 mg, 0.1 mmol)
and benzyl alcohol 2 (5-10 mmol) in H2O (4 mL) was heated for 20 h
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 7 of 10
View Article Online
DOI: 10.1039/C7GC03780E
Journal Name
ARTICLE
N-(1,2-Diphenylethyl)-2-morpholino-5-(trifluoromethyl)aniline 3e
Following the general procedure, 3e was obtained as a white solid.
320 mg (75%); mp 120-122 °C; IR (KBr) (cm-1) 3330, 2845, 1604,
Following the general procedure, 3i was obtained as a white solid.
269 mg (70%); mp 118-120 °C; IR (KBr) (cm-1) 3400, 3326, 2818,
1597, 1510; 1H-NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.27 (s,
1587, 1517; 1H-NMR (400 MHz, CDCl3) δ 2.66 (brs, 2H), 2.90 (brs, 3H), 2.54 (brs, 2H), 2.73 (brs, 2H), 2.90 (dd, J=13.2, 9.2 Hz, 1H), 3.07
2H), 2.99 (dd, J=14.4, 9.2 Hz, 1H), 3.27 (d, J=14.4, 5.2 Hz, 1H), 3.77 (dd, J=13.6, 4.4 Hz, 1H), 3.71 (brs, 4H), 4.49 (dt, J=9.6, 4.8 Hz, 1H),
(brs, 4H), 4.58 (dt, J=9.2, 4.4 Hz, 1H), 5.30 (d, J=4.0 Hz, 1H), 6.48 (d, 5.23 (d, J=4.8 Hz, 1H), 6.19 (d, J=8.4 Hz, 1H), 6.47 (td, J=7.2, 1.2 Hz,
J=2.0 Hz, 1H), 6.85 (dd, J=8.0, 1.6 Hz, 1H), 6.95 (dd, J=7.6 Hz, 1H), 1H), 6.70 (dd, J=7.6, 1.2 Hz, 1H), 6.88 (d, J=7.6, 1.2 Hz, 1H), 7.10 (d,
7.18 (d, J=6.8, 1.6 Hz, 2H), 7.21-7.37 (m, 8H); 13C-NMR (100 MHz, J=7.6 Hz, 2H), 7.12 (d, J=7.6 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.28 (dd,
DMSO-d6) δ 44.7, 51.3, 58.8, 67.1, 107.1 (q, JCF=3.8 Hz), 113.6 (q, J=8.4 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ 21.2, 44.7, 51.9, 58.7,
JCF=3.8 Hz), 119.9, 125.0 (q, JCF=270.8 Hz), 125.3 (q, JCF=31.5 Hz), 67.3, 111.4, 116.7, 119.8, 125.1, 126.7, 129.4, 129.5, 129.7, 135.8,
126.8, 127.1, 127.6, 128.9, 129.0, 129.8, 138.8, 142.2, 143.9; MS 136.0, 136.2, 138.8, 141.7, 142.3; MS (FAB): m/z 387 [M+H]+; Anal.
(FAB): m/z 427 [M+H]+; Anal. Calcd for C25H25F3N2O: C, 70.41; H, Calcd for C26H30N2O: C, 80.79; H, 7.82; N, 7.25. Found: C, 80.87; H,
5.91; N, 6.57. Found: C, 70.71; H, 5.84; N, 6.59.
7.90; N, 7.20.
N-(1,2-Bis(4-methoxyphenyl)ethyl)-2-morpholinoaniline 3f
N-(1,2-Bis(4-isopropylphenyl)ethyl)-2-morpholinoaniline 3j
Following the general procedure, 3f was obtained as a white solid.
Following the general procedure, 3j was obtained as a white solid.
255 mg (61%); mp 125-127 °C; IR (KBr) (cm-1) 3394, 2818, 1609, 319 mg (72%); mp 104-106 °C; IR (KBr) (cm-1) 3387, 3326, 2964,
1598, 1585, 1511; 1H-NMR (400 MHz, DMSO-d6) δ 2.55 (brs, 2H), 2850, 1595, 1507; 1H-NMR (400 MHz, CDCl3) δ 1.22 (d, J=6.8 Hz,
2.75 (brs, 2H), 2.87 (dd, J=14.0, 10.0 Hz, 1H), 3.03 (dd, J=14.0, 4.8 6H), 1.22 (dd, J=6.8, 1.2 Hz, 6H), 2.59 (brs, 2H), 2.80-2.95 (m, 5H),
Hz, 1H), 3.69 (s, 3H), 3.71 (s, 3H), 3.71 (brs, 4H), 4.45 (dt, J=9.6, 4.8 3.21 (dd, J=14.4, 4.8 Hz, 1H), 3.75 (brs, 4H), 4.49 (dt, J=10.0, 4.0 Hz,
Hz, 1H), 5.20 (d, J=5.6 Hz, 1H), 6.19 (dd, J=8.4, 1.6 Hz, 1H), 6.47 (td, 1H), 5.25 (d, J=3.6 Hz, 1H), 6.28 (dd, J=7.6, 0.8 Hz, 1H), 6.58 (td,
J=7.6, 1.6 Hz, 1H), 6.70 (d, J=8.0, 1.6 Hz, 1H), 6.81-6.90 (m, 5H), 7.18 J=7.6, 1.2 Hz, 1H), 6.81 (td, J=7.2, 1.6 Hz, 1H), 6.92 (dd, J=8.0, 1.6 Hz,
(d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H); 13C-NMR (100 MHz, DMSO- 1H), 7.15 (s, 4H), 7.19 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H); 13C-
d6) δ 44.3, 51.8, 55.5, 58.4, 67.4, 111.4, 114.2, 116.7, 119.8, 125.1, NMR (100 MHz, CDCl3) δ 24.0, 24.1, 33.7, 45.5, 51.7, 59.0, 67.8,
127.8, 130.8, 136.5, 138.8, 142.3, 158.4, 158.5; MS (FAB): m/z 419 111.5, 116.5, 119.5, 125.1, 126.0, 126.6, 126.7, 129.2, 135.5, 138.5,
[M+H]+; Anal. Calcd for C26H30N2O3: C, 74.61; H, 7.23; N, 6.69. 141.6, 142.7, 147.3, 147.4; MS (FAB): m/z 443 [M+H]+; Anal. Calcd
Found: C, 74.77; H, 7.31; N, 6.65.
for C30H38N2O: C, 81.40; H, 8.65; N, 6.33. Found: C, 81.67; H, 8.77; N,
6.29.
N-(1,2-Bis(4-ethoxyphenyl)ethyl)-2-morpholinoaniline 3g
Following the general procedure, 3g was obtained as a white solid. N-(1,2-Bis(2-methoxyphenyl)ethyl)-2-morpholinoaniline 3k
237 mg (53%); mp 111-113 °C; IR (KBr) (cm-1) 3400, 3326, 2818,
Following the general procedure, 3k was obtained as a white solid.
254 mg (61%); mp 132-134 °C; IR (KBr) (cm-1) 3357, 2964, 2835,
1607, 1598, 1584, 1509; 1H-NMR (400 MHz, CDCl3) δ 1.39 (t, J=7.2
Hz, 3H), 1.41 (t, J=7.2 Hz, 3H), 2.68 (brs, 2H), 2.89 (dd, J=14.4, 8.8 1598, 1511; 1H-NMR (400 MHz, CDCl3) δ 2.73 (brs, 2H), 2.91 (brs,
Hz, 1H), 2.92 (brs, 2H), 3.12 (dd, J=14.4, 5.2 Hz, 1H), 3.99 (q, J=6.8 2H), 3.05 (dd, J=13.6, 8.8 Hz, 1H), 3.18 (dd, J=13.6, 4.8 Hz), 3.81 (s,
Hz, 2H), 4.01 (qd, J=7.2, 1.2 Hz, 2H), 4.44 (dt, J=8.4, 4.0 Hz, 1H), 5.25 3H), 3.82 (brs, 4H), 3.91 (s, 3H), 5.03 (brs, 1H), 5.38 (brs, 1H), 6.32
(d, J=3.6 Hz, 1H), 6.30 (dd, J=8.4, 0.8 Hz, 1H), 6.59 (td, J=7.2, 1.6 Hz, (dd, J=8.4, 1.2 Hz, 1H), 6.40 (td, J=7.6, 1.2 Hz, 1H), 6.79-6.87 (m, 4H),
6.89-6.93 (m, 2H), 7.09-7.26 (m, 4H); 13C-NMR (100 MHz, CDCl3) δ
1H), 6.76-6.88 (m, 5H), 6.93 (dd, J=7.6, 1.2 Hz, 1H), 7.05 (d, J=8.8 Hz,
2H), 7.22 (d, J=8.8 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ 14.8, 14.9, 36.7, 51.7, 52.6, 55.4, 55.6, 67.8, 110.4, 110.6, 111.2, 116.0, 119.2,
44.9, 51.7, 58.7, 63.4, 67.8, 111.6, 114.4, 114.5, 116.6, 119.5, 125.1, 120.3, 120.7, 125.1, 126.9, 127.5, 127.6, 130.8, 132.0, 138.3, 142.4,
127.3, 129.8, 130.3, 135.8, 138.5, 142.5, 157.8, 157.9; MS (FAB): 156.9, 157.9; MS (EI): m/z (%) 418 (M+, 8.9), 297 (100); HRMS-EI:
m/z 447 [M+H]+; Anal. Calcd for C28H34N2O3: C, 75.31; H, 7.67; N, m/z (M+) calcd for C26H30N2O3418.2256, found 418.2253.
6.27. Found: C, 75.48; H, 7.58; N, 6.25.
N-(1,2-Diphenylethyl)-2-(piperidin-1-yl)-5-(trifluoromethyl)aniline 3l
N-(1,2-Bis(4-butoxyphenyl)ethyl)-2-morpholinoaniline 3h
Following the general procedure, 3l was obtained as a white solid.
260 mg (61%); mp 139-141 °C; IR (KBr) (cm-1) 3350, 3326, 2936,
1602, 1584; 1H-NMR (400 MHz, CDCl3) δ 1.67 (brs, 4H), 2.64 (brs,
Following the general procedure, 3h was obtained as a white solid.
252 mg (50%); mp 86-88 °C; IR (KBr) (cm-1) 3407, 3320, 2949, 2869,
1597, 1585, 1509; 1H-NMR (400 MHz, CDCl3): δ 0.96 (t, J=7.6 Hz, 2H), 2.86 (brs, 2H), 3.01 (dd, J=13.6, 8.8 Hz 1H), 3.22 (dd, J=14.0, 5.2
3H), 0.97 (t, J=7.6 Hz, 3H), 1.48 (sext, J=7.2 Hz, 2H), 1.49 (sext, J=7.2 Hz 1H), 4.54 (dt, J=9.2, 5.2 Hz 1H), 5.38 (d, J=4.4 Hz 1H), 6.47 (s, 2H),
Hz, 2H), 1.75 (sext, J=7.2 Hz, 4H), 2.66 (brs, 2H), 2.88 (dd, J=14.0, 6.82 (d, J=8.0 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.17 (d, J=6.8 Hz, 2H),
7.20-7.35 (m, 8H); 13C-NMR (100 MHz, CDCl3) δ 24.3, 26.8, 45.4,
9.2 Hz, 1H), 2.90 (brs, 2H), 3.12 (dd, J=13.6, 4.4 Hz, 1H), 3.78 (brs,
2H), 3.92 (t, J=7.2 Hz, 2H), 3.94 (t, J=7.2 Hz, 2H), 4.44 (dt, J=8.8, 4.0
Hz, 1H), 5.24 (d, J=3.6 Hz, 1H), 6.29 (dd, J=8.4, 1.6 Hz, 1H), 6.59 (td,
J=8.0, 1.6 Hz, 1H), 6.77-6.88 (m, 5H), 6.93 (dd, J=8.0, 1.6 Hz, 1H),
7.06 (d, J=8.8 Hz 2H), 7.21 (d, J=8.8 Hz 2H); 13C-NMR (100 MHz,
52.6, 59.4, 107.3 (q, JCF=3.8 Hz), 113.5 (q, JCF=3.8 Hz), 119.1, 124.4
(q, JCF=269.9 Hz), 126.1 (q, JCF=31.5 Hz), 126.2, 126.7, 127.2, 128.5,
128.7, 129.3, 137.7, 142.3, 143.2; MS (FAB): m/z 425 [M+H]+; Anal.
Calcd for C26H27F3N2: C, 73.56; H, 6.41; N, 6.60. Found: C, 73.31; H,
CDCl3) δ 13.9, 19.2, 19.3, 31.3, 31.4, 44.9, 51.7, 58.8, 67.7, 67.8, 6.13; N, 6.58.
111.6, 114.5, 116.6, 119.5, 127.2, 129.8, 130.3, 135.8, 138.5, 142.5,
158.0, 158.1; MS (FAB): m/z 503 [M+H]+; Anal. Calcd for C32H42N2O3: N-(4-Fluorobenzyl)-2-morpholinoaniline 4b
C, 76.46; H, 8.42; N, 5.57. Found: C, 76.49; H, 8.43; N, 5.62.
Following the general procedure, 4b was obtained as a white solid.
223 mg (78%); mp 94-96 °C; IR (KBr) (cm-1) 3345, 2967, 1595, 1508;
1H-NMR (400 MHz, CDCl3) δ 2.92 (t, J=4.6 Hz, 4H), 3.83 (brs, 4H),
4.33 (brs, 2H), 5.14 (brs, 1H), 6.56 (dd, J=9.2, 1.4 Hz, 1H), 6.72 (td,
N-(1,2-Di-p-tolylethyl)-2-morpholinoaniline 3i
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 8 of 10
View Article Online
DOI: 10.1039/C7GC03780E
ARTICLE
Journal Name
Nagaraj, G. Ravi, S. S. Kumar, S. Raghaveer, N. Rana,
Research & Reviews: Journal of Chemistry, 2014, , 17-21.
(a) M. Su, N. Hoshiya, S. L. Buchwald, Org. Lett. 2014, 16
J=7.8, 1.4 Hz, 1H), 6.96-7.02 (m, 2H), 7.04 (dd, J=8.7, 2.8 Hz, 2H),
7.31 (dd, J=8.7, 5.5 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ 47.4, 51.8,
67.7, 110.5, 115.4 (d, JCF=21.1 Hz), 117.2, 119.6, 125.3, 128.5 (d,
JCF=7.7 Hz), 135.5 (d, JCF=3.8 Hz), 138.5, 142.9, 161.9 (d, JCF=244.4
Hz); MS (FAB): m/z 287 [M+H]+; Anal. Calcd for C17H19FN2O: C,
71.31; H, 6.69; N, 9.78. Found: C, 71.41; H, 6.73; N, 9.70.
3
5
6
7
,
,
832-835; (b) Y. Hirai, Y. Uozumi, Chem. Asian J. 2010,
1788-1795.
5
Reviews see: (a) B. M. Trost, L. C. Czabaniuk, Angew. Chem.,
Int. Ed. 2014, 53, 2826–2851; (b) R. Kuwano, Synthesis 2009,
1049- 1061.
(a) S. Sahnoun, S. Messaoudi, J.-D. Brion, M. Alami,
ChemCatChem 2011, 3, 893–897; (b) L. Ackermann, S.
Barfsser, C. Kornhaass, A. R. Kapdi, Org. Lett. 2011, 13, 3082–
3085; (c) S. L. Marquard, D. C. Rosenfeld, J. F. Hartwig,
Angew. Chem., Int. Ed. 2010, 49, 793 –796; (d) S. Fan, C.-Y.
He, X. Zhang, Chem. Commun. 2010, 4926–4928; (e) A. M.
Kearney, A. Landry-Bayle, L. Gomez, Tetrahedron Lett. 2010,
51, 2281–2283; (f) T. Mukai, K. Hirano, T. Satoh, M. Miura,
Org. Lett. 2010, 12, 1360–1363.
A mixture of 2-morpholinoailine (1a) (1.78 g, 10 mmol), K2CO3
(2.76 g, 20 mmol), and benzylchloride (1.15 mL, 10 mmol) in DMF
(20 mL) was stirred at 80 oC for 20 h under Ar. 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 the N-
monobenzylated product 4a (385 mg, 1.43 mmol, 14%) and N,N-
dibenzylated product 5 (412 mg, 1.15 mmol, 12%).
8
9
M. Yokogi, R. Kuwano, Tetrahedron Lett. 2007, 48, 6109–
6112.
N-Benzyl-2-morpholinoaniline 4a 26
(a) H. Narahashi, I. Shimizu, A. Yamamoto, J. Organometallic
Chem. 2008, 693, 283–296; (b) H. Narahashi, A. Yamamoto, I.
Shimizu, Chem. Lett. 2004, 33, 348–349; (c) G. Verspui, G.
Papadogianakis, R. A. Sheldon, Catal. Today, 1998, 42, 449–
458; (d) G. Papadogianakis, L. Maat, R. A. Sheldon, J. Chem.
Tech. Biotechnol. 1997, 70, 83–91.
Amorphous; IR (KBr) (cm-1) 3338, 2852, 1601, 1508; 1H-NMR (400
MHz, CDCl3) δ 2.93 (d, J=4.8 Hz, 4H), 2.83 (brs, 4H), 4.37 (d, J=5.6 Hz,
2H), 5.16 (brs, 1H), 6.60 (dd, J=7.6, 1.2 Hz, 1H), 6.71 (td, J=7.6, 1.2
Hz, 1H), 7.00 (td, J=8.0, 1.6 Hz, 1H), 7.04 (dd, J=7.6, 1.2 Hz, 1H),
7.26-7.30 (m, 1H), 7.34 (d, J=1.6 Hz, 2H), 7.36 (s, 2H); 13C-NMR (100
MHz, CDCl3) δ 48.2, 51.9, 67.8, 110.6, 117.1, 119.6, 125.4, 127.1,
128.7, 138.6, 139.9, 143.2; MS (EI): m/z (%) 268 (M+, 65.5), 72 (100).
10 (a) G. Verspui, G. Papadogianakis, R. A. Sheldon, Catal.
Today, 1998, 42, 449 458; (b) G. Papadogianakis, L. Maat, R.
–
A. Sheldon, J. Chem. Tech. Biotechnol. 1997, 70, 83-91.
11 T. Maji, K. Ramakumar, J. A. Tunge, Chem. Commun. 2014,
14045-14048.
12 X. Cao, Y. Zhang, Green. Chem. 2016, 18, 2638-2641.
13 (a) H. Nakamura, H. Iwama, Y. Yamamoto, J. Chem. Soc.,
Chem. Commun. 1996, 1459–1460; (b) H. Nakamura, Y.
Yamamoto, J. Am. Chem. Soc. 1996, 118, 6641–6647.
14 S. Zhang, A. Ullah, Y. Yamamoto, M. Bao, Adv. Synth. Catal.
2017, 359, 2723-2728.
N,N-Dibenzyl-2-morpholinoaniline 5
White solid; mp 149-151
1588; 1H-NMR (400 MHz, CDCl3)
°
C; IR (KBr) (cm-1) 3066, 3030, 2955,
3.27 (brt, J=4.4 Hz, 4H), 3.86
δ
(t, J=4.4 Hz, 4H), 4.35 (s, 4H), 6.76 (d, J=8.0 Hz, 1H), 6.87-6.94
(m, 1H), 6.99 (d, J=5.2, 0.8 Hz, 2H), 7.08 (dd, J=8.0, 1.6 Hz, 4H),
7.20-7.30 (m, 6H); 13C-NMR (100 MHz, CDCl3)
δ 50.6, 53.6,
67.7, 118.8, 121.9, 122.7, 123.1, 127.0, 128.3, 129.0, 138.4,
143.7, 144.4; MS (EI): m/z (%) 358 (M+, 3.4), 267 (100); Anal.
Calcd for C24H26N2O: C, 80.41; H, 7.31; N, 7.81. Found: C, 80.17; H,
15 N. Solin, J. Kjellgren, K. J. Szabó, J. Am. Chem. Soc. 2004, 126
7026-7033.
,
16 (a) H. Hikawa, T. Koike, K. Izumi, S. Kikkawa, I. Azumaya, Adv.
Synth. Catal. 2016, 358 784–791; (b) H. Hikawa, M.
,
7.42; N, 7.96
.
Toyomoto, S. Kikkawa, I. Azumaya, Org. Biomol. Chem. 2015,
13, 11459-11465; (c) H. Hikawa, I. Azumaya, Org. Biomol.
Chem. 2014, 12, 5964–5972; (d) H. Hikawa, N. Matsuda, H.
Suzuki, Y. Yokoyama, I. Azumaya, Adv. Synth. Catal. 2013,
355, 2308.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number
16K08179.
17 (a) H. Hikawa, K. Izumi, Y. Ino, S. Kikkawa, Y. Yokoyama, I.
Azumaya, Adv. Synth. Catal. 2015, 357, 1037–1048; (b) H.
Hikawa, Y. Yokoyama, Org. Lett. 2011, 13, 6512–6515.
18 (a) H.-H. Zhang, S. Yu, J. Org. Chem. 2017, 82, 9995-10006;
(b) N. Chen, X.-J. Dai, H. Wang, C.-J. Li, Angew. Chemie, Int.
Ed. 2017, 56, 6260-6263; (c) H. Mei, X. Ji, J. Han, Y. Pan, Eur.
J. Org. Chem. 2011, 5783-5786; (d) Y. Zhang, T. Yan, W.
Cheng, J. Zuo, W. Zhao, Tetrahedron Lett. 2009, 50, 2925–
2928; (e) E. L. Gall, C. Haurena, S. Sengmany, T. Martens, M.
Troupel, J. Org. Chem. 2009, 74, 7970–7973.
Notes and references
1
Z, Leilei, Y. Tianming, X. Xilei, L. Gang, Bioorg. Med. Chem.
Lett. 2015, 25, 2937-2942.
2
(a) S. O. Abdul-Hay, T. D. Bannister, H. Wang, M. D. Cameron,
T. R. Caulfield, A. Masson, J. Bertrand, E. A. Howard, M. P.
McGuire, U. Crisafulli, T. R. Rosenberry, C. L. Topper, C. R.
Thompson, S. C. Schurer, F. Madoux, P. Hodder, M. A.
Leissring, ACS Chem. Biol. 2015, 10, 2716-2724; (b) Y.-Y.
Cheung, H. Yu, K. Xu, B. Zou, M. Wu, O. B. McManus, M. Li, C.
W. Lindsley, C. R. Hopkins, J. Med. Chem. 2012, 55, 6975-
6979.
19 (a) Q. Sun, Y. Wang, D. Yuan, Y. Yao, Q. Shen, Dalton Trans.,
2015, 44, 20352-20360; (b) J. C.-H. Yim, J. A. Bexrud, R. O.
Ayinla, D. C. Leitch, L. L. Schafer, J. Org. Chem. 2014, 79
,
2015−2028; (c) C. Brahms, P. Tholen, W. Saak, S. Doye, Eur. J.
Org. Chem. 2013, 7583–7592; (d) K. Born, S. Doye, Eur. J.
Org. Chem. 2012, 764-771; (e) H. Duan, S. Sengupta, J. L.
Petersen, N. G. Akhmedov, X. Shi, J. Am. Chem. Soc. 2009,
131, 12100–12102.
3
4
V. G. Melissa, F. Oleg, I. David, D. Chunyun, C. Tamsyn, H.
Claire, H. Masatoshi, D. D. Andrew, C. Russell, J. H. Steven, C.
H. Jules, K. Stefan, O. B. David, Invest. Ophthalmol. Vis. Sci.
2013, 54, 6052-6062.
(a) Y. Gong, K. S. Somersan X. Guo, P. Zheng, B. Gold, Y. Ma,
D. Little, J. Roberts, T. Warrier, X. Jiang, M. Pingle, C. F.
Nathan, G. Liu, Eur. J. Med. Chem. 2014, 75, 336-353; (b) A.
20 B. M. Trost, B. M. O'Boyle, D. Hund, Chem. Eur. J. 2010, 16
9772–9776.
21 (a) S. Hajra, S. Singha Roy, S. M. Aziz, D. Das, Org. Lett. 2017,
19, 4082-4085; (b) R. S. Tukhvatshin, A. S. Kucherenko, Y. V.
Nelyubina, S. G. Zlotin, ACS Catal. 2017, 7, 2981–2989; (c) M.
,
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 9 of 10
View Article Online
DOI: 10.1039/C7GC03780E
Journal Name
ARTICLE
A. Ali, X. Yao, G. Li, H. Lu, Org. Lett. 2016, 18, 1386–1389; (d)
V. Satheesh, M. Sengoden, T. Punniyamurthy, J. Org. Chem.
2016, 81, 9792–9801; (e) G. B. Vamisetti, R. Chowdhury, M.
Kumar, S. K. Ghosh, Org. Lett. 2016, 18, 1964–1967; (f) M. A.
Ali, X. Yao, H. Sun, H. Lu, Org. Lett. 2015, 17, 1513-1516; (g)
Y. Zhang, B.-W. Wei, H. Lin, L. Zhang, J.-X. Liu, H.-Q. Luo, X.-L.
Fan, Green Chem. 2015, 17, 3266-3270; (h) S. Narayan, J.
Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharpless,
Angew. Chem., Int. Ed. 2005, 44, 3275-3279.
22 (a) R. N. Butler, A. G. Coyne, Org. Biomol. Chem. 2016, 14
,
9945-9960; (b) Y. Jung, R. A. Marcus, J. Am. Chem. Soc. 2007,
129, 5492-5502.
23 SRPIN340,
N-[2-(1-piperidinyl)-5-
(trifluoromethyl)phenyl]isonicotinamide, inhibits SRPK1 and
SRPK2 kinase activities potently. see) Y. Karakama, N.
Sakamoto, Y. Itsui, M. Nakagawa, M. Tasaka-Fujita, Y.
Nishimura-Sakurai, S. Kakinuma, M. Oooka, S. Azuma, K.
Tsuchiya, H. Onogi, M. Hagiwara, M. Watanabe, Antimicrob.
Agents Chemother. 2010, 54, 3179-3186.
24 A. Galano, A. Perez-Gonzalez, R. Castaneda-Arriaga, L.
Munoz-Rugeles, G. Mendoza-Sarmiento, A. Romero-Silva, A.
Ibarra-Escutia, A. M. Rebollar-Zepeda, J. R. Leon-Carmona,
M. A. Hernández-Olivares, J. R. Alvarez-Idaboy, J. Chem. Inf.
Model. 2016, 56, 1714−1724.
25 (a) I. I. Strambeanu, M. C. White, J. Am. Chem. Soc. 2013,
135, 12032–12037; (b) A. J. Young, M. C. White, Angew.
Chem. Int. Ed. 2011, 50, 6824- 6827; (c) E. M. Stang, M. C.
White, Nature Chemistry 2009,
R. Mazzotti, M. C. White, J. Am. Chem. Soc. 2009, 131
1, 547-551; (d) S. A. Reed, A.
,
11701−11706; (e) M. S. Chen, N. Prabagaran, N. A. Labenz,
M. C. White, J. Am. Chem. Soc. 2005, 127, 6970-6971.
26 C. E. Hendrick, S. L. McDonald, Q. Wang, Org. Lett. 2013, 15
3444-3447.
,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Green Chemistry
Page 10 of 10
View Article Online
DOI: 10.1039/C7GC03780E
A strategy for the palladium-catalyzed dehydrative tandem benzylation of 2-morpholinoanilines with
benzyl alcohols has been developed. This cascade reaction is devised as a straightforward and efficient
synthetic route for
N-(1,2-diphenylethyl)-2-morpholinoanilines in moderate to good yields. The “on
water” protocol, which affords the corresponding desired products with water as the sole co-product,
can be achieved under mild reaction conditions without the need for base or other additives on the
atom-economic process.