Buchwald-Hartwig Amination of (Hetero)Aryl Tosylates Using a Well-Defined N-Heterocyclic Carbene/Palladium(II) Precatalyst

Article abstract of DOI:10.1021/acs.joc.5b01272

The cross-coupling of aryl tosylates with amines and anilines was achieved by using for the first time a Pd-NHC system based on the popular Pd-PEPPSI precatalyst platform in which the anchoring imidazol-2-ylidene ligand IPr (NMe₂)₂ incorporates two dimethylamino groups as backbone substituents enhancing both the electronic and steric properties of the carbene. The system optimization and its application scope are disclosed.

Full text of DOI:10.1021/acs.joc.5b01272

Page 1 of 23
The Journal of Organic Chemistry
1
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BuchwaldꢀHartwig Amination of (Hetero)Aryl Tosylates
Using a WellꢀDefined NꢀHeterocyclic Carbene /
Palladium(II) PreꢀCatalyst
5
6
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,‡,§
, §,‡,†
,‡,§
Yin Zhang Guy Lavigne
and Vincent César*
‡
CNRS, LCC (laboratoire de Chimie de Coordination), 205 route de Narbonne, Fꢀ31077 Toulouse
Cedex 4, France
§
Université de Toulouse, UPS, INPT, 31077 Toulouse, France
†
Deceased on 04/23/2015
Eꢀmail: vincent.cesar@lccꢀtoulouse.fr
ABSTRACT
The crossꢀcoupling of aryl tosylates with
amines and anilines was achieved by using
for the first time a PdꢀNHC system based
on the popular PdꢀPEPPSI preꢀcatalyst
platform in which the anchoring imidazolꢀ
Me N
NMe2
R1
R2
2
Ar
+
HN
OTs
N
N
C
K PO tAmOH 1d
3
4,
Cl
1
20°C
(1-4 mol%
Pd
N
R1
Cl
25 examples
(66-96%)
1d
Ar
N
R2
Cl
2 2
(NMe )
2
ꢀylidene ligand IPr
, incorporates two dimethylamino groups as backbone substituents enhancing
both the electronic and steric properties of the carbene. The system optimization and its application
scope are disclosed.
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INTRODUCTION
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5
6
The palladiumꢀcatalyzed BuchwaldꢀHartwig amination has been successfully established as a highly
2
valuable method for the formation of C(sp )ꢀN bonds, having important applications in both academia
1,2
and industry. Whereas the amination of aryl halides and triflates is efficiently performed by numerous
catalytic systems under very mild reaction conditions, only a handful of catalytic systems were reported
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
,4
for the Pdꢀcatalyzed amination of aryl sulfonates such as aryl tosylates and mesylates. These
alternative electrophiles are attractive as commodity chemicals being readily available from phenols,
easy to purify and stable against hydrolysis, but the activation/cleavage of the C ꢀO bond remains a
aryl
challenging problem.
5
NꢀHeterocyclic Carbenes (NHCs) have been well established as ubiquitous and highly efficient
6
supporting ligands in Pdꢀcatalyzed crossꢀcoupling reactions, thanks to their strong electron donation
and steric protection of the palladium center. Yet, – to our knowledge – the amination of aryl sulfonates
7
,8
using a PdꢀNHC catalyst has never been documented previously. Starting from the wellꢀknown and
9
popular PdꢀPEPPSIꢀIPr preꢀcatalyst, originally disclosed by Organ, we report herein that tuning of the
stereoelectronic structure of the NHC ligand is the clue to success in their implementation in this
challenging catalytic reaction.
RESULTS AND DISCUSSION
The PdꢀPEPPSIꢀNHC complexes 1a-d and 2a-b were selected as preꢀcatalysts for the study (Figure
1). Based on the assumption that the rateꢀlimiting step of the process resides in the oxidative addition of
2
the C(sp )ꢀO bond of aryl tosylates and that it would be facilitated by electronic enhancement of the
Pd(0) species, we selected complexes 1c and 1d, previously disclosed as preꢀcatalysts in our earlier
1
0
work. The adjunction of one or two dimethylamino groups as backbone substituents of IPr was indeed
NMe
2
shown to sequentially increase the electron donation and steric hindrance of the resulting IPr
and
(
2 2
NMe )
IPr
carbenes, resulting in a considerable and sequential enhancement of the catalytic performances
of the corresponding 1c and 1d preꢀcatalysts in the BuchwaldꢀHartwig amination of aryl chlorides. On
the other hand, for comparative purposes, we chose to test the preꢀcatalysts 2a-b bearing the sterically
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Cl
2
hindered, yet flexible NHCs IPent and IPent , since they still represent the most efficient PdꢀNHC
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
catalytic systems in amination reactions up to date. For the sake of comparison, complex 1b, featuring
Cl
2
the IPr ligand, was also included in the study.
X
Y
X
X
N
N
N
N
0
1
2
3
4
5
6
7
8
9
0
1
2
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1
2
3
4
5
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7
8
9
0
C
C
Cl
Cl
Pd
N
Pd
N
Cl
Cl
Cl
X
Cl
[Pd] NHC
Y
[Pd] NHC
X
1
1
1
1
a
b
c
d
IPr
IPr
IPr
IPr
H
Cl
H
Cl
H
2a
2b
IPent
IPent
H
Cl
Cl
NMe
NMe
2
Cl
2
2
NMe2
NMe2 NMe2
(
2 2
)
Figure 1. Palladium PEPPSIꢀtype complexes considered in this study (PEPPSI = PyridineꢀEnhanced
Precatalyst Preparation Stabilization and Initiation). IPr = 1,3ꢀbis(2,6ꢀdiisopropylphenyl)ꢀ2Hꢀimidazolꢀ
2ꢀylidene; IPent = 1,3ꢀbis(2,6ꢀbis(3ꢀpentyl)phenyl)ꢀ2Hꢀimidazolꢀ2ꢀylidene.
Their respective catalytic efficiencies were evaluated in the coupling between aryl tosylates 3a-b and
morpholine 4a as model reaction to yield the corresponding arylated amines 5aa and 5ba (Table 1).
Table 1. Screening of pre-catalysts 1a-d and 2a-b and reaction conditions for the Buchwald-
[a]
Hartwig amination of ArOTs.
[b]
Entry
Preꢀcatalyst Substrate
base
solvent
tAmOH
tAmOH
T (°C)
120
GC yield (%)
1
2
1a
1a
3a
3b
K PO
3
5
1
4
4
K PO
3
120
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3
4
5
6
7
8
9
1b
1b
1c
1c
1d
1d
2a
2a
2b
2b
1d
1d
1d
1d
1d
1d
1d
1d
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3a
3a
3a
3a
3a
3a
3a
K PO
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tBuOH
DMF
120
120
120
120
120
120
120
120
120
120
110
100
110
110
110
110
110
110
4
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
K PO
3
0
K PO
3
15
3
K PO
3
K PO
3
99
43
99
36
91
31
96
44
94
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
K PO
3
K PO
3
1
0
1
2
3
4
5
K PO
3
1
1
1
1
1
K PO
3
K PO
3
K PO
3
K PO
3
K PO
3
16
17
18
19
20
K PO
3
K PO
3
dioxane
tAmOH
tAmOH
tAmOH
26
95
4
K PO ,2H O
3
4
2
K CO
2
3
Cs CO
73
2
3
[a] Reaction conditions: ArOTs (0.5 mmol), morpholine (0.75 mmol), pre-catalyst (0.01 mmol, 2 mol%), base (1.5 mmol),
solvent (1.5 mL), 18h. [b] Calibrated GC yields were reported using dodecane as the internal standard and were averaged
over two runs.
Under the standard conditions (2 mol% of preꢀcatalyst, K PO as base, tertꢀamyl alcohol as solvent
3
4
and 120°C as reaction temperature), the reference PdꢀPEPPSIꢀIPr (1a) showed almost no ability to give
Cl2
products 5aa and 5ba (Entries 1ꢀ2). Whereas the moreꢀelectron deficient PdꢀPEPPSIꢀIPr (1b) gave
even worse results, the incorporation of one dimethylamino group onto the backbone of IPr induced a
(NMe2)
clear, yet still limited improvement of the activity of PdꢀPEPPSIꢀIPr
(1c) (Entries 3ꢀ6). To our
delight, a dramatic catalytic enhancement was observed when a second dimethylamino group was
incorporated into the IPrꢀskeleton, with a 99% yield in 5aa and 43% yield in 5ba using PdꢀPEPPSIꢀ
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(
NMe2)2
IPr
(1d) as preꢀcatalyst (Entries 7ꢀ8). Such performances were approached upon using the Pdꢀ
1
2
PEPPSIꢀIPent (2a) but with a smaller 36% yield in 5ba starting from the more difficult 4ꢀ
methoxyphenyl tosylate 3b (Entry 10), compared to the 43% yield obtained using 1d. As in the IPr
series, diminishing the electron donation of the IPent ligand by incorporating two chlorides in 2b led to
a small decrease in product yields compared to 2a. Taken together, these results suggest that the
amination of aryl tosylates is facilitated by a synergy between an electronic enrichment of the metallic
center and an increase in the steric crowding of the NHC ligand, with an optimal catalytic performance
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(NMe2)2
10a,12
reached with the PdꢀPEPPSIꢀIPr
(1d).
A further rapid optimization of the previous standard
reaction conditions using the latter preꢀcatalyst (1d) revealed a strong influence of the temperature on
the outcome of the reaction with diminished yields of 96% and 44% when reducing the temperature to
110°C and 100°C respectively (Entries 13ꢀ14). As observed earlier in most reported cases of amination
of aryl tosylates, the reaction proceeds well only in alcoholic solvents such as tBuOH or, even better
tAmOH, probably due to the good solubility of the substrates in these solvents. The use of K PO
3
4
(indifferently anhydrous or hydrated) as a base was found to be crucial for the success of the coupling,
since the use of carbonate bases gave lower yields (Entries 19ꢀ20), and that stronger bases such as KOH
or KOtBu only led to the hydrolysis of the sulfonate ester.
With the fully optimized catalytic conditions in hand, the substrate scope was then investigated,
starting with the variation of the (hetero)aryl tosylate partner using morpholine 4a as the common amine
and 2 mol% of preꢀcatalyst 1d (Table 2). Aryl tosylates 3a-d bearing electronicallyꢀdiverse para
substituents (methyl, methoxy, acetyl, cyano respectively) were efficiently coupled in good yields
(Entries 1ꢀ4). Nevertheless, for the most difficult 3b, it appeared necessary to increase the catalyst
loading up to 4 mol% to reach an acceptable 73% isolated yield. The meta substitution of the aryl group
was found not problematic (substrates 3e-f, entries 5ꢀ6), and the electronꢀrich 3,5ꢀdimethoxyphenyl
tosylate 3e could be successfully employed to give 5ea in an excellent 91% yield. Gratifyingly, the
mildly basic conditions of the reaction tolerate the presence of baseꢀsensitive functional groups as aryl
group substituents. Whereas the sterically highly crowded mesityl tosylate 3i remained untouched under
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these conditions (Entry 9), the coupling of orthoꢀsubstituted substrates 3g-h bearing a fluoro or methoxy
substituent smoothly proceeded to give 5ga and 5ha in 66% and 88% (with 4 mol% of 1d in the latter
case) respectively, indicating that the catalytic species can adapt to some steric constraint in the aryl
tosylate partner. Furthermore, whereas the naphthylꢀbased amines 5ia-ja were obtained in very good
yields, 2ꢀand 3ꢀpyridinyl tosylates 3k-l were shown to be suitable substrates and yielded the
corresponding amines in good yields (Entries 10ꢀ11 and 12ꢀ13).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Buchwald-Hartwig amination of (hetero)aryl tosylates 3a-l with morpholine (4a) using
[a]
pre-catalyst 1d.
[
b]
Entry
1
substrate
product
Yield (%)
95
3
a
5aa
[
c]
2
3
4
73
3
b
5ba
87
3c
5ca
5da
[
d]
80
3d
5
6
91
77
3
e
5ea
5fa
3
f
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The Journal of Organic Chemistry
1
7
66
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
g
5ga
5ha
[
c]
8
9
88
3h
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ
0
3
i
10
84
95
3
j
5ja
1
1
2
3k
5ka
5la
1
70
87
3
l
13
3m
5ma
[a] Reaction conditions: ArOTs (0.5 mmol), morpholine (0.75 mmol), 1d (2 mol%), K PO (1.5 mmol), tAmOH (1.5 mL),
3
4
120°C. [b] Isolated yield, average of two runs. [c] 4 mol% of 1d. [d] 1 mol% of 1d.
We next turned our attention to the scope of the reaction with respect to the nature of the amine using
4ꢀtoluenyl tosylate 3a as the electrophile partner (Table 3). Irrespective to their electronic and steric
nature, secondary cyclic (4a-d), acyclic (4e) amines, as well as Nꢀmethyl aniline 4f and even the
crowded and weakly nucleophilic diphenylamine 4g underwent the transformation in good to excellent
yields (Entries 1ꢀ6). Starting with the unsubstituted aniline 4h yielded the coupling product 5ah in 91%
isolated yield and no trace of the corresponding diꢀarylated aniline could be detected (Entry 7). More
challenging anilines 4i-j bearing electronꢀwithdrawing groups such as 4ꢀfluoro and 3ꢀtrifluoromethyl
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respectively and the crowded 2,6ꢀdimethylaniline 4k were smoothly engaged in this reaction in
excellent yields, albeit requiring a small increase of the catalyst loading up to 4 mol% for the first two
anilines. However, no conversion was detected when employing the low nucleophilic 2ꢀand 3ꢀ
aminopyridines 4l-m (Entries 11ꢀ12), leaving the substrate 3a untouched. The primary aliphatic amines
were found to be suitable coupling partners, but exhibiting different outcomes according to their steric
hindrance. The reaction between 3a and octylamine 4n proceeded well but appeared not very selective,
affording the monoꢀand bisꢀarylation products 5an and 5an’ in a 27/73 ratio (Entry 13). Under the same
conditions, the use of the slightly more crowded cyclohexylamine 4o allowed the efficient isolation of
the monoꢀarylated product 5ao in 93% yield (Entry 14), but the catalytic system appeared inefficient in
coupling 3a with the highly congested tertꢀbutylamine 4p (Entry 15). Finally, the procedure could be
extended to the hydrazine derivative 4ꢀaminomorpholine 4q. The general applicability of the catalytic
system throughout the above screening led us to conclude that the amine partner might not be involved
in the rate determining step of the catalytic cycle, our observations being more consistent with the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
cleavage of the C ꢀO bond of the aryl tosylate as being the rate limiting step of the catalytic cycle.
Ar
Table 3. Buchwald-Hartwig amination of 4-toluenyl tosylate 3a with amines and anilines using
[a]
pre-catalyst 1d.
[
b]
Entry
1
substrate
product
Yield (%)
91
4b
5ab
5ac
2
82
4
c
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
96
91
4d
5ad
4
5
4e
5ae
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
91
4
f
5
af
[
c]
6
7
94
4g
5ag
91
4
h
5
ah
[
[
c]
8
9
96
92
4i
5ai
5aj
c]
4j
10
85
5ak
4
k
1
1
2
-
-
0
0
4
l
1
4
m
[
e]
82
[
d]
1
3
4n
[f]
5an
5an’
(27/73 )
93
14
4o
5
ao
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15
ꢀ
0
4p
16
83
4
q
5aq
[
a] Reaction conditions: 3a (0.5 mmol), amine (0.75 mmol), 1d (2 mol%), K PO (1.5 mmol), tAmOH (1.5 mL), 120°C. [b]
3 4
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0
Isolated yield, average of two runs. [c] 4 mol% of 1d. [d] octyl = n-C H , Tol = p-tolyl. [e] Global yield based on 3a. [f]
8
17
Ratio between mono and bis arylation products 5an and 5an’.
To further extend the application potential of this methodology, we were thus prompted to take
advantage of the different reactivity profiles between aryl chlorides and tosylates in BuchwaldꢀHartwig
amination to selectively install different amines on the same bisꢀelectrophilic substrate and under the
same catalytic conditions. As representative example, Nꢀ(4ꢀ(piperidinyl)phenyl)morpholine 6 could be
synthesized from 4ꢀchlorophenyl tosylate 3n, readily available from 4ꢀchlorophenol (Scheme 1).
Gratefully, when piperidine 4c was employed as the amine partner under the standard conditions, but at
90°C instead of 120°C, 4ꢀ(piperidinyl)phenyl tosylate 3o was obtained as the sole product in 95% yield
(
pathway 1). After purification and isolation, the latter was engaged in the second amination reaction
with morpholine 4a using the standard conditions. More remarkably, thanks to the high
chemoselectivity of the transformation, it was possible to carry out the bisꢀamination in a oneꢀpot
protocol without the need to isolate the intermediate 3o (pathway 2). The overall 57% yield in 7 was
fully acceptable considering the strong electronꢀdonating character of the piperidinylꢀsubstituent in 3o.
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The Journal of Organic Chemistry
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59
60
Scheme 1. Sequential (eq. 1) and oneꢀpot (eq. 2) chemoselective bisꢀamination leading to bisꢀamine 6.
CONCLUSION
In summary, we have disclosed the first efficient and general catalytic PdꢀNHC system for the
amination of aryl tosylates. The optimization strategy of the PdꢀPEPPSI preꢀcatalyst relied on
stereoelectronic modifications of the supporting imidazolꢀ2ꢀylidene ligand and proved very powerful in
(NMe2)2
finding out the best candidate, namely the PdꢀPEPPSIꢀIPr
. The optimized catalytic system was
shown to achieve the amination with a wide range of amines and anilines, and to be slightly more
sensitive to the nature of the aryl tosylate, indicating that the limiting step of the catalytic cycle is the
oxidative addition of the C ꢀO bond onto the Pd(0) species. Further studies aiming at utilizing this
Ar
strategy to unveil better catalysts and new reactivities as well at understanding the beneficial features of
the decorated NHC ligand are currently underway in our laboratory.
EXPERIMENTAL SECTION
General information. All manipulations were performed under an inert atmosphere of dry nitrogen
by using standard vacuum line and Schlenk tube techniques. Glassware was dried at 120°C in an oven
for at least three hours. 1,4ꢀdioxane was distilled from sodium/benzophenone, tBuOH, tAmOH and
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The Journal of Organic Chemistry
Page 12 of 23
toluene from sodium, and dichloromethane was dried over CaH and subsequently distilled. DMF was
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
degassed by bubbling N for 15 min and was stored over activated 4 Å MS. PdꢀPEPSSI preꢀcatalysts
2
9
13
10a
10a
14
13
1a, 1b, 1c, 1d, 2a, and 2b, were synthesized according to literature procedures. Aryl tosylate
substrates were synthesized upon reaction of the corresponding phenol derivative with paraꢀ
1
5
toluenesulfonyl chloride according to literature procedure. All other reagents were commercially
available and used as received, except the liquid amines which were distilled prior to use. Anhydrous
K PO was purchased from Acros and Cs CO was purchased from Alfa Aesar. NMR spectra were
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
4
2
3
recorded on 300 MHz or 400 MHz spectrometers. Chemical shifts are reported in ppm (δ) compared to
1
13
16
TMS ( H and C) using the residual peak of deuterated solvent as internal standard. GC analyses were
performed on a chromatograph equipped with a 30ꢀm capillary column (fused silica capillary column,
3
0 m × 0.32 mm × 0.25 ꢀm film thickness, stationary phase: poly(5% diphenyl/95% methyl siloxane)),
using Helium as the vector gas. GC yields were measured according to an authentic sample/dodecane
calibration curve. HRMS measurements were recorded using a TOF mass analyzer.
General procedure for the optimization of the reaction conditions (Table 1)
4
ꢀtoluenyl tosylate 3a (131 mg, 0.5 mmol, 1.0 eq) or 4ꢀmethoxyphenyl tosylate 3b (139 mg, 0.5
mmol, 1.0 eq.), base (1.5 mmol, 3.0 eq) and Pd preꢀcatalyst (0.01 mmol, 2 mol%) were charged under
air into a Schlenk tube (15 mL volume) that was sealed with a septum, and the tube was evacuated and
flushed with nitrogen for three times. Morpholine (66 µL, 0.75 mmol, 1.5 eq) and solvent (1.5 mL) were
subsequently added via syringe at room temperature. The mixture was stirred for about one minute at
room temperature and was then placed into a preꢀheated oil bath at the desired temperature. The reaction
was allowed to stir for 18 h. The reaction mixture was cooled, diluted with 10 mL ethyl acetate and
dodecane was added (112 µL, 0.5 mmol) as internal standard. Yields were measured by passing an
aliquot of the solution through a plug of silica gel using ethyl acetate as eluant and monitoring the
relative areas of the peaks compared to that of dodecane in the GC chromatogram.
General procedure for screening of aryl tosylates (Table 2)
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Aryl tosylate (0.5 mmol, 1.0 eq), K PO (318 mg, 1.5 mmol, 3.0 eq) and complex 1d (7.7 mg, 0.01
3
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mmol, 2 mol%) were charged under air into a Schlenk tube (15 mL volume) that was sealed with a
septum, and the tube was evacuated and flushed with nitrogen for three times. Morpholine 4a (66 µL,
0
.75 mmol, 1.5 eq) and tAmOH (1.5 mL) were subsequently added via syringe at room temperature.
The mixture was stirred for about one minute at room temperature and then transferred to a preheated
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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8
9
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8
9
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
°
oil bath at 120 C and the reaction was stirred for 18 h. At that point, the reaction mixture was cooled
down to room temperature and diluted with EtOAc (10 mL), filtered through a small plug of Silica gel
and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified via
silica gel flash chromatography.
1
0a
1
4
-(4-methylphenyl)morpholine (5aa): Hexane/EtOAc = 20/1, white solid, 85.2 mg (96%); H
NMR (400 MHz, CDCl ): δ = 7.10 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 3.90ꢀ3.83 (m, 4H),
3
13
1
3
5
.15ꢀ3.08 (m, 4H), 2.29 (s, 3H); C{ H} NMR (101 MHz, CDCl ): δ = 149.3, 129.9, 129.7, 116.2, 67.1,
3
0.1, 20.6.
10a
1
4
-(4-methoxylphenyl)morpholine (5ba): Hexane/EtOAc = 4/1, white solid, 70.0 mg (73%); H
NMR (400 MHz, CDCl ): δ = 6.94ꢀ6.80 (m, 4H), 3.91ꢀ3.83 (m, 4H), 3.77 (s, 3H), 3.09ꢀ3.02 (m, 4H);
3
1
3
1
C{ H} NMR (101 MHz, CDCl ): δ = 154.1, 145.8, 118.0, 114.7, 67.2, 55.7, 51.0.
3
1
0b
1
4-(4-acetylphenyl)morpholine (5ca):
Hexane/EtOAc = 2/1), yellow solid, 89.0 mg (87%); H
NMR (300 MHz, CDCl ): δ = 7.88 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H), 3.93ꢀ3.76 (m, 4H),
3
1
3
1
3
.36ꢀ3.23 (m, 4H), 2.52 (s, 3H); C{ H} NMR (75 MHz, CDCl ): δ = 196.6, 154.3, 130.5, 128.3, 113.4,
3
66.7, 47.7, 26.3.
1
0b
4
-morpholinophenylnitrile (5da): Pentane/Et O = 3/2), white solid, 75.0 mg (80%).
2
1
H NMR (300 MHz, CDCl ): δ = 7.56ꢀ7.43 (m, 2H), 6.85 (d, J = 9.0 Hz, 2H), 3.92ꢀ3.74 (m, 4H),
3
13
1
3
.38ꢀ3.15 (m, 4H). C{ H}NMR (75 MHz, CDCl ): δ = 153.6, 133.6, 120.0, 114.2, 101.0, 66.5, 47.4.
3
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5
5
5
6
1
7
1
4
-(3,5-dimethoxyphenyl)morpholine (5ea): Hexane/EtOAc = 8/1, white solid, 102 mg (91%); H
NMR (400 MHz, CDCl ): δ = 6.09 (d, J = 2.0 Hz, 2H), 6.05 (t, J = 2.1 Hz, 1H), 3.84 (t, J = 5.2 Hz, 4H),
3
13
1
3
6
.78 (s, 6H), 3.14 (t, J = 4.9 Hz, 4H); C{ H}NMR (101 MHz, CDCl ): δ = 161.7, 153.2, 95.0, 92.2,
3
6.9, 55.4, 49.6.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
18
1
4
-(3-acetylphenyl)morpholine (5fa): Hexane/EtOAc = 2/1, yellow oil, 78.8 mg (77%); H NMR
(400 MHz, CDCl ): δ = 7.49 (s, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 8.3,
3
1
3
1
1
.9 Hz, 1H), 3.85 (t, J = 4.5 Hz, 4H), 3.19 (t, J = 4.7 Hz, 4H), 2.57 (s, 3H); C{ H} NMR (101 MHz,
CDCl ): δ = 198.5, 151.5, 138.1, 129.4, 120.3, 114.5, 66.8, 49.1, 26.8.
3
19
1
4
-(2-methoxyphenyl)morpholine (5ga): Hexane/EtOAc = 10/1), colorless oil, 85 mg (88%); H
NMR (400 MHz, CDCl ): δ = 7.05ꢀ6.98 (m, 1H), 6.95ꢀ6.91 (m, 2H), 6.87 (d, J = 7.9 Hz, 1H), 3.92ꢀ3.87
3
1
3
1
(m, 4H), 3.86 (s, 3H), 3.20ꢀ2.97 (m, 4H); C{ H} NMR (101 MHz, CDCl ): δ = 152.3, 141.2, 123.2,
3
1
21.1, 118.1, 111.4, 67.3, 55.4, 51.2.
1
9
1
4
-(2-fluorophenyl)morpholine (5ha): Hexane/EtOAc = 10/1, colorless oil, 60 mg (66%); H NMR
13
1
(
300 MHz, CDCl ): δ = 7.12ꢀ6.89 (m, 4H), 3.93ꢀ3.84 (m, 4H), 3.13ꢀ3.04 (m, 4H). C{ H} NMR (75
3
MHz, CDCl ): δ = 155.8 (d, J = 244 Hz), 140.1 (d, J = 9 Hz), 124.6 (d, J = 4 Hz), 122.8 (d, J = 8 Hz),
3
1
18.8 (d, J = 3 Hz), 116.3 (d, J = 19 Hz), 67.1, 51.0 (d, J = 4 Hz).
1
8
1
4-(napht-2-yl)morpholine (5ja): Hexane/EtOAc = 8/1), white solid, 89.6 mg (84%); H NMR (400
MHz, CDCl ): δ = 7.85ꢀ7.60 (m, 3H), 7.46ꢀ7.39 (m, 1H), 7.35ꢀ7.29 (m, 1H), 7.26 (dd, J = 9.0, 2.5 Hz,
3
13
1
1
H), 7.13 (d, J = 1.9 Hz, 1H), 3.93 (t, J = 4.7 Hz, 4H), 3.27 (t, J = 4.9 Hz, 4H); C{ H} NMR (101
MHz, CDCl ): δ = 149.1, 134.6, 129.0, 128.9, 127.6, 126.9, 126.5, 123.7, 119.0, 110.3, 67.0, 50.0.
3
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The Journal of Organic Chemistry
1
8
1
4
-(napht-1-yl)morpholine (5ka): Hexane/EtOAc = 10/1, yellowish solid, 104.5 mg (98%); H
1
2
NMR (400 MHz, CDCl ): δ = 8.30ꢀ8.21 (m, 1H), 7.91ꢀ7.82 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.56ꢀ7.48
3
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(m, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.12 (dd, J = 7.4, 1.1 Hz, 1H), 4.01 (t, J = 4.5 Hz, 4H), 3.19 (t, J = 4.5
13
1
Hz, 4H); C{ H} NMR (101 MHz, CDCl ): δ = 149.5, 134.9, 128.9, 128.6, 126.0, 125.5, 123.9, 123.5,
3
1
14.8, 67.5, 53.6.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10a
1
4
-(pyridin-2-yl)morpholine (5la): Pentane/Et O = 5/1, colorless oil; 56 mg (68%); H NMR (400
2
MHz, CDCl ): δ = 8.22ꢀ8.15 (m, 1H), 7.53ꢀ7.43 (m, 1H), 6.68ꢀ6.58 (m, 2H), 3.84ꢀ3.77 (m, 4H), 3.51ꢀ
3
1
3
1
3
.44 (m, 4H); C{ H} NMR (101 MHz, CDCl ): δ = 159.7, 148.0, 137.6, 113.9, 107.0, 66.9, 45.7.
3
1
0a
1
4-(pyridin-3-yl)morpholine (5ma): Hexane/EtOAc = 1/1, yellow oil, 71 mg (87%); H NMR (300
MHz, CDCl ): δ = 8.32ꢀ8.27 (m, 1H), 8.15ꢀ8.08 (m, 1H), 7.19ꢀ7.12 (m, 2H), 3.95ꢀ3.76 (m, 4H), 3.28ꢀ
3
1
3
1
3
.08 (m, 4H). C{ H} NMR (75 MHz, CDCl ): δ = 147.0, 141.3, 138.5, 123.6, 122.2, 66.8, 48.7.
3
General procedure for the screening of the amine partner (Table 3)
4
ꢀtoluenyl tosylate 3a (131 mg, 0.5 mmol, 1.0 eq), K PO (318 mg, 1.5 mmol, 3.0 eq) and complex 1d
3 4
(7.7 mg, 0.01 mmol, 2 mol%) were charged under air into a Schlenk tube (15 mL volume) that was
sealed with a septum, and the tube was evacuated and flushed with nitrogen for three times. The amine
(0.75 mmol, 1.5 eq) and tAmOH (1.5 mL) were subsequently added via syringe at room temperature. In
case of diphenylamine, which is solid at room temperature, it was introduced into the tube prior to
purging with nitrogen. The mixture was stirred for about one minute at room temperature and then
°
transferred to a preheated oil bath at 120 C and the reaction was stirred for 18 h. At this point, the
reaction mixture was cooled down to room temperature and diluted with EtOAc (10 mL), filtered
through a small plug of Silica gel and washed with ethyl acetate. The filtrate was concentrated under
reduced pressure and purified via silica gel flash chromatography.
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20
1
1
-(4-methylphenyl)pyrolidine (5ab): Pentane/Et O = 10/1, white solid, 73.7 mg (91%); H NMR
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
400 MHz, CDCl ): δ =7.06 (d, J = 8.4 Hz, 2H), 6.53 (d, J = 8.5 Hz, 2H), 3.28 (t, J = 6.5 Hz, 4H), 2.28
3
13
1
(s, 3H), 2.15ꢀ1.88 (m, 4H); C{ H} NMR (101 MHz, CDCl ): δ = 146.2, 129.8, 124.7, 112.0, 48.0,
3
2
5.5, 20.4.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1
1
1
-(4-methylphenyl)piperidine (5ac): Hexane/EtOAc = 50/1, colorless oil, 70.2 mg (80%); H
NMR (400 MHz, CDCl ): δ = 7.13ꢀ7.06 (m, 2H), 6.95ꢀ6.85 (m, 2H), 3.12 (t, J = 5.4 Hz, 4H), 2.30 (s,
3
13
1
3H), 1.75 (p, J = 5.6 Hz, 4H), 1.64ꢀ1.55 (m, 2H); C{ H} NMR (101 MHz, CDCl ): δ = 150.3, 129.6,
3
1
28.9, 117.1, 51.5, 26.1, 24.4, 20.5.
2
2
1-(4-methylphenyl)-4-phenylpiperazine (5ad): Hexane/EtOAc = 10/1, white shining crystals, 121
1
mg (96%); H NMR (400 MHz, CDCl ): δ = 7.31 (t, J = 7.9 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.00 (d, J
3
13
1
=
8.1 Hz, 2H), 6.97ꢀ6.86 (m, 3H), 3.40ꢀ3.25 (m, 8H), 2.30 (s, 3H); C{ H} NMR (101 MHz, CDCl ): δ
3
= 151.4, 149.2, 129.8, 129.3, 120.2, 116.9, 116.5, 50.2, 49.6, 20.6.
1
0a
4
-methyl-N-ethyl-N-benzyl-aniline (5ae): Hexane/EtOAc = 95/5, colorless oil, 102.9 mg (91%);
1
H NMR (400 MHz, CDCl ): δ = 7.40ꢀ7.26 (m, 5H), 7.12ꢀ7.02 (m, 2H), 6.82ꢀ6.58 (m, 2H), 4.55 (s, 2H),
3
13
1
3
.51 (q, J = 7.0 Hz, 2H), 2.31 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H); C{ H} NMR (101 MHz, CDCl ): δ =
3
146.5, 139.7, 129.8, 128.6, 126.8, 126.7, 125.3, 112.6, 54.3, 45.4, 20.3, 12.2.
1
0a
4
-methyl-N-methyl-N-phenylaniline (5af): Hexane/EtOAc = 20/1, yellowish oil, 89.5 mg (91%);
1
H NMR (300 MHz, CDCl ): δ = 7.48ꢀ7.38 (m, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.24ꢀ7.17 (m, 2H), 7.18ꢀ
3
13
1
7
.11 (m, 2H), 7.11ꢀ7.03 (m, 1H), 3.47 (s, 3H), 2.52 (s, 3H); C{ H} NMR (75 MHz, CDCl ): δ = 149.4,
3
1
46.7, 132.0, 130.0, 129.1, 122.6, 119.9, 118.3, 40.3, 20.8.
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3
1
N,N-diphenyl-4-methylaniline (5ag): Hexane/DCM = 10/1, white solid, 122.4 mg (94%); H NMR
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
(
300 MHz, CDCl ): δ = 7.36ꢀ7.22 (m, 4H), 7.20ꢀ6.96 (m, 10H), 2.39 (s, 3H); C{ H} NMR (75 MHz,
3
CDCl ): δ = 148.2, 145.4, 132.8, 130.0, 129.2, 125.1, 123.7, 122.3, 21.0.
3
1
0a
1
4
-methyl-N-phenylaniline (5ah): Hexane/EtOAc = 95/5, white solid, 80.0 mg (87%); H NMR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
400 MHz, CDCl ): δ = 7.37ꢀ7.25 (m, 2H), 7.16 (d, J = 8.3 Hz, 2H), 7.11ꢀ7.02 (m, 4H), 6.95 (t, J = 7.3
3
13
1
Hz, 1H), 5.64 (br, s, 1H), 2.38 (s, 3H); C{ H} NMR (101 MHz, CDCl ): δ = 144.1, 140.4, 131.0,
3
130.0, 129.4, 120.4, 119.0, 117.0, 20.8.
24
1
4
-fluoro-N-(4-methylphenyl)aniline (5ai): Hexane/EtOAc = 20/1, white solid, 96.5 mg (96%); H
NMR (300 MHz, CDCl ): δ = 7.16ꢀ7.07 (m, 2H), 7.06ꢀ6.88 (m, 6H), 5.49 (br, s, 1H), 2.34 (s, 3H);
3
13
1
C{ H} NMR (75 MHz, CDCl ): δ = 157.7 (d, J = 238 Hz), 141.2, 139.9 (d, J = 2 Hz), 130.6, 130.0,
3
1
19.5 (d, J = 7 Hz), 118.0, 116.0 (d, J = 22 Hz), 20.7.
22
3
-trifluoromethyl-N-(4-methylphenyl)aniline (5aj): Hexane/EtOAc = 20/1, white solid, 115 mg
1
(
92%); H NMR (300 MHz, CDCl ): δ = 7.31 (t, J = 7.9 Hz, 1H), 7.23ꢀ6.98 (m, 7H), 5.73 (br, s, 1H),
3
1
3
1
2
.34 (s, 3H); C{ H} NMR (75 MHz, CDCl ): δ = 145.0, 139.1, 132.6, 131.8 (q, J = 32 Hz), 130.2,
3
1
29.9, 124.3 (q, J = 271 Hz), 120.3, 119.0, 116.4 (q, J = 4 Hz), 112.5 (q, J = 4 Hz), 20.9.
25
2
,6-dimethyl-N-(4-methylphenyl)aniline (5ak): Pentane/Et O = 9/1, white solid, 90.0 mg (85%);
2
1
H NMR (400 MHz, CDCl ): δ = 7.23ꢀ7.12 (m, 3H), 7.06 (d, J = 8.0 Hz, 2H), 6.60ꢀ6.47 (m, 2H), 5.14
3
1
3
1
(br, s, 1H), 2.34 (s, 3H), 2.30 (s, 6H). C{ H} NMR (101 MHz, CDCl ): δ = 143.9, 138.8, 135.6, 129.8,
3
1
28.6, 127.5, 125.5, 113.9, 20.6, 18.5.
4
-methyl-N-(oct-1-yl)-aniline (5an) and N,N-bis(4-methylphenyl)octyl-1-amine (5an’):
Hexane/EtOAc = 98/2; a first crop of pure 5an’ was collected as the first fraction (29.4 mg) but, due to
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coꢀelution of the two products, the second fraction consisted of a mixture of 5an and 5an’ in a 2/1 ratio
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
26
1
determined by integration of the H NMR spectrum (41.1 mg). 5an: 0.11 mmol (22%); H NMR (400
MHz, CDCl ): δ = 7.01 (d, J = 8.1 Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H), 3.46 (br s, 1H), 3.11 (t, J = 7.1 Hz,
3
13
1
2
H), 2.27 (s, 3H), 1.73ꢀ1.53 (m, 2H), 1.48ꢀ1.20 (m, 10H), 1.01ꢀ0.82 (m, 3H). C{ H} NMR (101 MHz,
:27
CDCl ): δ = 146.4, 129.8, 126.4, 113.1, 44.6, 32.0, 29.8, 29.6, 29.4, 27.3, 22.8, 20.5, 14.2. 5an’
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
colorless oil, 0.15 mmol (60%); H NMR (400 MHz, CDCl ): δ = 7.06 (d, J = 8.2 Hz, 4H), 6.87 (d, J =
3
8
.0 Hz, 4H), 3.62 (t, J = 7.0 Hz, 2H), 2.30 (s, 6H), 1.64 (p, J = 7.6 Hz, 2H), 1.39ꢀ1.19 (m, 10H), 0.88 (t,
1
3
1
J = 6.8 Hz, 3H). C{ H} NMR (101 MHz, CDCl ): δ = 146.0, 130.2, 129.7, 120.8, 52.5, 31.8, 29.4,
3
2
9.3, 27.5, 27.1, 22.7, 20.6, 14.1.
2
8
1
4-methyl-N-cyclohexylaniline (5ao): Hexane/EtOAc = 95/5, white solid, 88 mg (93%); H NMR
(
400 MHz, CDCl ): δ = 6.97 (d, J = 8.1 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 3.58 (br, s, 1H), 3.22 (tt, J =
3
1
0.1, 3.7 Hz, 1H), 2.23 (s, 3H), 2.11ꢀ2.00 (m, 2H), 1.75 (dt, J = 12.9, 3.6 Hz, 2H), 1.65 (dt, J = 12.6, 3.7
1
3
1
Hz, 1H), 1.42ꢀ1.29 (m, 2H), 1.27ꢀ1.08 (m, 3H). C{ H} NMR (101 MHz, CDCl ): δ = 144.9, 129.9,
3
1
26.5, 113.9, 52.4, 33.6, 26.1, 25.2, 20.5.
2
9
1
4
-methyl-N-(morpholin-4-yl)aniline (5aq): Hexane/EtOAc = 4/1, yellowish oil, 80 mg (83%); H
NMR (400 MHz, CDCl ): 7.03 (d, J = 9.1 Hz, 2H), 6.88ꢀ6.81 (m, 2H), 4.32 (br, s, 1H), 3.81 (t, J = 4.6
3
1
3
1
Hz, 4H), 2.75 (s, 4H), 2.27 (s, 3H). C{ H} NMR (101 MHz, CDCl ): δ = 144.8, 129.8, 129.1, 114.1,
3
6
7.2, 56.5, 20.6.
4-piperidinylphenyl tosylate (3o): 4ꢀchlorophenyl tosylate 3n (141.4 mg, 0.5 mmol, 1.0 eq), K PO
3
4
(265 mg, 1.25 mmol, 2.5 eq) and preꢀcatalyst 1d (7.7 mg, 0.01 mmol, 2 mol%) were charged under air
into a Schlenk tube (15 mL volume) that was sealed with a septum, and the tube was evacuated and
flushed with nitrogen for three times. Piperidine (59 µL, 0.6 mmol, 1.2 eq) and tAmOH (1.5 mL) were
subsequently added via syringe at room temperature. The mixture was stirred for about one minute at
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The Journal of Organic Chemistry
°
room temperature and then transferred to a preheated oil bath (90 C). The reaction was stirred for
another 18 h. The reaction mixture was diluted with 10 mL ethyl acetate, filtered through a small plug of
Silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
purified via silica gel flash chromatography (SiO , Hexane/EtOAc: 2/1) to afford compound 3o as a
2
1
white solid (158.3 mg, 96% yield); mp = 123ꢀ124°C; H NMR (300 MHz, CDCl ): δ = 7.75ꢀ7.64 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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7
8
9
0
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7
8
9
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8
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0
3
2
1
H), 7.33ꢀ7.24 (m, 2H), 6.90ꢀ6.67 (m, 4H), 3.14ꢀ3.05 (m, 4H), 2.44 (s, 3H), 1.73ꢀ1.62 (m, 4H), 1.60ꢀ
13
1
.52 (m, 2H); C{ H} NMR (75 MHz, CDCl ): δ = 151.0, 145.1, 142.0, 132.7, 129.8, 128.7, 122.9,
3
116.8, 50.7, 25.9, 24.2, 21.8; IR (ATR): ν = 2936, 2854, 2815, 1595, 1508, 1450, 1372, 1246, 1188,
ꢀ1
1
176, 1157, 1124, 1092, 1019, 1007, 915, 859, 809, 754, 693, 656 cm ; MS (ESI): m/z (%): 332 (100)
+
[M + H] ; HRMS (ESI): m/z calcd. for C H NO S: 332.1320; found: 332.1321, ε = 0.3 ppm;
18
22
3
r
elemental analysis calcd (%) for C H NO S (MW = 331.43): C 65.23, H 6.39, N 4.23, found: C 64.98,
1
8
21
3
H 6.42, N 4.19.
30
4
-(4-piperidinylphenyl)morpholine (6): 4ꢀpiperidinylphenyl tosylate 3o (165.7 mg, 0.5mmol, 1.0
eq), K PO (318 mg, 1.5 mmol, 2.5 eq) and complex 1d (15.4 mg, 0.02 mmol, 4 mol%) were charged
3
4
under air into a Schlenk tube (15 mL volume) that was sealed with a septum, and the tube was
evacuated and flushed with nitrogen for three times. Morpholine (66 µL, 0.75 mmol, 1.5 eq) and
tAmOH (1.5 mL) were subsequently added via syringe at room temperature. The mixture was stirred for
°
about one minute at room temperature and then transferred to a preheated oil bath (120 C). The reaction
was stirred for another 18 h. The reaction mixture was diluted with 10 mL ethyl acetate, filtered through
a small plug of Silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced
pressure and purified via silica gel flash chromatography (SiO , Hexane/EtOAc: 2/1) to afford the title
2
compound as a white solid (74.2 mg, 60% yield).
1
H NMR (300 MHz, CDCl ): δ = 7.00ꢀ6.78 (m, 4H), 3.97ꢀ3.74 (m, 4H), 3.13ꢀ2.98 (m, 8H), 1.82ꢀ1.60
3
13
1
(
m, 4H), 1.63ꢀ1.45 (m, 2H); C{ H} NMR (75 MHz, CDCl ): δ = 146.9, 145.1, 118.4, 117.4, 67.2,
3
5
2.0, 50.7, 26.2, 24.3.
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9
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5
5
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5
5
5
5
6
One-pot procedure: 4ꢀchlorophenyl tosylate 3n (141.4 mg, 0.5 mmol, 1.0 eq), K PO (265 mg, 1.25
3
4
mmol, 2.5 eq) and preꢀcatalyst 1d (7.7 mg, 0.01 mmol, 2 mol%) were charged under air into a Schlenk
tube (15 mL volume) that was sealed with a septum, and the tube was evacuated and flushed with
nitrogen for three times. Piperidine (59 µL, 0.6 mmol, 1.2 eq) and tAmOH (1.5 mL) were subsequently
added via syringe at room temperature. The mixture was stirred for about one minute at room
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
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2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
°
temperature and then transferred to a preheated oil bath at 90 C for 6 h to observe the full conversion
(checked by TLC). After cooling down to the room temperature, K PO (318 mg, 1.5 mmol, 3.0 eq),
3
4
preꢀcatalyst 1d (15.4 mg, 0.02 mmol, 4.0 mol%) and morpholine (66 µL, 0.75 mmol, 1.5 eq) were
°
subsequently added to the solution upon a flow of N . The mixture was heated at 120 C for another 18
2
h. The reaction mixture was diluted with 10 mL ethyl acetate, filtered through a small plug of Silica gel
and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified via
silica gel flash chromatography (SiO , Hexane/EtOAc: 2/1) to afford compound 6 as a white solid (70.0
2
mg, 57% yield).
ACKNOWLEDGEMENTS
We thank the CNRS for financial support and the Chinese Scholarship Council (CSC) for a PhD.
Grant to Y.Z.
SUPPORTING INFORMATION
1
13
Copies of H and C NMR spectra. This material is available free of charge via the internet at
http://pubs.acs.org.
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The Journal of Organic Chemistry
(
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(
8) On contrary, several NiꢀNHC catalytic systems were reported to be active in amination of aryl
1
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5
6
7
8
9
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1
1
1
1
1
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1
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5
5
5
5
5
6
tosylates, but they suffer from several disadvantages such as a high catalyst loading, the required use of
a strong base such as tertꢀbutoxide and a quite narrow substrate scope. See: (a) Fine Nathel, N. F.; Kim,
J.; Hie, L.; Jiang, X.; Garg, N. K. ACS Catal. 2014, 4, 3289; (b) Jiang, J.; Zhu, H.; Shen, Y.; Tu, T. Org.
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1
2
3
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5
6
7
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9
0
(9) PEPPSI: PyridineꢀEnhanced Preꢀcatalysts Preparation Stabilization and Initiation. See: O'Brien, C.
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3
223; (b) Valente, C.; Pompeo, M.; Sayah, M.; Organ, M. G. Org. Process. Res. Dev. 2013, 18, 180; (c)
H. Hoi, K.; Coggan, J. A.; Organ, M. G. Chem. Eur. J. 2013, 19, 843; (d) Hoi, K. H.; Çalimsiz, S.;
Froese, R. D. J.; Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2012, 18, 145; (e) Hoi, K. H.; Çalimsiz,
S.; Froese, R. D. J.; Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2011, 17, 3086.
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Meiries, S.; Slawin, A. M. Z.; Falivene, L. ; Cavallo, L.; Nolan, S. P. Organometallics 2013, 32, 3249.
(
13) Pompeo, M.; Froese, R. D. J.; Hadei, N.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 11354.
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(
15) Wilson, D. A.; Wilson, C. J.; Moldoveanu, C.; Resmerita, A.ꢀM.; Corcoran, P.; Hoang, L. M.;
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(16) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.;
1
2
Bercaw, J. E.; Goldberg, K. I. Organometallics 2010, 29, 2176.
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(17) Lü, B.; Li, P.; Fu, C.; Xue, L.; Lin, Z.; Ma, S. Adv. Synth. Catal. 2011, 353, 100.
(
(
(
(
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