Discovery and mechanistic studies of a general air-promoted metal-catalyzed aerobic n- alkylation reaction of amides and amines with alcohols

Article abstract of DOI:10.1021/jo200862p

The thermodynamically unfavorable anaerobic dehydrogenative alcohol activation to aldehydes and hydridometal species is found to be the bottleneck in metal-catalyzed N-alkylations due to a general and unnoticed catalyst deactivation by amines/amides. Thus, different from the anaerobic dehydrogenation process in borrowing hydrogen or hydrogen autotransfer reactions that require noble metal complexes or addition of capricious ligands for catalyst activation, the water-producing, exothermic, metal-catalyzed aerobic alcohol oxidation is thermodynamically more favorable and the most effective and advantageous aldehyde generation protocol. This leads to a general and advantageous air-promoted metal-catalyzed aerobic N-alkylation methodology that effectively uses many simpler, less expensive, more available, and ligand-free metal catalysts that were inactive under typical anaerobic borrowing hydrogen conditions, avoiding the use of preformed metal complexes and activating ligands and the exclusive requirement of inert atmosphere protection. This aerobic method is quite general in substrate scope and tolerates various amides, amines, and alcohols, revealing its potentially broad utilities and interests in academy and industry. In contrast to the commonly accepted borrowing hydrogen mechanism, based on a thorough mechanistic study and supported by the related literature background, a new mechanism analogous to the relay race game that has never been proposed in metal-catalyzed N-alkylation reactions is presented.

Full text of DOI:10.1021/jo200862p

ARTICLE
pubs.acs.org/joc
Discovery and Mechanistic Studies of a General Air-Promoted
Metal-Catalyzed Aerobic N-Alkylation Reaction of Amides
and Amines with Alcohols
Chuanzhi Liu, Shiheng Liao, Qiang Li, Sunlin Feng, Qing Sun, Xiaochun Yu,* and Qing Xu*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P.R. China
S Supporting Information
b
ABSTRACT: The thermodynamically unfavorable anaerobic dehy-
drogenative alcohol activation to aldehydes and hydridometal spe-
cies is found to be the bottleneck in metal-catalyzed N-alkylations
due to a general and unnoticed catalyst deactivation by amines/
amides. Thus, different from the anaerobic dehydrogenation process
in borrowing hydrogen or hydrogen autotransfer reactions that
require noble metal complexes or addition of capricious ligands for
catalyst activation, the water-producing, exothermic, metal-catalyzed
aerobic alcohol oxidation is thermodynamically more favorable and
the most effective and advantageous aldehyde generation protocol. This leads to a general and advantageous air-promoted metal-
catalyzed aerobic N-alkylation methodology that effectively uses many simpler, less expensive, more available, and ligand-free metal
catalysts that were inactive under typical anaerobic borrowing hydrogen conditions, avoiding the use of preformed metal complexes
and activating ligands and the exclusive requirement of inert atmosphere protection. This aerobic method is quite general in
substrate scope and tolerates various amides, amines, and alcohols, revealing its potentially broad utilities and interests in academy
and industry. In contrast to the commonly accepted borrowing hydrogen mechanism, based on a thorough mechanistic study and
supported by the related literature background, a new mechanism analogous to the relay race game that has never been proposed in
metal-catalyzed N-alkylation reactions is presented.
’
INTRODUCTION
dehydrative N-alkylation of amines with alcohols was discovered
10
1
ꢀ5
more than 100 years ago, the early methods were usually
performed under harsh conditions of high temperature and/or
The catalytic construction of carbonꢀnitrogen bonds
is a
topic of great interest since nitrogen functionalities occur in
numerous compounds of synthetic and pharmaceutical signifi-
cance as well as in important biologically active molecules. For-
9f
high pressure. After the pioneering work on the homogeneous
transition-metal-catalyzed reactions reported by Grigg and Wa-
6
11
8,9,11ꢀ16
mation of CꢀN bonds not only is of concern for chemical
tanabe in 1981, the field progressed.
Current transition-
1
ꢀ5
and pharmaceutical syntheses
but also is applicable to ex-
metal-catalyzed dehydrative N-alkylation methods (Scheme 1)
7
8
plorations of the role of prebiotic synthesis in the origins of life.
In comparison with other transition-metal-catalyzed methodol-
ogies, e.g., amination of organohalides (BuchwaldꢀHartwig
include direct amination reactions (path a) and borrowing hy-
9
,11ꢀ16
drogen or hydrogen autotransfer methodology (path b),
with the latter being one of the most significant ways for amine
1
1ꢀ5
amination), reductive amination of carbonyl compounds or
derivative synthesis.
Direct amination reactions proceed
2
3
reductive alkylation of amines, hydroamination, and hydroa-
through a nucleophilic substitution of the alcohol’s hydroxy
4
8
bꢀk
minomethylation of carbonꢀcarbon unsaturated compounds,
group by amines/amides 2 via Lewis acid
complex-catalyzed
or transition metal
dehydrative formation of a carbocation or
coordinated cationic allylic-metal complexes. In contrast, the
5
8lꢀp
etc., the N-alkylation of amines/amides 2 with alcohols 1 (eq 1),
with only water produced as the byproduct, may serve as a
8
,9
relatively green and environmentally benign alternative. The
use of alcohols as the alkylating agent is direct and simple as the
alcohols are readily available, highly stable, low in toxicity, easily
stored and handled, low in cost, and relatively high in atom efficiency.
9aꢀe
9f,g
borrowing hydrogen
/hydrogen autotransfer
methodol-
ogy is usually held to allow the reactions to proceed at lower
temperatures via a transition-metal-mediated dehydrogenative
alcohol activation to yield aldehydes 4 with generation of the
hydridometal species (MH or MH ) (path b, step i) that serves as
2
the reducing agent in subsequent reduction of intermediate
However, alcohols are inactive in nature and require demand-
ing procedures to activate the hydroxyl group. Although the
Received: April 28, 2011
Published: June 09, 2011
8,9
r 2011 American Chemical Society
5759
dx.doi.org/10.1021/jo200862p
|J. Org. Chem. 2011, 76, 5759–5773

The Journal of Organic Chemistry
ARTICLE
Scheme 1. Literature Protocols for N-Alkylation of Amines and Amides with Alcohols
Scheme 2. Literature and Potential Protocols for in Situ Alcohol Activation/Oxidation in Alcohol-Based Tandem Multistep
Reactions
a
imines 5 to afford product amines 3 (path b, step iii), thus
furnishing the borrowed hydrogen and regenerating the cycle.
The dehydrogenative activation of alcohols to aldehydes and
the generation of the hydridometal species (Scheme 1, path b,
step i) in the borrowing hydrogen reactions are thermodynami-
Table 1. Condition Screening and Optimization
9c
cally unfavorable processes, and thus, noble metal complexes
derived from ruthenium and iridium or addition of capricious
9,11ꢀ13
ligands for catalyst activation are usually required.
There-
b
run
x, y, z
atm, T, t
3aa % yield
fore, developing more economical and efficient methods that can
be carried out under greener and milder conditions is highly
desirable. Only recently, a few less expensive metals have been
c,d
f
1
6, 5, 100
N
2
, 100ꢀ120 °C, 8 h
, 120 °C, 24 h
ND
c
g
2
6, 5, 100
N
2
(67)
14,15
found suitable for some substrates.
To our knowledge, never
c
h
3
6, 5, 100
air, 120 °C, 4 h
air, 135 °C, 24 h
air, 135 °C, 36 h
99 (96)
a different methodology or a new mechanism that is greener and
e
17,18
4
1.33, 0.5, 10
1.1, 0.5, 10
90 (83)
95
more efficient has been discovered and proposed up to date.
The metal-mediated dehydrogenation of alcohols to alde-
e
5
a
9a,b
Abbreviations used in the table: x, equivalents of added 1a to 2a; y,
percent catalyst loading based on 2a; z, percent base loading based on
2a; atm, air or N atmosphere; T, reaction temperature; t, reaction time.
Reactions monitored by TLC and/or GCꢀMS. GC yields (isolated
yields in parentheses) based on 2a. 3aa/5aa ratios measured from GC
are usually >99/1. Undegassed commercial 1a (containing trace amount
of benzaldehyde 4a as confirmed by GC) was used unless
otherwise noted. 1a (x mmol, x equiv) and 2a (1 mmol) in a 50 mL
Schlenk tube. Absolute 1a (dried over CaH
stored under nitrogen in a Schlenk flask, without any contaminants as
proved by GC analysis) was used. 1a (3x mmol, x equiv) and 2a (3
hydes is by nature an alcohol oxidation reaction. The oxida-
tion of alcohols for aldehyde and ketone syntheses has been the
19,20
2
focus of numerous reviews and reports,
and since metal-
b
catalyzed versions of the reaction are recognized as one of the
2
0
greenest processes, we therefore considered an alcohol-based
tandem multistep reaction sequence (Scheme 2), as an alter-
9
,11ꢀ16
c
native to the borrowing hydrogen strategy
and the accep-
9
b,21,22
d
torless processes.
should utilize other oxidants
can convert the alcohol to the aldehyde. However, despite the
We envisioned that this new protocol
2
, degassed, distilled, and
19,20
23ꢀ25
or hydrogen acceptors
that
e
f
1
9,20
mmol) in a 20 mL Schlenk tube. Monitored by TLC (ND, not
detected). Undegassed commercial 1a was directly added. 92% GC
yield in 2 h.
above-mentioned literature background
ods found in CꢀC bond constructions,
functionalization reactions (the cross-dehydrogenative couplings),
and the parallel meth-
g
h
2
4,25
amine activation-
26
27
and aerobic imine preparations from alcohols and amines, they
9
,11ꢀ16
17
have not been accepted in the field yet.
Although a few
remains to be fully clarified and recognized. Only recently, we
18
N-alkylation reactions have been carried out under aerobic condi-
and Crabtree became aware of air’s crucial influence on aerobic
CꢀN and CꢀC bond-forming reactions and utilized it with
purpose.
15
tions and found more efficient than the anaerobic reactions, the
role air played in the reactions and how it promoted the reactions
5
760
dx.doi.org/10.1021/jo200862p |J. Org. Chem. 2011, 76, 5759–5773

The Journal of Organic Chemistry
ARTICLE
Table 2. Scope of Metal Catalysts in the Air-Promoted Metal-Catalyzed Aerobic N-Alkylation Reactions
a
run
M
x, y, z
ligand (mol %)
atm, T, t
3aa % yield
b
1
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
RhCl
3
3H
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
6, 5, 100
air, 120 °C, 8 h
83
3
3
3
3
3
3
3
3
3
b
d
2
3
3
3
3
3
3
3
3
3H
3H
3H
3H
3H
3H
3H
3H
6, 5, 100
N
2
, 120 °C, 8 h
air, 120 °C, 8 h
, 120 °C, 8 h
air, 120 °C, 8 h
, 120 °C, 8 h
ND
b
3
6, 5, 100
PPh
3
3
(15)
(15)
99
81
83
b
4
6, 5, 100
PPh
N
2
b
5
6, 5, 100
Ph
3
3
P(O) (15)
P(O) (15)
b
d
6
6, 5, 100
Ph
N
2
trace
b
7
4, 5, 100
air, 120 °C, 8 h
air, 135 °C, 24 h
89
c
8
1.33, 0.5, 10
1.33, 0.5, 10
4, 5, 100
90
c
9
N
2
, 135 °C, 24 h
trace
99
b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Rh
Rh
Rh
Rh
Rh
Rh
2
2
2
2
2
2
O
3
air, 120 °C, 8 h
air, 135 °C, 36 h
c
c
b
c
c
c
c
c
c
c
c
c
c
c
c
c
c
O
O
3
3
1.33, 0.5, 10
1.33, 0.5, 10
4, 5, 100
80
N
2
, 135 °C, 36 h
67
(OAc)
4
4
4
air, 120 °C, 8 h
air, 135 °C, 24 h
84
(OAc)
(OAc)
1.33, 0.5, 10
1.33, 0.5, 10
1.3, 1, 20
92
N
2
, 135 °C, 24 h
trace
69
RuCl
RuCl
RuCl
3
3
3
nH
2
2
2
O
O
O
air, 135 °C, 8 h
3
3
3
nH
nH
1.3, 1, 20
N
N
2
, 135 °C, 8 h
, 135 °C, 8 h
trace
94
1.3, 1, 20
PPh
3
(5)
(5)
2
RuO
2
1.33, 0.5, 10
1.33, 0.5, 10
1.5, 1, 20
air, 135 °C, 36 h
, 135 °C, 36 h
air, 135 °C, 24 h
99
RuO
2
N
2
61
IrCl
IrCl
IrCl
IrCl
IrCl
3
95
3
3
3
3
1.5, 1, 20
N
N
2
, 135 °C, 24 h
, 135 °C, 24 h
trace
95
1.5, 1, 20
PPh
3
2
1.5, 1, 10
air, 135 °C, 29 h
air, 135 °C, 24 h
air, 135 °C, 36 h
93
1.5, 0.5, 20
1.33, 0.5, 10
1.33, 0.5, 10
83
IrO
2
90
IrO
2
N
2
, 135 °C, 36 h
55
a
b
c
Reactions monitored by TLC and/or GCꢀMS. GC yields based on 2a. 1a (x mmol, x equiv) and 2a (1 mmol) in a 50 mL Schlenk tube. 1a (3x mmol,
d
x equiv) and 2a (3 mmol) in a 20 mL Schlenk tube. Not detected (ND) or trace as monitored by TLC.
9
,11ꢀ13
Herein we report in detail our findings in the area by provid-
ing a mild, efficient, and potentially useful air-promoted metal-
ruthenium and iridium
have been used as metal catalysts in
N-alkylation reactions, catalysis by rhodium was almost comple-
tely unknown. Only a few Rh catalysts have been briefly men-
tioned by Grigg and Tanaka. Thus, we started our study by
investigating the reactions of sulfonamides and alcohols using the
famous Wilkinson’s catalyst RhCl(PPh ) (Table 1).
17
catalyzed aerobic N-alkylation methodology, which is rather
general in catalyst and substrate scope that uses many simpler,
cheaper, more available, and ligand-free metal catalysts, and a
wide range of amines, amides and alcohols behave more effec-
tively in activities and reactivities than those under the conven-
tional anaerobic conditions. Moreover, based on a thorough mecha-
nistic study and also supported by a broad background of
literature, an unprecedented mechanism in the metal-catalyzed
N-alkylation reactions is presented for the first time for the
aerobic N-alkylation reactions.
11a
29
1
7
3
3
Initially, no target product was detected when the mixture of
benzenesulfonamide 2a and benzyl alcohol 1a was heated
(
100ꢀ120 °C) under nitrogen in the presence of RhCl(PPh )
3
3
and K CO (Table 1, run 1). Subsequent attempts under a series
2
3
of anaerobic conditions even using solvents to promote the
reaction failed. Instead, surprisingly, when undegassed commer-
cial 1a was accidentally added, the reaction dramatically afforded
7% isolated yield of the target N-benzylbenzenesulfonamide
aa in high selectivity (run 2). Another reaction using commer-
cial substrates without any treatments was directly heated under
air, affording almost quantitative yield of the product in only 4 h
run 3). Beside the observed crucial role of air, catalyst RhCl-
(PPh and base were also found indispensable for the reaction.
’
RESULTS AND DISCUSSION
6
3
Discovery and Condition Screening of a Rhodium-Cata-
lyzed Aerobic N-Alkylation Reaction of Sulfonamides with
Alcohols. Our interests in pharmaceutically significant sulfon-
2
8
(
amide derivatives led us to undertake a study of metal-catalyzed
N-alkylation reactions of simple sulfonamides using alcohols.
)
3 3
9
30
Alcohols are good candidates as the alkylating agents because
Without catalyst, no product could be detected. Without base,
they are abundant, inexpensive, and varied in structure and
because they are good reagents for green chemistry. Although
the byproduct (also an intermediate) imine N-benzylideneben-
27,30,31
zenesulfonamide 5aa was observed.
The best results were
5
761
dx.doi.org/10.1021/jo200862p |J. Org. Chem. 2011, 76, 5759–5773

The Journal of Organic Chemistry
ARTICLE
Table 3. Air-Promoted Metal-Catalyzed Aerobic N-Alkylation Reactions of Amides and Amines with Alcohols
a
run
1
2
M
x, y, z
atm, T, t
3 % yield
b
1
PhCH
2
OH (1a)
PhSO
2a
2
NH
2
(2a)
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
3
3
3
3
3
)
)
)
)
)
3
3
3
3
3
1.33, 0.5, 10
2, 0.5, 10
2, 0.5, 10
2, 0.5, 10
2, 0.5, 10
3, 5, 50
air, 135 °C, 24 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 150 °C, 24 h
3aa: 90 (83)
3ba: 99
b
b
b
b
b
b
b
b
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
p-ClC
6
H
4
CH
CH
CH
CH
2
OH (1b)
OH (1c)
OH (1d)
OH (1e)
m-ClC
6
H
4
2
2a
3ca: 99
p-CH
3
OC
6
H
4
2
2a
3da: 92 (78)
3ea: 89
o-CH
3
OC
6
H
4
2
2a
Ph(CH
2
2
)
2
OH (1f)
2a
IrCl
IrCl
IrCl
IrCl
3
3
3
3
3fa: 99 (78)
3fa: 69
1f
2a
3, 5, 50
N
2
, 150 °C, 24 h
air, 150 °C, 24 h
, 150 °C, 24 h
Ph(CH
1g
)
3
OH (1g)
2a
2, 5, 50
3ga: 74
2a
2, 5, 50
N
2
3ga: trace
3ab: 99 (86)
3ac: 98 (86)
3ad: 99 (83)
3ae: 74
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
c
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
1a
p-CH
3
C
6
H
4
2
SO NH
2
(2b)
(2c)
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
3
3
3
3
3
3
3
3
3
3
3
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
1.33, 0.5, 10
1.33, 0.5, 10
1.33, 0.5, 10
1.33, 0.5, 10
1.33, 0.5, 10
1.33, 0.5, 10
1.33, 0.5, 10
1.33, 0.5, 10
1.5, 0.5, 10
1.5, 0.5, 10
1.5, 0.5, 10
1.5, 0.5, 10
3, 2, 20
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
1a
o-CH
3
6
C H
4
SO
2
NH
2
1a
p-ClC
6
H
4
SO
SO
OC
2-naphthalene-sulfonamide (2g)
2
NH
2
(2d)
1a
o-ClC
6
H
4
2
NH
SO
2
(2e)
1a
p-CH
3
6
H
4
2
NH
2
(2f)
3af: 98
1a
3ag: 80
1a
CH
2h
2b
2b
2b
2b
2b
2b
2f
3
SO
2
NH
2
(2h)
3ah: 99 (65)
3ah: 52
1a
2
N , 135 °C, 36 h
1b
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 24 h
N , 135 °C, 24 h
2
air, 135 °C, 36 h
air, 180 °C, 4 h
3bb: 99
3cb: 99
1c
1d
3db: 95
3eb: 75
1e
2-thiophenemethanol (1h)
RhCl
3
3
3H
3H
2
O
3hb: 78
3hb: 50
3bf: 99
3
3
1h
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1d
1a
1a
1a
1a
1a
1a
RhCl
2
O
3, 2, 20
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
3
3
3
3
)
3
3
3
3
1.5, 0.5, 10
6, 5, 100
PhCONH
2
(2i)
)
)
)
3ai: 90
c
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
6, 5, 100
N
2
, 180 °C, 4 h
3ai: 43
b
c
2, 1, 20
air, 180 °C, 36 h
air, 120 °C, 48 h
3ai: 64
RuCl
RuCl
RuCl
RuCl
RuCl
RuCl
RuCl
RuCl
2
2
2
2
2
3
3
3
(PPh
3
3
3
3
3
)
)
)
)
)
3
3
3
3
3
6, 5, 100
3ai: 76
c
(PPh
(PPh
(PPh
(PPh
6, 5, 100
N
2
, 120 °C, 24 h
3ai: trace
3ai: 74
c
6, 5, 100
air, 150 °C, 16 h
c
6, 5, 100
N
2
2
, 150 °C, 16 h
, 180 °C, 4 h
3ai: trace
3ai: 73
c
6, 5, 100
N
b
b
b
c
1.5, 1, 20
1.5, 0.5, 10
1.5, 1, 20
6, 5, 100
air, 150 °C, 24 h
air, 150 °C, 24 h
air, 150 °C, 24 h
air, 135 °C, 20 h
air, 150 °C, 12 h
air, 135 °C, 32 h
air, 150 °C, 20 h
air, 135 °C, 28 h
air, 150 °C, 12 h
air, 150 °C, 36 h
air, 150 °C, 12 h
air, 150 °C, 12 h
air, 150 °C, 12 h
air, 180 °C, 12 h
air, 150 °C, 20 h
3ai: 66
3ai: 66
3ai: 65
IrCl
IrCl
IrCl
IrCl
IrCl
IrCl
IrCl
IrCl
IrCl
IrCl
IrCl
3
3
3
3
3
3
3
3
3
3
3
3ai: 86
c
6, 5, 100
3ai: 99
b
b
b
b
b
b
b
b
b
b
b
c
1.5, 1.5, 20
1.5, 1.5, 20
1.5, 1.5, 10
1.5, 1.5, 10
1.5, 1, 10
3, 5, 100
3ai: 74 (53)
3ai: 82
3ai: 72
3ai: 74
3ai: 89
3bi: 81 (75)
3di: (69)
3aj: 58
3, 5, 100
p-CH
3
OC
6
H
4
CONH
2
(2j)
3, 5, 100
nicotinamide (2k)
3, 5, 100
3ak: 74
2-aminopyrimidine (2l)
RhCl(PPh
RhCl(PPh
RhCl(PPh
RhCl(PPh
3
3
3
3
)
3
)
3
)
3
)
3
1.3, 0.5, 20
1.3, 1, 20
6, 5, 100
3al: 80
2l
N
2
, 150 °C, 24 h
3al: 67
2-aminopyridine (2m)
air, 120 °C, 12 h
air, 135 °C, 36 h
3am: (67)
3am: 85
b
2m
1.5, 1, 20
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The Journal of Organic Chemistry
ARTICLE
Table 3. Continued
run
a
1
2
M
x, y, z
atm, T, t
3 % yield
b
5
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1a
1a
1a
1b
1d
1a
1a
1a
1a
1a
1a
1a
1a
1a
2m
2m
2m
2m
2m
RhCl(PPh
3
)
3
1.3, 0.5, 20
1.3, 0.5, 20
1.3, 0.5, 20
1.5, 1, 40
1.5, 1, 40
1.5, 1, 40
1.5, 1, 40
1.5, 1, 40
1.5, 1, 40
1.5, 1, 40
1.5, 5, 40
1.5, 5, 40
1.5, 5, 40
1.5, 5, 40
air, 135 °C, 24 h
air, 135 °C, 24 h
N , 135 °C, 24 h
2
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 36 h
air, 135 °C, 12 h
3am: 70
3am: 82
3am: 75
3bm: 82 (90)
3bm: 89 (55)
3an: 90
b
5
5
5
5
5
5
5
5
6
6
6
6
6
RhCl
RhCl
RhCl
RhCl
RhCl
3
3
3
3
3
3H
3H
3H
3H
3H
2
2
2
2
2
O
3
3
3
3
3
b
O
O
O
O
b
b
b
2-amino-5-chloropyridine (2n)
b,d
b,d
b,d
b,d
b,e
b,e
b,e
b,e
3-aminopyridine (2o)
RhCl(PPh
3
3
)
3
3ao: 92
2o
2o
2o
RhCl(PPh
)
3
N
2
, 135 °C, 36 h
air, 135 °C, 12 h
, 135 °C, 36 h
air, 150 °C, 24 h
, 150 °C, 24 h
3ao: 92
RhCl
3
3
3H
3H
2
O
3ao: 99 (79)
3ao: 99
3
3
RhCl
2
O
N
2
PhNH
2
(2p)
NH
IrCl
IrCl
IrCl
IrCl
3
3
3
3
3ap: 99
2p
N
2
3ap: 99
p-EtOC
6
H
4
2
(2q)
air, 150 °C, 24 h
air, 150 °C, 24 h
3aq: 99
2q
3aq: 98
a
Reactions monitored by TLC and/or GCꢀMS. GC yields (isolated yields in parentheses) based on 2. Unless otherwise noted, K
2 3
CO was used as
d
b
c
the base. 1 (3x mmol, x equiv) and 2 (3 mmol) in a 20 mL Schlenk tube. 1 (x mmol, x equiv) and 2 (1 mmol) in a 50 mL Schlenk tube. NaOH was
used as the base. CsOH was used as the base.
e
Scheme 3. Possible One-Pot and Multistep Tandem Processes for N-Alkylation of Amides/Amines with Alcohols
obtained when the reaction was carried out under solvent-
During the catalyst screening studies, the usually ineffective
30
free conditions. K CO was determined to be the best base.
anaerobic reactions of RhCl , RuCl , and IrCl (Table 2, runs 2,
2
3
3
3
3
Reactions at a lower temperature or with lesser amounts of sub-
17, and 22) gave high yields of the product if a phosphine ligand
30
strate and catalyst loadings were still effective, but under
these conditions, a higher temperature (such as 135 °C) gave much
better results. Thus, alcohol loading could be reduced to only
such as PPh was added (runs 4, 18, and 23). These ligand-
3
promoted reactions are hallmarks of the borrowing hydro-
gen reactions, in which external ligands are employed for
catalyst activation to achieve effective reactions with simple
1
.1ꢀ1.33 equiv, RhCl(PPh ) to 0.5 mol %, and K CO to 10 mol %
3
3
2
3
9
,11ꢀ13
(runs 4 and 5). It is worth noting that, in our hands, the volume of the
catalysts.
Possibly, the ligands first activate the metal
reaction vessel related to the amount of air was also found to have an
catalysts, and then the in situ generated metal complexes
30
9
effect, with 20 mL tubes being the optimum size.
activate the alcohol and thus promote the whole reaction.
Scope of Metal Catalysts and Substrates in the Air-Pro-
moted Metal-Catalyzed Aerobic N-Alkylation Reactions.
Since almost all metal-catalyzed N-alkyalktion reactions were
Notably, the yields of these ligand-assisted reactions are com-
parable with those carried out under air (runs 1, 16, and 21).
These results indicate that catalyst activation by adding ligands
can be avoided by simply carrying out the reactions under air. In
other words, by simply conducting the reactions under air,
many less reactive, cheaper, more available, and ligand-free
metal catalysts can be used instead of the preformed metal
complexes or the activation of catalysts by the addition of
capricious ligands, most probably because alcohol activation to
aldehyde could be achieved more easily under air as we deduced
(Scheme 2) and proved (vide infra). In contrast, the corre-
9,11ꢀ16
previously carried under an inert atmosphere,
the above
surprising observation that the Rh-catalyzed reaction did not take
place under nitrogen but could proceed in a dramatically efficient
way under air prompted us to examine the mechanism (vide
infra) and the catalyst and substrate scopes (Tables 2 and 3) of
the reaction.
We identified several simpler, less expensive, more available,
and ligand-free metal catalysts derived from Rh, Ru, and Ir that
were inactive under borrowing hydrogen conditions, but that
were found to be very active catalysts under aerobic conditions,
giving the product in yields comparable to RhCl(PPh ) and with
sponding phosphine oxide Ph P(O) showed no activating
3
capacity at all (runs 1 and 2 vs runs 5 and 6).
In reactions catalyzed by metal oxides such as Rh
O , RuO ,
2 3 2
3
3
high selectivities (Table 2, runs 1, 7, 8, 13, 14, 16, 21, 24, and 25).
In contrast, the corresponding parallel anaerobic reactions were
ineffective, affording no or only trace amounts of product (runs 2,
and IrO , although the anaerobic reactions (Table 2, runs 12, 20,
2
and 27) were somewhat less effective than the corresponding
aerobic ones (runs 11, 19, and 26), they were still more efficient
than reactions conducted with other catalysts (runs 2, 9, 15, 17,
9
, 15, 17, and 22).
5
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The Journal of Organic Chemistry
ARTICLE
Table 4. Metal-Catalyzed Aerobic Alcohol Oxidation
Scheme 4. Alcohol and Aldehyde Decarbonylation in the
Absence of Sulfonamides
a
run
M
y, z
additive (mol %)
T, t
yield %
b
1
RhCl(PPh
RhCl(PPh
RhCl(PPh
3
3
3
)
)
)
3
3
3
2.5, 50
2.5, -
120 °C, 2 h
120 °C, 2 h
rt, 24 h
29
b
2
22
c
3
2.5, 17
3.91
3.93
0
4
8 h
rt, 24 h
8 h
rt, 24 h
8 h
rt, 24 h
8 h
c
4
RhCl(PPh
3
)
3
2.5, 17
2.5, 17
2.5, 17
2a (17)
2a (17)
4
0
d
5
RuCl
3
3
15.0
23.1
1.40
1.96
4
d
6
RuCl
borrowing hydrogen pathway. Similarly, ligand-free catalysts
IrCl and RuCl could also catalyze the reactions of carboxamides
4
3
3
a
2
iꢀk under aerobic conditions, giving moderate to high yields of
Absolute 1a (100% purity as confirmed by GC) was used. Reactions
b
monitored by GCꢀMS. GC yields based on 1a. 2a (2 mmol) was
the products (runs 33ꢀ46).
heated in a sealed 50 mL Schlenk tube. Yields are combined yields of 4a
This aerobic method is also suitable for aromatic and hetero-
aromatic amines (Table 3, runs 47ꢀ64). With 2-aminopyrimi-
dine 2l and aminopyridines 2mꢀo (runs 47ꢀ60), the aerobic
reactions (runs 47, 52, 57, and 59) were generally more efficient
than the corresponding anaerobic ones (runs 48, 53, 58, and 60)
with respect to catalyst loadings, yields, and reaction times, but
the differences between the two conditions were less prono-
unced. Indeed, with anilines 2pꢀq, the aerobic and anaerobic
reactions were indistinguishable (runs 61ꢀ64). Thus, the reac-
tions can be readily performed under aerobic conditions, greatly
simplifying the operations.
and other oxidation products such as PhCO
(
tube open to air. 1a (6 mmol) was stirred in a Schlenk tube open to air.
2
CH
2
Ph and PhCH-
c
OH)OCH Ph. 1a (2 mmol) and additives were stirred in a Schlenk
2
d
and 22). Possibly, these metal oxides are also good catalysts/
oxidants for alcohol oxidation as documented in the literature.
This idea is also consistent with our deductions (Scheme 2) and
findings that external oxidants can facilitate the reaction by
19,20
32
oxidizing the alcohol to the aldehyde (Table 7).
All of these results showed that these aerobic reactions are
milder, more convenient, and more efficient than many recently
Individual Reactions of the Metal-Catalyzed Aerobic
N-Alkylation Sequence. Our dramatically opposite results ob-
tained in the aerobic and anaerobic reactions (Tables 1ꢀ3)
clearly revealed the crucial role that air (oxygen) played in the
12ꢀ16
reported N-alkylaltion reactions of sulfonamides,
for exam-
ple, lower in alcohol loading, lower in reaction temperature, higher
in reaction efficiency, and avoids inert atmosphere protection
and the use of activating ligands and solvents, revealing the
advantages of employing the aerobic protocol.
We then applied the new metal-catalyzed aerobic N-alkylation
protocol to reactions of various sulfonamides, carboxamides, and
aromatic and heteroaromatic amines with a series of benzylic,
heterobenzylic, and aliphatic alcohols (Table 3). High selectiv-
ities (>99/1) of the products were usually obtained. For benzylic
alcohols and sulfonamides (Table 3, runs 1ꢀ5, 10ꢀ24), Rh-
catalyzed aerobic reactions under the optimized condition gave
generally high yields of the products. As in previous observations,
anaerobic reactions conducted with either methanesulfonamide
8
reactions. Since the literature also revealed that the transition-
metal-catalyzed N-alkylation reactions may not always follow the
borrowing hydrogen mechanism, and the typical borrowing
hydrogen reaction is conducted under an inert atmosphere with
9,11ꢀ16
the generation of the active hydridometal species,
which
are known prone to react with and deactivated by molecular
oxygen, our experiments suggested that these aerobic N-alkyla-
tion reactions may not proceed via the borrowing hydrogen
sequence (Scheme 3, path 1) but another path involving air
(oxygen) participating in one of its individual reactions such as
the aldehyde generation step (path 2), which could therefore be
easily inhibited by the absence of air (oxygen). Although air may
also activate the Wilkinson’s catalyst, which is still unclear at
present and may not be the case with most of the other catalysts,
it is more possible for air to oxidize the alcohol to aldehyde via the
2
h or 2-thiophenemethanol 1h gave much lower product yields
runs 17 and 23) than the aerobic ones (runs 16 and 22). With
aliphatic alcohols 1fꢀg, IrCl was found to be a better catalyst
(
3
(runs 6 and 8), and their corresponding anaerobic reactions were
20
9b
also less effective (runs 7 and 9).
metal-catalyzed way. As having been pointed out, the mecha-
nism of a reaction may also depend on the substrates, catalysts,
and/or the conditions employed, the challenge therefore is to define
catalysts and conditions that lead to the same transformations under
In contrast with the sulfonamides, the Rh-catalyzed reactions
with carboxamides such as benzamide 2i were less efficient and
required higher temperatures (Table 3, runs 25ꢀ27). Again, the
aerobic reaction (run 25) was more efficient than the anaerobic
one (run 26). In reactions with 2i, RuCl (PPh ) was found to be
9b
milder conditions. Regarding the related literature as mentioned
9b,15,17ꢀ20,24ꢀ27
above,
we decided to investigate the mechanistic
2
3 3
a more active catalyst (runs 28ꢀ32). When the typical borrowing
aspects of the aerobic reactions in an unprecedented manner to
get deeper insights into the aerobic reactions.
9
,12
hydrogen catalyst
RuCl (PPh ) was used, the ineffective
2 3 3
9f,33
anaerobic reactions
conducted at lower temperatures (runs
Several observations permitted us to exclude the possibility
that the reaction undergoes a Lewis acid- catalyzed direct
2
9 and 31) were promoted greatly by conducting them under
8
air (runs 28 and 30). These results indicated that, under the
aerobic conditions, these Ru-catalyzed N-alkylation reactions of
benzamide 2i may also follow a new mechanism other than the
amination process: (1) Instead of detecting an ether that is
8
,34
usually generated under Lewis acid catalyzed conditions, we
always observed small amounts of byproducts, aldehyde 4a and
5
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The Journal of Organic Chemistry
ARTICLE
Scheme 5. Alcohol and Aldehyde Decarbonylation in the Presence of Sulfonamides
Table 5. Metal-Promoted Condensation of Sulfonamide and
Aldehyde
Table 6. Rh-Catalyzed Transfer Hydrogenation of Inter-
mediate Imine to Product Amide by Alcohol
a
a
f
run
x, y, z
atm, T, t
3aa% yield
4a % yield
4a/3aa
a
run
M
x, y, z
6, 0, 0
atm, T, t
yield %
b
1
6, 5, 100
N
2
, 100 °C, 2 h
82
83
98
87
14
13
36
31
b
1
N
N
2
, 120 °C, 8 h
, 120 °C, 8 h
65
97
96
84
99
68
67
b
2
6, 5, 100 air, 100 °C, 4 h
1.3, 1, 10 , 120 °C, 4 h
1.3, 1, 10 air, 120 °C, 4 h
b
2
RhCl(PPh
3
)
3
3
6, 5, 0
2
c
3
N
2
b
3
RhCl(PPh
3
)
6, 5, 0
air, 120 °C, 8 h
, 120 °C, 8 h
air, 120 °C, 8 h
, 100 °C, 2 h
air, 100 °C, 2 h
c
4
b
4
6, 0, 100
6, 0, 100
1.33, 1, 0
1.33, 1, 20
N
2
c,d
e
e
5
1.3, 1, 20
N
2
, 100 °C, 2 h
45 (49)
23 (55)
1.12/1
b
5
e
e
4
h
76 (86)
28 (78)
0.91/1
c
6
RhCl(PPh
3
)
3
3
N
2
a
b
Reactions monitored by GCꢀMS. GC yields based on 5aa. 5aa
c
7
RhCl(PPh
3
)
c
(
1 mmol) and 1a (6 mmol, 6 equiv) in a 50 mL Schlenk tube. 1a
a
b
GC yields based on 2a. 2a (1 mmol) and 4a (6 mmol, 6 equiv) in a
0 mL Schlenk tube. 2a (3 mmol) and 4a (4 mmol, 1.33 equiv) in a
0 mL Schlenk tube.
(
3x mmol, x equiv) and 5aa (3 mmol) in a 20 mL Schlenk tube.
Catalyst RhCl(CO)(PPh
calculated based on proton integrations of the H NMR spectra. 4a/3aa
ratios based on H NMR spectroscopic analysis.
c
5
2
d
e
3
)
2
(III) was used. Yields in parentheses was
1
f
1
2
7,31
imine 5aa,
which may be the intermediates of the reaction
(
Scheme3). (2) Ester andhemiacetalbyproductsthatwere possibly
generated due to aerobic oxidation of alcohol 1a to aldehyde 4a
were also detected in minor amounts in many cases. (3) In
reactions with reduced alcohol loadings, relatively lower ratios of
aa/5aa were detected at the beginning of the reaction that
were gradually enhanced as the reaction progressed. (4) Simi-
larly, large amounts of 5aa instead of 3aa were detected under
aerobic base-free conditions.
reaction most probably proceeds via path 2 of Scheme 3 invol-
ving aldehydes 4 and imines 5 as the intermediates, which may
also be generated prior to product amine 3. In an effort to clarify
the mechanism for the present aerobic N-alkylation reactions, we
investigated the details of the corresponding individual reactions
as shown in Scheme 3, path 2.
The first step of the reaction, the metal-catalyzed aerobic
alcohol oxidations, has been well-studied.
catalyzed aerobic oxidation of alcohols to intermediate alde-
hydes could possibly be another means to activate the alcohol
temperature stirring of pure alcohol 1a in open air with RhCl-
2
0
(PPh
was totally inhibited by the addition of sulfonamide 2a (run 4).
Also worth noting is that the efficient RuCl -catalyzed oxidation
(run 5) was also greatly inhibited by 2a (run 6). These results
can only be explained by deactivation of the metal catalysts by the
sulfonamides and that this deactivation can be a general phe-
nomenon for various metal catalysts.
deactivation has seldom been taken into account in the past,
our NMR spectroscopic analyses support its occurrence.
As shown in Scheme 4, in the absence of sulfonamides 2, the
reactions of p-chlorobenzyl alcohol (1b)
zaldehyde (4b)
carbonylated Rh complex III via intermediates I and II under
several aerobic or anaerobic conditions (Scheme 4). The catalytic
activity of III was also found to be similar (eq 2) with that of
) gave a detectable amount of aldehyde 4a (run 3), which
3 3
3
35
20
30
3
27,30
38,39
These results indicated that the
Although this catalyst
9,12,13
9
b,40,41
or p-chloroben-
with RhCl(PPh ) easily afforded the final
3 3
43
9
b,41,42
19,20
Indeed, the metal-
RhCl(PPh ) , showing that alcohol decarbonylation and the
3 3
3
3
6
7
presence of a CO ligand on Rh do not affect Rh’s catalytic
activity. Furthermore, the corresponding anaerobic reactions
were ineffective, giving only trace amounts of product (eq 2).
(
Schemes 2 and 3) in present aerobic N-alkylation reactions.
This activation/oxidation is also supported by our own experi-
mental results as shown in Table 4.
When Rh-catalyzed aerobic alcohol oxidation reactions were
heated at 120 °C in the absence of sulfonamide 2a, considerable
amounts of benzaldehyde 4a and oxidation byproducts were
afforded in either the presence or the absence of base (Table 4,
runs 1 and 2), confirming the occurrence of the Rh-catalyzed
3
7
aerobic alcohol oxidation step and also showing that base is not
However, a completely different outcome occurred upon
addition of sulfonamide 2 (Scheme 5). Although decarbonyla-
tion and formation of III from the mixture of RhCl(PPh ) and
essential in the oxidation. Other metal catalysts behaved simi-
larly, generating 4a in considerable amounts. Moreover, room
30
3
3
5
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The Journal of Organic Chemistry
ARTICLE
Table 7. Rh-Catalyzed N-Alkylation of Sulfonamide in the Presence of Initiators
a
run
x, y, z
additive
T, t
3aa % yield
b
1
6, 5, 100
air (6 mL, O
2
: 2.5% v/v, 5.6 mol %)
120 °C, 24 h
64
99
88
84
79
88
80
81
98
99
63
81
48 h
b
2
6, 5, 100
6, 5, 100
1.1, 1, 20
6, 5, 100
1.3, 1, 10
1.3, 1, 30
2, 1, 50
air (20 mL, O
2
: 8.4% v/v, 18.8 mol %)
120 °C, 13 h
120 °C, 12 h
135 °C, 24 h
120 °C, 16 h
135 °C, 18 h
135 °C, 24 h
135 °C, 24 h
135 °C, 24 h
135 °C, 36 h
135 °C, 36 h
b
3
4a (5 mol %)
c
4
4a (10 mol %)
PhCHdNSO
b
5
2
Ph 5aa (10 mol %)
c
6
5aa (10 mol %)
c
7
PhI(OAc)
2
2
(10 mol %)
(20 mol %)
c
8
PhI(OAc)
c
9
1.3, 1, 20
1.5, 0.5, 10
1.5, 0.5, 10
TEMPO (20 mol %)
CH dCHCOOEt (20 mol %)
PhCHdCH (20 mol %)
c
1
0
1
2
c
1
2
a
b
Reactions monitored by TLC and/or GCꢀMS. GC yields (isolated yields in parentheses) based on 2a. 2a (1 mmol) and 1a (x mmol, x equiv) in a
c
5
0 mL Schlenk tube. 1a (3x mmol, x equiv) and 2a (3 mmol) in a 20 mL Schlenk tube.
4
b in the presence of 2b were easily detected after heating the
180 °C gave only poor yields of the product. In comparison, the
same reactions under air were much faster, giving much higher
product yields.
reaction mixture under nitrogen (eq 5.1), the corresponding
reaction of alcohol 1b and RhCl(PPh ) did not take place, even
3
3
when heated to 120 °C (eq 5.2), revealing that under anaerobic
conditions, decarbonylation and III’s formation from alcohol and
RhCl(PPh ) can be greatly inhibited by 2, supporting the idea
Furthermore, condensation of 2 with 4 giving intermediate
imines 5, a standard organic reaction, was easily confirmed
46
3
3
(Table 5). According to the above analysis, aerobic alcohol
2
0,37
that the lone Rh catalyst is incapable of dehydrogenating the
alcohol under an inert atmosphere. In contrast, the same mixture
under air using solvent that had not been degassed gave III
smoothly at 70 °C (eq 5.3), showing that, even in the presence of
sulfonamide 2, alcohol dehydrogenation (oxidation) followed by
the inevitable decarbonylation can be facilitated by air (oxygen).
The observation in eq 5.2 is (1) consistent with previously observed
inhibition in aerobic alcohol oxidations (Table 4), (2) a great
contrast with easy decarbonylation of the alcohol in the absence
of sulfonamides (Scheme 4), and (3) a great contrast with easy
anaerobic aldehyde decarbonylation (eq 5.1) and aerobic alcohol
decarbonylation (eq 5.3) in the presence of 2. Besides, 2a and 2b
were very helpful in dissolving RhCl(PPh ) in d -THF, resulting
oxidation to aldehyde
and subsequent condensation with
2
7
2
should be responsible for the formation of intermediate 5.
However, it is not clear if metal catalysts promote this reaction.
9
b
The assumption implicit in the borrowing hydrogen concept that
metals do not affect this step may not hold because aldehyde
binding to an electrophilic metal fragment should greatly in-
crease the electrophilicity of the carbonyl carbon and thus
9b
enhance nucleophilic attack. This idea may be true, since metal
insertions into aldehydes are indeed very common with many
9b,41,42
metals.
The above NMR studies and the results of the
controlled condensations as summarized in Table 5 may also
support this point. Thus, without metal catalysts and base, 2a and
4a gave moderate yield of 5aa under the reaction condition
(Table 5, run 1), showing that neither catalyst nor base are
essential in this reaction. However, complete conversion of 2a
3
3
8
in total solvation of RhCl(PPh ) to give a transparent NMR
3
3
3
8,44,45
solution at room temperature.
Anaerobic dehydrogenative alcohol activation is known as a
did not occur, even after 8 h, supporting the condensation
9c
15a,b,46
thermodynamically unfavorable process. In contrast, the aero-
bic oxidation of alcohol resulting in the production of water is an
exothermic process that may serve as the driving force for the
reaction. Thus, the reaction is thermodynamically more favorable
because the energy required for aldehyde formation can be com-
pensated by this oxidation, and it can promote the reaction to
occur at a relatively lower temperature. Vice versa, the anaerobic
reactions should be able to occur at higher temperatures because
the energy required can be achieved by high-temperature heat-
ing. Thus, as we observed, the anaerobic reaction of 1a and 2a at
equilibrium.
Reactions in the presence of the Rh catalyst
and/or the base showed that each additive could facilitate the
3
0
reaction independently (runs 2ꢀ5) and cooperatively.
Furthermore, reactions at a lower temperature and/or with
reduced aldehyde and catalyst loadings were still efficient in a
30
very short time (runs 6 and 7).
We then investigated the transfer hydrogenation step of the
reaction (Scheme 3). Transition-metal-catalyzed transfer hydro-
genation reactions using alcohols as the reducing agent have been
9b,47,48
well-documented in the literature.
They serve as a good
1
80 °C is also very effective (eq 3), whereas the reactions below
alternative for conventional hydrogenations and have been
47,49
widely adopted in asymmetric synthesis.
In the present
reactions (Table 6), no reaction occurred without Rh catalyst
30
and base. With the lone Rh catalyst under air, no reaction
50
occurred at the reaction temperature, but with the hydrolysis of
imine 5aa and the oxidation of alcohol 1a to aldehyde 4a,
30
resulting in the detection of a large amount of 4a. Base was
5
766
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ARTICLE
5
1
then found crucial to promote the transfer hydrogenation as
Aldehydes are also good initiators. Under the original
conditions, a reaction with 5 mol % 4a could give 3aa in 84%
yield in 12 h (Table 7, run 3). With reduced 1a loading, the
reaction became slower (run 4) but was still a good contrast to
the ineffective anaerobic reactions (eq 3). Similarly, the reactions
in the presence of imine 5aa, which can regenerate 4a via transfer
hydrogenation, also afforded high yield of the product under
nitrogen (runs 5 and 6).
50d
B €a ckvall had pointed out. Thus, in the presence of RhCl-
PPh ) and K CO , reduction of 5aa by 1a proceeded efficiently
(
3
3
2
3
30
to give a high yield of 3aa with considerable 4a regenerated.
With a large excess of alcohol, the reaction is very fast even at a
lower temperature (runs 1 and 2). With reduced alcohol load-
ings, the reaction is still fast at 120 °C (runs 3 and 4). Catalyst III
also showed good activity in the reaction (run 5), in which the
1
amount of byproduct 4a was also measured by H NMR spec-
The well-known oxidants of alcohols, such as PhI(OAc)
(Table 7, runs 7 and 8) and TEMPO (run 9),
acceptors, such as the activated alkenes ethyl acrylate and styrene
2
19,20
troscopic analysis, showing that quantitative 4a could be
and hydrogen
3
0
regenerated. On the basis of the above Rh-catalyzed alcohol
activation/oxidation studies, this transfer hydrogenation reaction
most probably does not involve the demanding formation of
2
3ꢀ25
(runs 10 and 11),
can also initiate the reaction effectively in
the presence of the catalyst, giving much higher product yield
than the blank reaction (eq 3). Herein, easy formation of
aldehyde 4a from alcohol 1a via dehydrogenation by ethyl
acrylate was also confirmed, giving large amounts of 4a efficiently
at only 50 °C (eq 4).
RhH or RhH species, whereas according to the mechanistic studies
2
9b,47
of the transfer hydrogenation reactions,
it is also possible to
proceed via a six-membered cyclic MeerweinꢀPondorfꢀVerley-
type transition state.
Although bases are similarly required in borrowing hydrogen
9
,11ꢀ16
reactions,
it was still unclear which catalytic step requires
9
b
base. In contrast, results of above controlled individual reac-
tions clearly showed that, unlike the alcohol oxidation and con-
densation steps that can both take place under base-free condi-
tions, transfer hydrogenation is the only base-dependent step in
the present reactions. This is also exemplified by the formation of
Mechanism of the Air-Promoted Metal-Catalyzed Arobic
N-Alkylation Methodology. The above studies on the indivi-
dual reactions and alternative routes to aldehyde generation
confirmed our previous deductions that air, external oxidants,
and hydrogen acceptors are all potentially useful alcohol activa-
tion protocols (Scheme 2). In comparison, performing the
reactions under air is clearly the greenest and most advantageous
protocol regarding convenience, efficiency, economy, environ-
mental considerations, etc. The ability of various catalysts,
regardless of their valence states or the presence of ligands, to
catalyze the reactions of various substrates (Tables 2 and 3) also
indicates that the reactions possibly have no inherent correlation
30
imine 5aa under aerobic and base-free conditions.
Alternative Protocols for Alcohol Activation/Oxidation
and Potential Initiators for the Metal-Catalyzed Anaerobic
N-Alkylation Reactions. Our examinations of the individual
reactions revealed that path 2 of Scheme 3, involving the aerobic
oxidation of the alcohol, is the most probable route for the present
aerobic N-alkylation reactions. Although both condensation and
transfer hydrogenation reactions can be conducted under air,
they can also take place with great ease at lower temperatures
and/or under nitrogen, indicating that the rate-limiting step of
the reaction should be initiation of the aldehyde formation. Thus,
only the alcohol activation step should require air to facilitate the
reaction, which is consistent with above findings on catalyst
deactivation and alcohol oxidation studies (Table 4, Schemes 4
and 5). The quantitative regeneration of aldehyde 4 during the
transfer hydrogenation step is a further indication that if aldehyde
5
2
with the valence state of the metal or the presence of the ligands.
Thus, a new mechanistic route as presented in Scheme 6 was
proposed for the air-promoted metal-catalyzed aerobic N-alkyla-
tion reactions. Since all the individual reactions of this new
17
mechanism are in fact supported by related independent reac-
1
9,20,37
46
tions, i.e., alcohol oxidation (i),
transfer hydrogenation (iii),
condensation (ii), and
this mechanism is the most
probable and natural route for the aerobicN-alkylation reactions.
To our best knowledge, it should be a new mechanism in metal-
4
7ꢀ50
4
could be recycled to condense with amide/amine 2, then
5
3
generation of only catalytic amounts of 4 is sufficient for the
whole reaction. Thus, only catalytic amounts of air (oxygen)
should be necessary to produce the catalytic amounts of starting
catalyzed N-alkylation reactions that has never been proposed
17,18
5
1
before.
4
.
Otherwise, large amount of byproducts 4 or 5 may be
produced, even becoming the major products in the presence of
As shown in Scheme 6, due to a potentially general metal
catalyst deactivation by the strong ligating amines/amides that
has seldom been considered in the past and just disclosed in
present research, the efficiency of the lone catalyst to abstract
hydrogens from the alcohol to afford aldehyde and to provide a
hydridometal species is reduced greatly, making it the rate-
limiting step of the whole reaction. Therefore, air, oxidants, or
H-acceptors can facilitate the metal-catalyzed oxidative aldehyde
formation step (Scheme 6, step i) to occur at lower temperatures
1
5,20,27
a large excess of air (oxygen).
Similar to air, as we
19
deduced, catalytic amounts of external oxidants or hydrogen
2
3ꢀ25
acceptors
should initiate the reaction by converting the
alcohol to aldehyde under anaerobic conditions (Scheme 2).
Indeed, the above hypothesis is consistent with previous
findings and the following control reactions (Table 7).
For example, addition of ∼6.3 mol % O (21% v/v) to 3 mmol
2
substrates in a typical 20 mL Schlenk tube has been found crucial
for an efficient reaction (Table 1, run 4). Similarly, when 6 mL of
air was carefully introduced under nitrogen to a 50 mL Schlenk
tube containing degassed substrates (1 mmol), the reaction afforded
0
(such as 100ꢀ135 °C), during which a new catalyst [M ] may be
54
generated. These measures were found to be relatively more
effective for activating the alcohol than the anaerobic dehydro-
genation protocol, for in the latter cases, heating at a much higher
temperature or adding an activating ligand will be required to
6
4% and 99% 3aa in 24 and 48 h, respectively (Table 7, run 1).
Another reaction with 20 mL air proceeded much faster, giving
8% product yield in 13 h (run 2). In comparison, the reaction
9
,11ꢀ13
0
8
achieve an efficient reaction.
[M ] then catalyzes the con-
under the original conditions is the fastest (50 mL air; O : 21% v/
densation (step ii) and transfer hydrogenation (step iii) reactions
2
v; 47 mol %), giving 92% product in only 2 h (Table 1, run 3).
efficiently even at lower temperatures and the aldehyde will be
5
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The Journal of Organic Chemistry
ARTICLE
Scheme 6. Simplified Reaction Path for the Air-Promoted
Metal-Catalyzed Aerobic N-Alkylation Reaction of Amides/
Amines with Alcohols
and a wide range of amides, amines, and alcohols, avoiding inert
atmosphere protection and the use of expensive preformed
metal complexes, activating ligands, and solvents. Mechanistic
studies revealed that, contrary to the conventional borrowing
hydrogen or hydrogen autotransfer mechanism, a new mechan-
ism analogous to a relay race game that has never been
proposed in metal-catalyzed N-alkylation reactions should be
involved in the aerobic reactions. In light of the related
53,54
9b,18ꢀ20,24ꢀ27,37ꢀ39,45,47ꢀ50
literature background,
our present
conclusions, and Crabtree’s opinion, some previous conclusions in
18
aerobic systems may need to be re-examined. Further extensions
and deeper mechanistic insights of these air-promoted metal-
catalyzed reactions are under way.
regenerated quantitatively and recovered (step iv) for the next
N-alkylation cycle. Interestingly, the latter alcohol 1 (in green)
transfers its own hydrogen atoms to the preceding alcohol 1 (in
red, in its imine form 5 via aldehyde 4) with itself being oxidized
to 4 and will then (also in imine form) receive new hydrogen
atoms from an even later alcohol in the next cycle; the process
is analogous to a relay race game with the “handing off” of
hydrogen atoms.
Besides, reactions should be more likely to proceed via an
easier route that holds the lower energy barrier and requires the
least energy. In present reactions, since condensation and transfer
hydrogenation can both take place easily at lower temperatures,
and rate-limiting step is the generation of the initiating aldehyde
in alcohol activation, it indicates that, once the reaction is
initiated by trace aldehdye that is generated via either route, it
will require no longer high temperature heating for the difficult
anaerobic dehydrogenative formation of aldehyde and hydrido-
metal species by the lone catalysts. On the contrary, the reaction
can cycle itself, with the aldehdye being continuously regenerated
in the transfer hydrogenation and recycled until completion of
the reaction even at the lower temperatures. That is indeed the
case as we have observed in present reactions.
’ EXPERIMENTAL SECTION
General Methods and Materials. Substrates and catalysts are all
purchased. In reactions carried out under air, substrates, solvents and
catalysts were used as purchased without further purification and degas-
sing. In reactions under N and mechanistic studies, absolute alcohols
2
(
2
1) (dried over CaH , newly distilled, degassed, and stored under
nitrogen in a Schlenk flask) and aldehydes (4) (100% purity without
any contaminants as proved by GC analysis) were used unless otherwise
noted. Reactions were carried out in sealed Schlenk tubes and monitored
by TLC and/or GCꢀMS. Products were purified by column chroma-
tography on silica gel using petroleum ether and ethyl acetate as eluent
1
and identified by usual physical methods, i.e., NMR, MS, HRMS, etc. H,
1
3
31
C, and P NMR spectra were recorded on a 500 MHz spectrometer
1
13
31
(
500 MHz for H, 125.4 MHz for C, and 202.4 MHz for P NMR
1
spectroscopy) or a 300 MHz spectrometer (300 MHz for H and
1
3
75 MHz for C NMR spectroscopy). Unless otherwise noted, CDCl
3
1
13
was used as the solvent. Chemical shift values for H and C were
3
1
referred to internal Me Si (0 ppm), and that for P was referred to
4
H
3
PO
Typical Procedure for Metal-Catalyzed Aerobic N-Alkyla-
tion of Amides/Amines with Alcohols. A mixture of benzenesul-
fonamide 2a (0.471 g, 3.0 mmol), RhCl(PPh (0.0139 g, 0.015 mmol,
0.5 mol %), and K CO (0.041 g, 0.3 mmol, 10 mol %) in benzyl alcohol
a (0.4 mL, 4.0 mmol, 1.33 equiv) was stirred at 135 °C under air in a
4 2
(85% solution in D O, 0 ppm).
Moreover, condensation of the carbonyl compounds with
amines followed by reduction of the generated imines (Scheme 6,
steps ii + iii) have been long defined as reductive amination
3 3
)
2
3
1
2
sealed 20 mL Schlenk tube and monitored by TLC and/or GCꢀMS.
The reaction was then quenched with ethyl acetate, and the product was
purified by column chromatography with ethyl acetate and petroleum
ether (60ꢀ90 °C) as eluent, giving N-benzylbenzenesulfonamide 3aa in
83% isolated yield. Constant but low amounts of intermediate benzal-
dehyde 4a (2ꢀ8%) and trace N-benzylidenebenzenesulfonamide 5aa
reactions. The above aldehyde-initiated reactions (Table 7) can
also be taken as one of such reactions. However, conventional
reductive amination reactions usually require more than stoi-
chiometric amounts of hazardous reducing reagents such as
2
hydrogen gas or metal borohydrides. In the present reactions,
we adopted a reducing alcohol that can be converted to the
reactant aldehyde by transfer hydrogenation, resulting in the
requirement of only catalytic amounts of the starting aldehyde.
Thus, the present method can also be considered as a rare case of
(
0%∼0.5%) were observed in reaction mixtures of 1a and 2a according
to GCꢀMS analysis.
Typical Procedure for Anaerobic Reactions. A mixture of
2,49
benzenesulfonamide 2a (0.157 g, 1.0 mmol), RhCl(PPh
3 3
) (0.0463 g,
the reductive amination of carbonyl compounds.
This may
0
.05 mmol, 5 mol %), and K CO (0.138 g, 1.0 mmol, 1 equiv) was
2
3
also be another support to the new mechanism we proposed in
present research.
degassed under vacuum and refilled with pure nitrogen for 3ꢀ5 times.
Then newly distilled, degassed, and dried benzylic alcohol 1a (0.6 mL,
6.0 mmol, 6 equiv) was added under nitrogen, and the tube was then
sealed heated at 100 or 120 °C. No reaction occurred as monitored by
TLC. In cases where different equivalents of the substrates were added
and other catalysts were used, trace product may be detected with large
amounts of the substrates remaining unreacted. Solvents were also
degassed prior to use in the anaerobic reactions.
’
CONCLUSION
In summary, by employing aerobic alcohol oxidation as a more
effective alcohol activation protocol than the conventional anae-
robic dehydrogenative processes, a milder, greener, more efficient,
and advantageous air-promoted metal-catalyzed N-alkylation
methodology has been developed for the versatile amide/amine
derivative sythesis. This aerobic method is rather general in
catalyst and substrate scopes in that it is suitable for many simple,
less expensive, readily available, and ligand-free metal catalysts
1
N-Benzylbenzenesulfonamide (3aa). White solid. H NMR
(300 MHz, CDCl ): δ 7.83 (d, J = 7.4 Hz, 2H), 7.54ꢀ7.42 (m, 3H),
3
13
7.20ꢀ7.17 (m, 5H), 5.29 (b, 1H), 4.09 (d, J = 6.0 Hz, 2H). C NMR
(125 MHz, CDCl ): δ 139.8, 136.2, 132.5, 129.0, 128.5, 127.72, 127.66,
3
126.9, 47.1. MS (EI): m/z (%) 246 (0.3), 143 (6), 141 (4), 125 (6), 106
5
768
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The Journal of Organic Chemistry
ARTICLE
(
100), 104 (12), 91 (15), 79 (21), 78 (14), 77 (39), 51 (15). This com-
Hz, 2H), 7.25ꢀ7.15 (m, 5 H), 5.38 (bt, J = 5.7 Hz, 1H), 4.12 (d, J = 6.1
16c
13
pound was known.
Hz, 2H). C NMR (125 MHz, CDCl ): δ 139.0, 138.5, 136.0, 129.2,
3
N-(4-Chlorobenzyl)benzenesulfonamide (3ba). White solid.
128.6, 128.5, 127.81, 127.78, 47.1. MS (EI): m/z (%) 281 (0.1), 280
1
H NMR (300 MHz, CDCl ): δ 7.82 (d, J = 7.6 Hz, 2H), 7.60ꢀ7.45 (m,
(0.2), 112 (6), 111 (16), 107 (8), 106 (100), 104 (15), 91 (15), 79 (19),
3
1
2a
3
2
1
(
(
H), 7.20ꢀ7.09 (m, 4H), 5.36 (bt, J = 6.3 Hz, 1H), 4.08 (d, J = 6.3 Hz,
77 (15), 75 (10). This compound was known.
1
3
H). C NMR (125 MHz, CDCl
29.14, 129.09, 128.7, 126.9, 46.4. MS (EI): m/z (%) 281 (0.09), 280
0.11), 142 (32), 140 (100), 138 (13), 125 (18), 113 (8), 89 (6), 77
3
): δ 139.6, 134.8, 133.5, 132.7,
N-Benzyl-2-chlorobenzenesulfonamide (3ae). White solid.
1
H NMR (500 MHz, CDCl ): δ 8.07 (d, J = 7.5 Hz, 1H), 7.50ꢀ7.46
3
(m, 2H), 7.41ꢀ7.38 (m, 1H), 7.26ꢀ7.17 (m, 5H), 5.30 (br, 1H), 4.12
8c
13
46). This compound was known.
N-(3-Chlorobenzyl)benzenesulfonamide (3ca). White solid.
(d, J = 6.0 Hz, 2H). C NMR (125 MHz, CDCl ): δ 137.2, 135.7, 133.7,
3
131.5, 131.3, 131.2, 128.6, 128.0, 127.9, 127.2, 47.5. MS (EI): m/z (%)
1
H NMR (500 MHz, CDCl
3
): δ7.85ꢀ7.84 (m, 2H), 7.60ꢀ7.57 (m,
281 (0.1), 280 (0.2), 176 (5), 159 (5), 111 (13), 106 (100), 104 (15), 91
16c
1
(
H), 7.52ꢀ7.49 (m, 2H), 7.21ꢀ7.15 (m, 3H), 7.09ꢀ7.07 (m, 1H), 5.06
(17), 79 (18), 77 (18), 75 (10). This compound was known.
13
bt, J = 6.0 Hz, 1H), 4.12 (d, J = 6.5 Hz, 2H). C NMR (125 MHz,
N-Benzyl-4-methoxybenzenesulfonamide (3af). White so-
1
CDCl ): δ 139.8, 138.3, 134.5, 132.8, 129.9, 129.2, 128.1, 128.0, 127.0,
lid. H NMR (300 MHz, CDCl ): δ 7.78 (d, J = 8.4 Hz, 2H), 7.23ꢀ7.20
3
3
1
1
25.9, 46.6. MS (EI): m/z (%) 281 (1), 142 (33), 140 (100), 125 (13),
(m, 5H), 6.93 (d, J = 8.7 Hz, 2H), 5.23 (bt, J = 5.7 Hz, 1H), 4.08 (d, J =
6.0 Hz, 2H), 3.85(s, 3H). C NMR (75 MHz, CDCl ): δ 162.7, 136.3,
5
5
13
13 (8), 78 (14), 77 (46), 51 (12). This compound was known.
N-(4-Methoxybenzyl)benzenesulfonamide (3da). White so-
3
131.3, 129.1, 128.5, 127.7, 127.6, 114.1, 55.5, 47.0. MS (EI): m/z (%)
1
lid. H NMR (300 MHz, CDCl
3
): δ 7.83 (d, J = 7.6 Hz, 2H), 7.58ꢀ7.44
277 (3), 212 (1), 171 (4), 155 (14), 127 (2), 123 (20), 108 (26), 106
1
2a
(
4
1
(
m, 3H), 7.08 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.2 Hz, 2H), 5.32 (b, 1H),
.04 (d, J = 5.5 Hz, 2H), 3.73 (s, 3H). C NMR (125 MHz, CDCl
(100), 91 (15), 79 (13), 77 (28), 64 (8). This compound was known.
13
1
3
): δ
N-Benzyl-2-naphthalenesulfonamide (3ag). White solid. H
59.0, 139.8, 132.5, 129.1, 128.9, 128.2, 126.9, 113.8, 55.1, 46.5. MS
NMR (300 MHz, CDCl ): δ 8.45 (s, 1H), 7.95ꢀ7.83 (m, 4H),
3
EI): m/z (%) 277 (5), 141 (2), 135 (100), 121 (29), 77 (26). This
7
4
.68ꢀ7.60 (m, 2H), 7.20ꢀ7.17(m, 5H), 5.25 (bt, J = 6.1 Hz, 1H),
13
56
compound was known.
3
.16 (d, J = 6.2 Hz, 2H). C NMR (75 MHz, CDCl ): δ 136.5, 136.1,
N-(2-Methoxybenzyl)benzenesulfonamide (3ea). White so-
134.7, 132.0, 129.4, 129.1, 128.7, 128.49, 128.45, 127.8, 127.7, 127.4,
122.2, 47.2. MS (EI): m/z (%) 298 (2), 297 (11), 192 (5), 175 (2), 144
(8), 128 (50), 127 (57), 115 (8), 106 (100), 91 (16), 79 (11), 77 (19).
1
lid. H NMR (500 MHz, CDCl ): δ7.77ꢀ7.75 (m, 2H), 7.48 (t, J = 7.5
3
Hz 1H), 7.39 (t, J = 8.0 Hz, 2H) 7.19ꢀ7.16 (m, 1H), 7.06ꢀ7.04
1
2a
(
m, 1H), 6.79 (t, J = 7.5, 1H), 6.71 (d, J = 5.5 Hz, 1H), 5.20 (bt, J = 6.0
This compound was known.
13
1
Hz, 1H), 4.16 (d, J = 6.5 Hz, 2H), 3.72 (s, 3H). C NMR (125 MHz,
CDCl ): δ 157.2, 140.3, 132.2, 129.8, 129.3, 128.7, 126.9, 124.2, 120.5,
N-Benzylmethanesulfonamide (3ah). White solid. H NMR
3
(300 MHz, CDCl ): δ 7.35 (m, 5H), 4.94 (br, 1H), 4.30 (d, J = 6.1 Hz,
3
1
3
1
(
10.1, 55.1, 44.0. MS (EI): m/z (%) 277 (5), 137 (9), 136 (100), 134
2
1
H), 2.84 (s, 3H). C NMR (125 MHz, CDCl ): δ 136.7, 128.9, 128.1,
27.9, 47.2, 41.1. MS (EI): m/z (%) 185 (1), 107 (8), 106 (100), 105
3
21), 121 (15), 119 (14), 107 (12), 91 (24), 77 (29). HRMS calcd for
+
C H NO S (M + Na) : 300.0670, found 300.0664.
1
4
15
3
(18), 104 (45), 91 (29), 79 (32), 78 (13), 77 (23), 51 (12). This
1
6c
N-(2-Phenylethyl)benzenesulfonamide (3fa). White solid.
compound was known.
1
H NMR (500 MHz, CDCl ): δ 7.81 (d, J = 8.0 Hz, 2H), 7.54 (t, J =
3
N-(4-Chlorobenzyl)-p-toluenesulfonamide (3bb). White so-
7
.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.24ꢀ7.16 (m, 3H), 7.18 (d, J = 7.0
1
lid. H NMR (300 MHz, CDCl ): δ 7.59 (d, J = 8.2 Hz, 2H), 7.16ꢀ6.99
13
3
Hz, 2H), 4.96 (bt, J = 5.5 Hz, 1H), 3.21ꢀ3.17 (q, J = 7.0 Hz, 2H), 2.74 (t,
(
m, 6H), 5.44 (bt, J = 6.3 Hz, 1H), 3.93 (d, J = 6.3 Hz, 2H), 2.32 (s, 3H).
C NMR (125 MHz, CDCl ): δ 143.5, 136.6, 134.9, 133.4, 129.6,
3
1
3
J = 7.0 Hz, 2H). C NMR (125 MHz, CDCl
3
): δ 139.8, 137.6, 132.5,
29.0, 128.6, 128.5, 126.9, 126.6, 44.2, 35.7. MS (EI): m/z (%) 261 (1),
71 (9), 170 (100), 142 (7), 141 (97), 104 (18), 92 (9), 91 (48), 78 (9),
1
1
7
1
1
29.1, 128.5, 127.0, 46.3, 21.4. MS (EI): m/z (%) 295 (0.06), 157 (4),
42 (30), 140 (100), 139 (10), 125 (12), 113 (7), 91 (37), 77 (12), 65
5
7
7 (89), 65 (18). This compound was known.
N-(3-Phenylpropyl)benzenesulfonamide (3ga). Yellow oil.
16c
(17). This compound was known.
N-(3-Chlorobenzyl)-p-toluenesulfonamide (3cb). White so-
1
H NMR(500 MHz, CDCl
3
):δ 7.87ꢀ7.85 (m, 2H), 7.57ꢀ7.54 (m, 1H),
.50ꢀ7.47 (m, 2H), 7.23 (t, J = 7.5 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 7.06
d, J = 7.5 Hz, 2H), 5.03 (bt, J = 6.0 Hz, 1H), 2.96 (q, J = 6.5 Hz, 2H),
1
lid. H NMR (300 MHz, CDCl
3
): δ 7.70 (d, J = 8.1 Hz, 2H), 7.26 (d, J =
7
(
2
7
6
1
.9 Hz, 2H), 7.17ꢀ7.07 (m, 4H), 5.38 (bt, J = 5.8 Hz, 1H), 4.07 (d, J =
13
.2 Hz, 2H), 2.41(s, 3H). C NMR (125 MHz, CDCl
3
): δ 143.6, 138.6,
13
.58 (t, J = 7.5 Hz, 2H), 1.78ꢀ1.75 (m, 2H). C NMR (125 MHz,
): δ 140.8, 139.9, 132.5, 129.0, 128.4, 128.3, 127.0, 126.0, 42.6,
2.6, 31.0. MS (EI): m/z (%) 276 (1), 275 (2), 170 (8), 141 (42), 134
8), 119 (11), 118 (100), 117 (23), 105 (11), 104 (12), 91 (29), 77 (84).
36.9, 134.4, 129.9, 129.7, 127.9, 127.8, 127.1, 126.0, 46.6, 21.5. MS
CDCl
3
(
(
EI): m/z (%) 295 (0.11), 294 (0.46), 155 (4), 142 (31), 140 (100), 125
7), 113 (7), 91 (43), 77 (13), 65 (19). This compound was known.
3
(
16c
58
N-(4-Methoxybenzyl)-p-toluenesulfonamide (3db). White
This compound was known.
1
1
solid; H NMR (300 MHz, CDCl
3
): δ 7.74 (d, J = 8.2 Hz, 2H), 7.29 (d, J
N-Benzyl-p-toluenesulfonamide (3ab). White solid. H NMR
300 MHz, CDCl
): δ 7.75 (d, J = 7.9 Hz, 2H), 7.29ꢀ7.21 (m, 7H), 5.21
b, 1H), 4.10 (d, J = 6.2 Hz, 2H), 2.43 (s, 3H). C NMR (125 MHz,
=
8.1 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 4.89 (bt,
(
(
3
13
13
J = 5.7 Hz, 1H), 4.03 (d, J = 6.1 Hz, 2H), 3.76 (s, 3H), 2.43 (s, 3H).
NMR (75 MHz, CDCl ): δ 159.1, 143.3, 136.8, 129.6, 129.1, 128.2,
27.0, 113.9, 55.1, 46.6, 21.4. MS (EI): m/z (%) 292 (1), 291 (4), 155
(2), 136 (99), 135 (100), 134 (56), 121 (30), 109 (11), 91 (27), 77 (12),
C
3
CDCl ): δ 143.4, 137.0, 136.5, 129.7, 128.6, 127.9, 127.8, 127.2, 47.2,
3
1
2
(
1.5. MS (EI): m/z (%) 261 (0.1), 260 (0.2), 157 (3), 107 (10), 106
1
2a
100), 92 (13), 91 (39), 79 (17), 77 (11). This compound was known.
6
0
1
65 (15). This compound was known.
N-Benzyl-o-toluenesulfonamide (3ac). White oil. H NMR
300 MHz, CDCl
): δ 7.96 (d, J = 7.9 Hz, 1H), 7.47ꢀ7.42 (m, 1H),
N-(2-Methoxybenzyl)-p-toluenesulfonamide (3eb). White
(
3
1
oil. H NMR (300 MHz, CDCl ): δ 7.66 (d, J = 8.2 Hz, 2H), 7.21ꢀ7.17
3
7
2
1
.31ꢀ7.15 (m, 7H), 5.28 (bt, J = 6.0 Hz, 1H), 4.11 (d, J = 6.2 Hz, 2H),
13
(m, 3H), 7.06 (d, J = 7.0 Hz, 1H), 6.82ꢀ6.71 (m, 2H), 5.17 (b, 1H), 4.13
.61 (s, 3H). C NMR (125 MHz, CDCl ): δ 138.0, 137.1, 136.5,
3
1
3
(
d, J = 6.4 Hz, 2H), 3.73 (s, 3H), 2.38 (s, 3H). C NMR (125 MHz,
32.8, 132.6, 129.5, 128.6, 127.9, 127.8, 126.2, 47.1, 20.3. MS (EI): m/z
(
%) 261 (0.13), 157 (2), 155 (1), 106 (100), 91 (50), 77 (12), 65 (18).
CDCl ): δ 157.2, 143.0, 137.3, 129.8, 129.4, 129.2, 127.1, 124.4, 120.5,
3
110.1, 55.2, 43.9, 21.4. MS (EI): m/z (%) 292 (1), 291 (3), 155 (2), 136
59
This compound was known.
N-Benzyl-4-chlorobenzenesulfonamide (3ad). White solid.
(100), 134 (14), 121 (13), 119 (9), 107 (11), 91 (39), 77 (8), 65 (15).
This compound was known.
1
12a
H NMR (300 MHz, CDCl ): δ 7.74 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.4
3
5
769
dx.doi.org/10.1021/jo200862p |J. Org. Chem. 2011, 76, 5759–5773

The Journal of Organic Chemistry
ARTICLE
1
N-(2-Thiophenylmethyl)-p-toluenesulfonamide (3hb). Yellow
N-(4-Chlorobenzyl)-(2-pyridyl)amine (3bm). White solid. H
1
solid. H NMR (300 MHz, CDCl ): δ 7.74 (d, J = 8.2 Hz, 2H), 7.29 (d, J =
NMR (500 MHz, CDCl ): δ 8.08 (d, J = 5.0 Hz, 1H), 7.40ꢀ7.38
3
3
8
1
.1 Hz, 2H), 7.17ꢀ7.16 (m, 1H), 6.87ꢀ6.84 (m, 2H), 5.14 (bt, J = 5.8 Hz,
(m, 1H), 7.31ꢀ7.27 (m, 4H), 6.61ꢀ6.59 (m, 1H), 6.34 (d, J = 8.5 Hz,
13
13
H), 4.30 (d, J = 6.1 Hz, 2H), 2.42 (s, 3H). C NMR (75 MHz, CDCl ): δ
1H), 4.91(br, 1H), 4.47 (d, J = 6.0 Hz, 2H). C NMR (125 MHz,
3
143.5, 138.9, 136.6, 129.6, 127.1, 126.7, 126.3, 125.6, 41.9, 21.4. MS (EI): m/z
CDCl ): δ 158.4, 148.2, 137.6, 132.9, 128.8, 128.7, 113.4, 106.9, 45.6.
3
(
(
%) 267 (0.17), 266 (1), 157 (3), 139 (6), 112 (100), 111 (16), 97 (20), 91
MS (EI): m/z (%) 220(16), 219 (12), 218 (51), 217 (19), 183 (5), 142
16c
25), 85 (18), 65 (12). This compound was known.
N-(4-Chlorobenzyl)-4-methoxybenzenesulfonamide (3bf).
(33), 140 (100), 125 (43), 113 (7), 107 (12), 89 (23), 79 (42), 78 (31).
1
3a
This compound was known.
N-(4-Methoxybenzyl)-(2-pyridyl)amine (3dm). White solid.
1
Whitesolid. H NMR(300 MHz, CDCl ):δ 7.74 (d, J = 8.6Hz, 2H), 7.20
3
1
H NMR (500 MHz, CDCl
1H), 7.29ꢀ7.26 (m, 2H), 6.88ꢀ6.86 (m, 2H), 6.59ꢀ6.56 (m, 1H), 6.36
d, J = 8.5 Hz, 1H), 4.85 (br, 1H), 4.42 (d, J = 5.5 Hz, 2H), 3.79 (s, 3H).
3
): δ 8.10ꢀ8.09 (m, 1H), 7.41ꢀ7.37 (m,
(
(
d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.26
13
bt, J = 5.8 Hz, 1H), 4.04 (d, J = 6.2 Hz, 2H), 3.86 (s, 3H). C NMR (125
): δ 162.9, 135.0, 133.5, 131.3, 129.2, 128.7, 114.2, 55.6, 46.4.
MS (EI): m/z (%) 311 (0.12), 142 (33), 140 (100), 125 (18), 105 (2), 77
(
MHz, CDCl
3
1
3
3
C NMR (125 MHz, CDCl ): δ 158.8, 158.6, 148.2, 137.4, 131.2,
61
128.7, 114.0, 113.0, 106.8, 55.2, 45.8. MS (EI): m/z (%) 214 (34), 213
(
47). This compound was known.
1
(6), 199 (40), 136 (25), 122 (9), 121 (100), 105 (7), 91 (9), 77 (11).
N-Benzylbenzamide (3ai). White solid. H NMR (300 MHz,
1
3a
This compound was known.
CDCl ): δ 7.79 (d, J = 7.4 Hz, 2H), 7.51ꢀ7.26 (m, 8H), 6.70 (b, 1H),
3
1
13
N-Benzyl-[2-(5-chloropyridyl)]amine (3an). White solid. H
4
1
2
3
.61 (d, J = 5.6 Hz, 2H). C NMR (125 MHz, CDCl ): δ 167.4, 138.2,
NMR (300 MHz, CDCl ): δ 7.93 (d, J = 2.1 Hz, 1H), 7.32ꢀ7.23
3
34.3, 131.5, 128.7, 128.5, 127.8, 127.5, 126.9, 44.0. MS (EI): m/z (%)
(
m, 6H), 6.27 (d, J = 8.8 Hz, 1H), 5.30 (br, 1H), 4.44 (d, J = 5.8 Hz, 2H).
11 (8), 210 (54), 106 (29), 105 (100), 91 (10),79 (6), 77 (61), 51 (16).
1
3
62
C NMR (125 MHz, CDCl
27.3, 119.8, 107.5, 46.4. MS (EI): m/z (%) 220 (14), 219 (12), 218
42), 217 (22), 183 (3), 141 (13), 112 (14), 106 (100), 91 (89), 79 (12),
3
): δ 156.9, 146.4, 138.7, 137.2, 128.6,
This compound was known.
1
(
1
N-(4-Chlorobenzyl)benzamide (3bi). White solid. H NMR
500 MHz, CDCl
): δ 7.77ꢀ7.79 (m, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.42
(
(
3
66
6
5 (26). This compound was known.
N-Benzyl-(3-pyridyl)amine (3ao). Yellow solid. H NMR (300
MHz, CDCl ): δ 8.07 (d, J = 2.9 Hz, 1H), 7.97ꢀ7.95 (m, 1H),
t, J = 7.5 Hz, 2H), 7.31ꢀ7.26 (m, 4H), 6.56 (br, 1H), 4.59 (d, J = 5.5 Hz,
1
13
2
1
2
3
H). C NMR (125 MHz, CDCl ): δ 167.4, 136.8, 134.2, 133.4, 131.7,
3
29.2, 128.9, 128.6, 126.9, 43.4. MS (EI): m/z (%) 247 (11), 246 (9),
7
.36ꢀ7.26 (m, 5H), 7.09ꢀ7.04 (m, 1H), 6.89ꢀ6.88 (m, 1H), 4.34
45 (35), 210 (3), 140 (9), 125 (5), 106 (11), 105 (100), 77 (42). This
13
(
3
br, 2H), 4.17 (br, 1H). C NMR (125 MHz, CDCl ): δ 144.0, 138.8,
62
compound was known.
1
1
38.5, 136.0, 128.8, 127.5, 127.4, 123.7, 118.6, 47.9. MS (EI): m/z (%)
1
N-(4-Methoxybenzyl)benzamide (3di). White solid. H NMR
500 MHz, CDCl
): δ 7.77 (d, J = 7.5 Hz, 2H), 7.49ꢀ7.41 (m, 3H),
.26ꢀ7.29 (m, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.40 (br, 1H), 4.57 (d, J =
84 (38), 183 (5), 92 (9), 91 (100), 78 (7), 77 (2), 65 (13), 51 (6). This
(
3
67
compound was known.
1
7
5
1
N-Benzylaniline (3ap). Colorless oil. H NMR (500 MHz, CDCl ):
3
13
.5 Hz, 2H), 3.80 (s, 3H). C NMR (125 MHz, CDCl
34.5, 131.5, 130.3, 129.3, 128.5, 126.9, 114.2, 55.3, 43.6. MS (EI): m/z
%) 242 (9), 241 (59), 210 (2), 136 (41), 121 (26), 109 (13), 105 (100),
3
): δ 167.2, 159.1,
δ 7.42ꢀ7.37 (m, 4H), 7.34ꢀ7.31 (m, 1H), 7.24ꢀ7.21 (m, 2H), 6.78ꢀ6.75
1
3
(
(
m, 1H), 6.69ꢀ6.67 (m, 2H), 4.30 (s, 2H), 3.99 (br, 1H). C NMR
(
125 MHz, CDCl ): δ 147.8, 138.0, 132.7, 129.2, 128.6, 127.4, 117.7, 112.8,
3
62
7
7 (54).This compound was known.
N-Benzyl-4-methoxybenzamide (3aj). White solid. H NMR
500 MHz, CDCl
): δ 7.70ꢀ7.67 (m, 2H), 7.27ꢀ7.20 (m, 5H),
.84ꢀ6.82 (m, 2H), 6.33 (br, 1H), 4.54 (d, J = 5.5 Hz, 2H), 3.76 (s,
47.5. MS (EI): m/z (%) 183 (56), 182 (21), 106 (22), 104 (11), 92 (9), 91
1
68
(100), 77 (18), 65 (15), 51 (7). This compound was known.
1
(
3
N-Benzyl-4-ethoxyaniline (3aq). Yellow oil. H NMR (300
6
3
1
MHz, CDCl ): δ 7.37ꢀ7.25 (m, 4H), 6.76 (d, 2H), 6.59ꢀ6.56
3
13
H). C NMR (125 MHz, CDCl
27.5, 126.7, 113.8, 55.4, 44.1. MS (EI): m/z (%) 242 (6), 241 (36), 211
1), 136 (10), 135 (100), 107 (12), 92 (10), 77 (17). This compound
3
): δ 166.9, 162.2, 138.4, 128.7, 127.9,
(m, 2H), 4.26 (s, 2H), 3.93 (q, J = 7.0 Hz, 2H), 1.35 (d, J = 7.0 Hz,
1
3
3H). C NMR (125 MHz, CDCl ): δ 151.5, 142.3, 139.6, 128.5, 127.6,
3
(
127.1, 115.8, 114.2, 64.1, 49.3, 15.0. MS (EI): m/z (%) 228 (8), 227
63
was known.
(51), 226 (3), 198 (19), 196 (5), 136 (11), 108 (30), 91 (100), 81 (5),
1
69
N-Benzylnicotinamide (3ak). White solid. H NMR (500 MHz,
CDCl ): δ 8.81 (d, J = 1.0 Hz, 1H), 8.47 (d, J = 4.5 Hz, 1H), 8.00 (t, J =
.0 Hz, 1H), 7.45 (br, 1H), 7.15ꢀ7.19 (m, 6H), 4.47 (d, J = 4.5 Hz, 2H).
77 (2), 65 (10). This compound was known.
3
1
’ ASSOCIATED CONTENT
1
3
3
C NMR (125 MHz, CDCl ): δ 165.5, 151.8, 147.9, 137.8, 135.2,
30.1, 128.6, 127.7, 127.5, 123.3, 43.9. MS (EI): m/z (%) 212 (55),
11 (17), 182 (2), 168 (4), 167 (2), 155 (7), 107 (10), 106 (100), 104
S
Supporting Information. Experimental procedures, con-
1
2
(
b
dition screening tables, details of mechanism studies, product
characterization and spectra of new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
5), 91 (22), 79 (24), 78 (55), 65 (11), 51 (23). This compound was
64
known.
1
N-Benzyl-(2-pyrimidyl)amine (3al). White solid. H NMR (300
MHz, CDCl ): δ 8.02(br, 2H), 7.37ꢀ7.25 (m, 5H), 6.70 (br, 1H), 6.40
’ AUTHOR INFORMATION
3
13
(
t, J = 4.8 Hz, 1H), 4.61 (d, J = 5.6 Hz, 2H). C NMR (125 MHz,
Corresponding Author
*
CDCl
3
): δ 162.2, 157.8, 139.0, 128.4, 127.5, 127.0, 110.3, 45.3. MS (EI):
E-mail: qing-xu@wzu.edu.cn; xiaochunyu@wzu.edu.cn.
m/z (%) 186 (12), 185 (90), 184 (63), 157 (5), 144 (3), 129 (3), 108
(
19), 106 (100), 91 (47), 79 (40), 77 (13), 65 (28). This compound was
65
known.
’
ACKNOWLEDGMENT
1
N-Benzyl-(2-pyridyl)amine (3am). White solid. H NMR (300
MHz, CDCl
): δ 8.10 (d, J = 4.9 Hz, 1H), 7.43ꢀ7.20 (m, 6H),
.64ꢀ6.57 (m, 1H), 6.37 (d, J = 8.4 Hz, 1H), 4.88 (s, 1H), 4.51 (d,
We thank National Natural Science Foundation of China
No. 20902070), Natural Science Foundation (No. Y4100579)
3
(
6
13
J = 5.7 Hz, 2H). C NMR (125 MHz, CDCl ): δ 158.6, 148.2, 139.2,
and Qianjiang Talents Program (No. QJD0902004) of Zhejiang
Province for financial supports. S.L. and Q.S. thank the Sci-
ence and Technology Department of Zhejiang Province (No.
2009R424045 and 2009R424048). Q.L. thanks the Postgraduate
3
1
37.5, 128.7, 127.4, 127.3, 113.2, 106.8, 46.3. MS (EI): m/z (%) 184
(14), 183 (100), 182 (47), 153 (5), 127 (5), 116 (2), 106 (34), 79 (11),
13a
66 (4). This compound was known.
5
770
dx.doi.org/10.1021/jo200862p |J. Org. Chem. 2011, 76, 5759–5773

The Journal of Organic Chemistry
ARTICLE
Department of Wenzhou University (3160603601010934). We
also thank Q. Liu, L. Jiang, Y. Shao, X. Zang and R. Shen for
repeating or performing some reactions and Prof. L. Hegedus
Ohshima, T.; Mashima, K. Org. Lett. 2007, 9, 3371. (o) Roggen, M.;
Carreira, E. M. J. Am. Chem. Soc. 2010, 132, 11917. (p) Ozawa, F.;
Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji, M.
J. Am. Chem. Soc. 2002, 124, 10968.
(
Colorado State University) for helpful discussions. Dedicated to
(
9) For reviews on borrowing hydrogen or hydrogen autotransfer
methodology, see: (a) Watson, A. J. A.; Williams, J. M. J. Science 2010,
29, 635 and references therein. (b) Dobereiner, G. E.; Crabtree, R. H.
the memory of Prof. Xian Huang.
3
’
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(
reactions differ from the borrowing hydrogen or hydrogen autotransfer
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(26) Similar transition-metal-catalyzed amine activations to inter-
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(
19) (a) Tojo, G.; Fern ꢀa ndez, M. Oxidation of Alcohols to Aldehydes
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(30) See Supporting Information for experimental detail and results.
(31) Constant but low amount of benzaldehyde 4a (2ꢀ8%) and
traces of intermediate imine N-benzylidenebenzenesulfonamide 5aa
(0ꢀ0.5%) were often detected by GCꢀMS in reactions of 1a and 2a.
Similarly, these intermediates were also frequently observed in the
literature. See refs 9,11ꢀ16.
2
010, 132, 8056. (c) Gunanathan, C.; Shimon, L. J. W.; Milstein, D.
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(32) Metal oxides are generally considered to be heterogeneous
catalysts. However, whether the reactions of heterogeneous catalysts
undergo borrowing hydrogen mechanisms as those of the homogeneous
catalysts was questioned by Crabtree (see ref 9b). Therefore, the
anaerobic reactions of these metal oxides are also more likely to undergo
the new mechanism we proposed (Scheme 6).
(22) Acceptor-less alcohol oxidation has been utilized for imine,
imide, and amide synthesis in the presence of amines: (a) Gnanaprakasam,
B.; Zhang, J.; Milstein, D. Angew. Chem., Int. Ed. 2010, 49, 1468. (b) Zhang,
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2 3
(34) In our hands, by using FeCl or FeCl as the catalyst (known
and used as Lewis acids, see refs 8eꢀ8g), reactions of 1a and 2a in the
absence of base did not give 3aa but afforded dibenzyl ether as the major
product. With base added, ether was not detected and no or only trace
3aa could be observed.
(35) Similar detection of more intermediate imine than product
amine at the begining of the reaction and gradual enhancement in
product amine/intemediate imine selectivity has been observed in
aerobic heterogeneous N-alkylation reactions. See refs 15c and 16h.
(f) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008,
1
3
30, 17672. (g) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007,
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(23) For examples of activated alkenes used as H-acceptors, see: (a)
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The Journal of Organic Chemistry
36) In conventional borrowing hydrogen reactions, metal-mediated
anaerobic dehydrogenative alcohol activation to aldehydes is by nature
an alcohol oxidation reaction. See refs 9a, 9b.
ARTICLE
(
co-workers: (a) Bower, J. F.; Kim, I. S.; Patman, R. L.; Krische, M. J.
Angew. Chem., Int. Ed. 2009, 48, 34. (b) Bechem, B.; Patman, R. L.;
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(d) Zhang, Y. J.; Yang, J. H.; Kim, A. H.; Krische, M. J. J. Am. Chem. Soc.
2010, 132, 4562.
(37) For examples of Rh-catalyzed aerobic alcohol oxidations, see
refs 20i, 20qꢀ20s. For examples of RhꢀO
2
complex, see: (a) Ahijado,
M.; Braun, T.; Noveski, D.; Kocher, N.; Neumann, B.; Stalke, D.;
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(50) It has been reported that the early base-free transition-metal-
catalyzed transfer hydrogenations had to be conducted at much higher
temperatures (ref aꢀc), while B €a ckvall and co-workers found that
dramatic enhancement of the reaction efficiency can be achieved by
addition of small amounts of base (ref d). Base possibly works to
deprotonate the alcohol and promotes its coordination with transition
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by corresponding aldehydes or incomplete degassing of air by inert gases
may lead to rather different results and mechanistic conclusions. Thus, in
our work, degassed even newly distilled alcohol free of both aldehyde (as
confirmed by GC analysis) and air was used in the control reactions and
mechanistic studies.
(
38) In fact, it has been documented that amides and amines,
including the sulfonamides, are good ligands having strong ligating
abilities toward metals: (a) Chohan, Z. H.; Shad, H. A.; Nasim, F.-H.
Appl. Organometal. Chem. 2009, 23, 319 and references therein. (b)
Cejudo-Mar ꢀi n, R.; Alzuet, G.; Ferrer, S.; Borr ꢀa s, J. Inorg. Chem. 2004,
4
2
3, 6805. (c) Zhang, T.; Wang, W.; Gu, X.; Shi, M. Organometallics 2008,
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39) Although complexation of amines with Ru and Ir catalysts had
2
(
9
,11ꢀ16
been taken into account by Watanabe and Yamaguchi, in most cases
it was ignored: (a) Watanabe, Y.; Morisaki, Y.; Kondo, T.; Mitsudo, T.
J. Org. Chem. 1996, 61, 4214. (b) Watanabe, Y.; Tsuji, Y.; Ige, H.; Ohsugi,
Y.; Ohta, T. J. Org. Chem. 1984, 49, 3359. (c) Fujita, K.-I.; Enkoi, Y.;
Yamaguchi, R. Tetrahedron 2008, 64, 1943.
(52) Similarly, it can also be easily drawn from corresponding
9
,11ꢀ16
literature
that conventional borrowing hydrogen reactions can
also be catalyzed by various homogeneous and heterogeneous catalysts
without defined valences and ligations.
(
40) Alcohol insertion onto transition metals and subsequent alco-
hol dehydrogenation are commonly recognized in the literature. See refs
b, 12, 13.
41) Reactions of alcohols with RhCl(PPh ) : (a) Baird, M. C.;
(53) On the other hand, how every individual reaction proceeds and
in what way does not affect the overall sequence and final outcome of the
whole reaction. See also refs 9b, 20, 37, 47 and 48.
9
(
(54) Although a coordinating CO ligand may be present in the case
3
3
Mague, J. T.; Osborn, J. A.; Wilkinson, G. J. Chem. Soc. A 1967, 1347. (b)
Tsuji, J.; Ohno, K. Tetrahedron Lett. 1965, 6, 3969. Conversion of I to II
possibly proceeds via dehydrogenation of the alcohol moiety with
extrusion of molecular hydrogen. See also ref 21.
of Rh catalysts as has been observed, the situation is still not clear with
other metals. Thus, [M] and [M ] are used on behalf of precatalysts and
catalysts. It seems this catalyst variation does not affect the results of
reactions.
0
(
42) For aldehyde insertion onto transition metals, addition and
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(
43) The formation of complex III, formed as yellow crystals from
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(
3 3 8
44) In contrast, solubility of RhCl(PPh ) in d -THF was found to
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be dissolved, giving suspensions only.
3
)
3
cannot
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(
45) Possibly an Rh-sulfonamide complex was generated, but this
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(
46) (a) Layer, R. W. Chem. Rev. 1963, 63, 489. (b) Sprung, M. M.
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(
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(
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(
49) A series of reductive (transfer hydrogenative) asymmetric
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5
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