Palladium-catalyzed N-alkylation of amides and amines with alcohols employing the aerobic relay race methodology

Article abstract of DOI:10.1002/cjoc.201200462

Possibly because homogeneous palladium catalysts are not typical borrowing hydrogen catalysts and ligands are thus ineffective in catalyst activation under conventional anaerobic conditions, they had not been used in the N-alkylation reactions of amines/amides with alcohols in the past. By employing the aerobic relay race methodology with Pd-catalyzed aerobic alcohol oxidation being a more effective protocol for alcohol activation, ligand-free homogeneous palladiums are successfully used as active catalysts in the dehydrative N-alkylation reactions, giving high yields and selectivities of the alkylated amides and amines. Mechanistic studies implied that the reaction most probably proceeds via the novel relay race mechanism we recently discovered and proposed. By employing the aerobic relay race methodology with Pd-catalyzed aerobic alcohol oxidation being a more effective protocol for alcohol activation, ligand-free homogeneous palladiums are successfully used as active catalysts in the dehydrative N-alkylation reactions of amines and amides with alcohols, giving high yields and selectivities of the alkylated amines and amides. Mechanistic studies implied that the reaction most probably proceeds via the novel relay race mechanism we recently discovered and proposed. Copyright

Full text of DOI:10.1002/cjoc.201200462

FULL PAPER
DOI: 10.1002/cjoc.201200462
Palladium-Catalyzed N-Alkylation of Amides and Amines with
Alcohols Employing the Aerobic Relay Race Methodology
Yu, Xiaochuna(余小春)
Jiang, Lana(姜澜)
Li, Qianga(李强)
Xie, Yuanyuanb(谢媛媛)
Xu, Qing*,a(徐清)
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, China
b College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
Possibly because homogeneous palladium catalysts are not typical borrowing hydrogen catalysts and ligands are
thus ineffective in catalyst activation under conventional anaerobic conditions, they had not been used in the
N-alkylation reactions of amines/amides with alcohols in the past. By employing the aerobic relay race methodol-
ogy with Pd-catalyzed aerobic alcohol oxidation being a more effective protocol for alcohol activation, ligand-free
homogeneous palladiums are successfully used as active catalysts in the dehydrative N-alkylation reactions, giving
high yields and selectivities of the alkylated amides and amines. Mechanistic studies implied that the reaction most
probably proceeds via the novel relay race mechanism we recently discovered and proposed.
Keywords palladium catalysis, amides, amines, alcohols, N-alkylation reaction, aerobic reaction, relay race
methodology
Introduction
usually employed, requiring an inert atmosphere protec-
tion and even special care in manipulation such as using
a glovebox.[5-7] All these drawbacks greatly limit the
utilities of the methods and make them not as green and
practical as was originally expected. Much space to im-
prove the methods still remains, thus a variety of
ligand-free heterogeneous catalysts based on noble met-
als have been developed[8,9] and homogeneous methods
using simpler, more available and more economic cata-
lysts that can be conducted under less demanding condi-
tions are also highly desirable.[10,11]
On the other hand, in contrast with Ru and Ir cata-
lysts,[5-7] rhodium and palladium catalysts that have
been widely applied in various types of catalytic reac-
tions[3,12] were seldom used in the N-alkylation reactions
in the past.[5] As to the Rh catalysts, recently we acci-
dentally found a more effective and more advantageous
air-promoted Rh-catalyzed aerobic N-alkylation
method,[11a] which was proved to proceed via a novel
mechanism analogous to the relay race game (Scheme
1b)[11b] that has never been discovered and proposed in
metal-catalyzed N-alkylation reactions.[5-10] A great dif-
ference and also the advantage of the new method to the
borrowing hydrogen methods is, by adopting the
metal-catalyzed aerobic alcohol oxidation under air
(step i) as a more effective and greener protocol for al-
cohol activation, many simpler, more available, less
inexpensive, and ligand-free Rh, Ru, and Ir catalysts
Amine and amide derivatives are of high importance
in synthesis and key moieties in numerous pharmaceu-
tically and biologically active molecules and various
natural products.[1] In the past decades, various method-
ologies have been developed for the synthesis of amines
and amide derivatives by constructing C—N bonds.[2-5]
In comparison with other methods[2-4] including the con-
ventional lowly selective N-alkylation of amines with
alkyl halides[2] and other transition metal-catalyzed
coupling and addition reactions,[3] transition metal-
catalyzed N-alkylation of amines and amides with alco-
hols,[5] namely the borrowing hydrogen[5a-5f] or hydro-
gen autotransfer[5g-5i] methodology (Scheme 1a), has
attracted much attention in recent years. Because the
method uses the greener alcohols as the alkylating re-
agents other than the more toxic and less economic or-
ganogalides[2] or carbonyl compounds,[4] achieves high
selectivity for secondary amines and high atom effi-
ciency, and yields water as the only byproduct, it was
considered to be a more economic and environmentally
benign alternative for amine and amide derivatives.[5]
However, because the anaerobic alcohol dehydrogena-
tion to aldehydes and the sensitive hydridometal species
(step i) is a thermodynamically unfavorable process,[5c]
expensive, not readily available, not easily handled,
preformed ruthenium[6] and iridium[7] complexes or ad-
dition of capricious ligands for catalyst activation, were
*
E-mail: qing-xu@wzu.edu.cn; Tel.: 0086-13857745327; Fax: 0086-577-86689300
Received May 12, 2012; accepted June 3, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200462 or from the author.
Chin. J. Chem. 2012, XX, 1—11
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Yu et al.
FULL PAPER
Scheme 1 Homogeneous transtion metal-catalyzed N-alkylation methods for amines and amides with alcohols
iv
H2O
air (1/2 O2)
OH
R1
NHR2
R1
OH
i
R1
R1
R1
[M]
3
1
O
O
cat. [M]
4
4
1
i
iii
R2
(rate-limiting)
R2NH2 2
R1
[MH2]
N
[M]
H
3
ii
R1
base
R1
NR2
O
iii (fast)
ii (fast)
4
5
R1
R2NH2
OH
R1
NR2
H2O
1
H2O
2
5
(b)
(a) M = Ru, Ir
L-free M (Rh, Ru, Ir, Mn, Cu)
This work: M = Pd
that used to be inactive under conventional anaerobic
borrowing hydrogen conditions[5-7] can be effectively
used as the catalysts under milder conditions. As we
found out, the new method has a wider scope of cata-
lysts, and more economic catalysts such as Mn and Cu
can also be used under the mild conditions,[11c-11e]
showing its advantage over the borrowing hydrogen
methods.
most probably proceeds via the novel relay race mecha-
nism.[11]
Results and Discussion
As shown in Table 1, various Pd catalysts were in-
vestigated in the model reaction of benzyl alcohol 1a
and benzenesulfonamide 2a under a series of sol-
vent-free conditions to optimize the condition. The re-
actions were initially carried out using large excess 1a
and 1 equiv. of base under air. All the tested palladium
catalysts, ligated (runs 1 and 2) or ligand-free ones (runs
3—5), heterogeneous (run 6) or homogeneous ones
(runs 1—5), showed high catalytic activities under this
condition and gave good to high yields of the target
product 3aa in high selectivity. Ligand-free PdCl2 and
Pd(OAc)2 were the most effective catalysts, both giving
quantitative yields of the product in only 4 h (runs 3 and
4). Above easy and efficient aerobic reactions lead us to
further investigate the corresponding anaerobic reac-
tions to distinguish the Pd catalysts’ activity in the reac-
tion. However, except the most active catalysts PdCl2
and Pd(OAc)2 that could afford high product yields only
in prolonged reaction time (runs 3 and 4), the anaerobic
reactions were found to be much less effective than the
parallel aerobic ones under the same condition (runs 1—
6). Based on our experiences,[11] these contrastive re-
sults revealed the key role air played in the reactions
and the advantages of employing the aerobic method. In
addition, Pd catalyst and base were also found essential
for the reaction since no reaction occurred with neither
of them.
When the condition was further optimized with
catalyst and base loadings greatly reduced (runs 7—12),
Pd(OAc)2 was found to be the best catalyst (run 10),
giving 96% yield (87% isolated yield) of the product
with very low loadings of the catalyst (0.5 mol%) and
the base (10 mol%). Similar to previous observations,
corresponding anaerobic reactions under the optimized
condition were not effective, either. Only trace product
was detected (runs 7—12). Worth noting is that, al-
though trace yield of the product was observed in the
anaerobic reaction using a degassed commercial sample
of 1a, no product could be detected when absolute al-
cohol 1a was used under the same condition (run 10).[13]
In comparison with several recently reported N-alkyla-
tion reactions of sulfonamides,[6-8,10] the present Pd-
As to the Pd catalysts, also surprisingly, only limited
heterogeneous Pd catalysts have been reported re-
cently;[9] homogeneous Pd catalysts had not been used
in the field in the past.[5] However, like other noble met-
als-catalyzed heterogeneous reactions,[8] severe draw-
backs still remain in the heterogeneous Pd-catalyzed
methods.[9] For example, they were all carried out under
inert atmosphere, require the use of solvents,[9a,9b] large
excess amounts of the amines[9b] or the alcohols,[9c] or
heating at high temperatures (150—180 ℃),[9b,9c] but
gave only low selectivities of the product amines,[9a,9b]
which could result in the requirement of a second hy-
drogenation process by using gas hydrogen to achieve
higher selectivities of the target amines.[9a] These unsat-
isfactory results may suggest that, in Pd-catalyzed
N-alkylation reactions, Pd catalyst screening and/or
modification, a thorough condition optimization or an
investigation on the homogeneous reactions prior to
heterogeneous ones are of high urgency and necessity.
With a curiosity on the catalytic activities of the
homogeneous Pd catalysts in the reaction and an interest
to further explore the scope of our aerobic method,[11]
and also with an intension to improve the Pd-catalyzed
methods that may provide a potentially useful reference
for the heterogeneous catalysis,[9] we set out to investi-
gate the reactions of various amides and amines with
alcohols by using the readily available homogeneous Pd
catalysts employing the aerobic protocol. Herein we
report an efficient low-loading ligand-free Pd-catalyzed
aerobic N-alkylation reaction of amides and amines with
alcohols that can be readily carried out under sol-
vent-free and aerobic conditions. We also disclose that,
unlike Rh, Ru and Ir catalysts,[5-7,11b] palladiums may
not be typical borrowing hydrogen catalysts and thus
cannot catalyze the reaction under conventional anaero-
bic conditions even in the presence of ligands, but are
very active catalysts under the aerobic conditions. Based
on the mechanistic studies and also supported by the
literature, the Pd-catalyzed aerobic N-alkylation reaction
2
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Chin. J. Chem. 2012, XX, 1—11

Palladium-Catalyzed N-Alkylation of Amides and Amines with Alcohols
Table 1 Screening of reaction conditions and Pd catalystsa
cat. Pd (y mol%)
2-pyridinemethanol 1g under the optimized condition
was found to be rather slow, thus only moderate yield of
the product (57%) could be obtained in 48 h (run 17). In
the case of 2-thiophenemethanol 1h, due to the forma-
tion of the byproduct, the corresponding ether from the
+
Ph
OH PhSO2NH2
1a
(x equiv.)
K2CO3 (z mol%)
air (N2), T, t
2a
Ph
NHSO2Ph
Ph
NSO2Ph
3aa
5aa
Table 2 Pd-catalyzed aerobic N-alkylation reaction of amides
RunPd
x, y, z
T, t
Yield of 3aab%
and amines with alcoholsa
1
2
3
4
5
6
7
8
9
PdCl2(PPh3)2 6, 5, 100
120 ℃, 4 h 96 (NDc)
120 ℃, 12 h 81 (trace)
120 ℃, 4 h 99 (traced)
120 ℃, 4 h 99 (tracee)
120 ℃, 12 h 99 (trace)
120 ℃, 12 h 94 (trace)
Pd(OAc)2 (y mol%)
R2
R1
R1
Pd(PPh3)4
PdCl2
6, 5, 100
6, 5, 100
6, 5, 100
6, 5, 100
6, 5, 100
+ R2-NH2
OH
+ H2O
N
base (z mol%)
air, T, t
2
H
1
3
(x equiv.)
Pd(OAc)2
Pd2(dba)3
Pd black
Pd(PPh3)4
PdCl2
Conditions
(x/y/z, T, t)
Yield of
3b/%
Run 1, 2
PhCH2OH (1a)
PhSO2NH2 (2a)
p-ClC6H4CH2OH (1b)
1.33/0.5/10
135 ℃, 24 h
2/0.5/10
135 ℃, 36 h
2/0.5/10
135 ℃, 36 h
1.33/0.5/10
135 ℃, 36 h
2/0.5/10
135 ℃, 48 h
2/0.5/10
135 ℃, 48 h
1.33/0.5/10
135 ℃, 24 h
1.33/0.5/20
135 ℃, 48 h
1.33/0.5/10
135 ℃, 24 h
1.5/0.5/10
135 ℃, 48 h
1.5/0.5/10
135 ℃, 24 h
1.5/0.5/10
1
96 (87)
83 (74)
99 (90)
70 (64)
78 (70)
45
1.3, 0.5, 20 135 ℃, 24 h 91 (trace)
1.3, 1, 20
135 ℃, 20 h 78 (trace)
2
Pd(OAc)2
1.1, 1, 20
135 ℃, 24 h 94 (trace)
2a
10 Pd(OAc)2
11 Pd2(dba)3
1.3, 0.5, 10 135 ℃, 24 h 96f (trace/ND)
m-ClC6H4CH2OH (1c)
2a
p-CH3C6H4CH2OH (1d)
2a
p-CH3OC6H4CH2OH (1e)
2a
o-CH3OC6H4CH2OH (1f)
2a
3
1.3, 1, 20
1.3, 1, 20
135 ℃, 24 h 73 (trace)
4
12 Pd black
a
135 ℃, 48 h 74 (trace)
b
Reactions monitored by TLC and/or GC-MS. GC yields of
aerobic reactions based on 2a (no product detected or trace in
parallel anaerobic reactions as shown in parenthesis). 3aa/5aa
5
c
d
6
ratios (GC) are usually ＞99/1. Trace product in 24 h. 99%
e
f
GC yield in 24 h. 97% GC yield in 24 h. 87% isolated yield.
Trace product detected with degassed commercial 1a. No product
detected with absolute 1a.[13]
1a
7
93 (81)
83
p-ClC6H4SO2NH2 (2b)
1a
o-ClC6H4SO2NH2 (2c)
1a
p-CH3C6H4SO2NH2 (2d)
8
catalyzed method is relatively milder in condition, such
as less in alcohol and base loadings, lower in tempera-
ture, higher in efficiency, and avoiding inert atmosphere
protection and the use of activating ligands and sol-
vents.
9
86 (79)
88 (78)
87 (85)
97 (93)
93 (84)
90 (83)
93 (80)
94 (87)
57
10
11
12
13
14
15
16
17
18
19
20
21c
22c
1b, 2d
1c, 2d
1e, 2d
The optimized condition of the Pd-catalyzed aerobic
N-alkylation method was then applied to various amides,
amines and alcohols to extend the scope of the reaction.
As shown in Table 2, this method is suitable for a vari-
ety of sulfonamides, amides, aromatic and heteroaro-
matic amines as well as benzylic and heterobenzylic
alcohols, and usually low loadings of the catalyst (0.5—
1 mol%) and the alcohols (1—2 equiv.) can be used.
Thus, like benzyl alcohol 1a, both the electron-rich and
-deficient and para- and meta-substituted benzylic al-
cohols 1b—1e reacted efficiently with 2a to give the
target sulfonamide derivatives in good to high yields in
high selectivities (runs 2—5). The reaction of an ortho-
substituted benzylic alcohol 1f gave a lower yield, pos-
sibly due to the steric hindrance of the ortho methoxy
group (run 6). Slight differently, all the electron-rich
and -deficient benzenesulfonamides 2b—2f, including
the sterically more bukly ortho-substituted ones (runs 8,
13), gave high yields of the products (runs 7—14). Be-
sides, other sulfonamides such as 2-naphthalenesul-
fonamide 2g and an alkyl sulfonamide 2h (methanesul-
fonamide), and heterobenzylic alcohols 1g—1h also
gave moderate to high yields of the products under
similar conditions (runs 15—19). The reaction of
135 ℃, 48 h
1.33/0.5/10
135 ℃, 24 h
1.33/0.5/10
135 ℃, 36 h
1.5/1/20
1a
o-CH3C6H4SO2NH2 (2e)
1a
p-CH3OC6H4SO2NH2 (2f)
1a
2-naphthalenesulfonamide (2g) 135 ℃, 36 h
1a
CH3SO2NH2 (2h)
2-pyridinemethanol (1g)
1.33/0.5/10
135 ℃, 36 h
2/0.5/10
135 ℃, 48 h
2/2/40
135 ℃, 48 h
6/5/100
135 ℃, 48 h
6/5/100
180 ℃, 36 h
1.5/1/40
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
2a
2-thiophenemethanol (1h)
2d
67
1h, 2d
99
1a
75
PhCONH2 (2i)
1a
2-aminopyrimidine (2j)
92 (90)
80
1a, 2j
Chin. J. Chem. 2012, XX, 1—11
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3

Yu et al.
FULL PAPER
alcohol, moderate yield of the product was obtained
under the optimized condition (run 18). In contrast, by
adding excess amounts of the alcohol, high yield of the
product could be achieved (run 19). In addition, unlike
the sulfonamides, the reaction of benzamide 2i is rela-
tively ineffective and had to be heated at a higher tem-
perature (run 20).
Continued
Conditions
(x/y/z, T, t)
1.33/0.5/10
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
1.5/1/40
135 ℃, 24 h
1.5/1/40
135 ℃, 24 h
1.5/1/40
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
2/0.5/10
Yield of
3b/%
Run 1, 2
23d 1a, 2j
24e 1a, 2j
25e 1b, 2j
26c 1d, 2j
27e 1d, 2j
61
82
In addition to above amides, the Pd catalyst can also
catalyze the reactions of heteroaromatic and aromatic
amines effectively under the aerobic conditions;
whereas, in these cases, K2CO3 was found to be not a
suitable base. We then investigated other bases and
found that, like the literature reports,[5-10] alkali metal
hydroxides were the better bases for these substrates. As
shown in Table 2, all the alkali metal hydroxides
showed good activities in these reactions. For example,
2-aminopyrimidine 2j reacted with the electron-rich and
-deficient alcohols to give moderate to high yields of the
alkylated pyrimidyl amines under the aerobic Pd cataly-
sis in the presence of these bases (runs 21—27). When 1
mol% Pd catalyst and 40 mol% NaOH were used, the
reactions were mostly highly efficient, affording the
products in high GC and isolated yields (runs 21, 26).
With catalyst and base loadings reduced to only 0.5
mol% and 10 mol%, the reactions were still very effi-
cient and afforded the products in good yields by using
NaOH or CsOH as the better bases (runs 22, 24). The
reaction of p-cholorobenzyl alcohol 1b afforded only
moderate yield of the product (run 25), possibly because
the present condition (40 mol% CsOH used) is much
more basic than those in the reactions of sulfonamides
(only 10 mol% K2CO3 used, the condition is less basic
and thus no decholorinated byproducts observed), which
could lead to decholorinated byproducts as observed in
the reaction media as in the literature report.[8a] Similar
to aminopyrimidine, the reactions of a series of amino-
pyridines 2k—2m (runs 28—39), aniline 2n (runs 40—
44) and substituted anilines 2o—2q (runs 45—47) also
gave good to high yields of the secondary amines under
similar conditions.
Above results revealed the broad substrate scope and
potential generality of the Pd-catalyzed N-alkylation
method. In addition, that all the reactions can be practi-
cally carried out under air and ligand- and solvent-free
conditions and thus require no inert atmosphere protec-
tion and capricious ligands for catalyst activation, re-
vealed the advantages of the Pd-catalyzed aerobic
N-alkylation method.
The opposite results obtained from the aerobic and
anaerobic reactions, as well as the differences of the
findings in present research to those of the heterogene-
ous reports,[9] attracted our attention on the determina-
tion of the active Pd catalysts and the mechanism of the
reaction. Above results not only revealed clearly the
crucial role of air played in the reactions, but suggested
that, rather than undergoing the well-documented an-
aerobic borrowing hydrogen mechanism in the metal-
catalyzed N-alkylation reactions,[5-10] the present Pd-
55
93 (92)
73
1a
28c
93
2-aminopyridine (2k)
29d 1a, 2k
30e 1a, 2k
31c 1d, 2k
32e 1d, 2k
33c 1e, 2k
34e 1e, 2k
81
96
97 (91)
95
94 (86)
98
135 ℃, 24 h
2/0.5/10
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
1.33/0.5/20
135 ℃, 24 h
1.33/0.5/20
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
1.33/0.5/10
135 ℃, 24 h
2/1/40
135 ℃, 24 h
2/1/40
135 ℃, 24 h
2/1/40
135 ℃, 24 h
2/1/40
135 ℃, 24 h
2/1/40
1a
35c
93 (85)
98
3-aminopyridine (2l)
36d 1a, 2l
37e 1a, 2l
97
1a
38d
92 (86)
83
4-aminopyridine (2m)
39e 1a, 2m
1a
40c
98 (95)
75
PhNH2 (2n)
41d 1a, 2n
42e 1a, 2n
43e 1d, 2n
44e 1e, 2n
94
97 (88)
90 (85)
81
135 ℃, 24 h
2/1/40
135 ℃, 24 h
2/1/40
135 ℃, 24 h
2/1/40
135 ℃, 24 h
1a
45e
p-CH3C6H4NH2 (2o)
1a
46c
70
p-ClC6H4NH2 (2p)
1a
47e
98
1-aminonaphthalene (2q)
a Unless otherwise noted, K2CO3 was used as the base. Reactions
monitored by TLC and/or GC-MS. b GC yields (isolated yields in
parenthesis) based on 2. 3/5 ratios measured by GC are usually
c
d
＞99/1. NaOH used as the base. KOH used as the base.
e CsOH•H2O used as the base.
4
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Chin. J. Chem. 2012, XX, 1—11

Palladium-Catalyzed N-Alkylation of Amides and Amines with Alcohols
catalyzed aerobic reaction is more likely to proceed via
the new relay race mechanism we recently discov-
ered.[11] Thus, complexation of Pd(OAc)2 with the sub-
strates and the corresponding individual reactions in
path b (Scheme 1, M＝Pd) were then investigated to
confirm the possibility for the reaction to undergo the
new mechanism.
As to the nature of the active Pd catalysts, as dis-
cussed below, homogeneous Pd complexes are likely
involved in the reactions. Firstly, Pd(OAc)2, the most
active precatalyst, and many other well-known homo-
geneous Pd catalyst precursors that may produce ho-
mogeneous Pd catalysts[12] are used in the reactions.
Secondly, amides and amines are also known as good
and air-insensitive ligands that have strong ligating
1a to 4a under the reaction condition (runs 1, 11, 12, 15).
The reactions at room temperature also gave consider-
able amounts of 4a (runs 3, 4, 13, 14, 16), indicating
that the aerobic oxidation can be very effective in the
presence of air or in the absence of sulfonamides. Con-
trol oxidation reactions in the presence or the absence of
base (runs 3, 4, 11-14) also revealed that base did not
affect this step too much and thus it should not be a key
additive in this step.
Table 3 Pd-catalyzed alcohol activation/oxidationa
Pd (2.5 mol%)
PhCH2OH
PhCHO
4a
K2CO3, additive, atm., T, t
1a
K2CO3, additive
T, t
Yield of
4ab%
RunPd
abilities toward metals.[14] Considering that coordina-
tions of amines with transition metals have also been
taken into account in N-alkylation reactions in the
past,[15] we deduce Pd-amide/amine complexes might be
generated in situ in the reaction media. For example,
when the mixture of Pd(OAc)2 and 4 equiv. of 2-amino-
pyridine (abbreviated as PyNH2) was subject to LC-MS
analysis under air by using methanol as the solvent,
complexes of the approximate compositions of
Pd(OAc)m(PyNH2)n (m, n＝0, 1, 2, etc.) were clearly
well-distributed in variant amounts in the spectra, with
Pd(PyNH)2 and Pd(OAc)(PyNH)(PyNH2) being the
major complexes (eq. 1).[16] This result implied that, in
present Pd-catalyzed aerobic N-alkylation reactions of
amides/amines with alcohols, homogeneous Pd catalysts
may be generated in situ due to the reason that the am-
ides/amines themselves are in effect air-stable ligands
that can complex with the metal catalyst precursors to
give the active catalysts.[12,14,15] The slight differences of
the different Pd precursors in the effectiveness of gener-
ating the active Pd catalysts may also account for their
different catalytic activities in the reaction (Table 1).
For example, the reaction of Pd black, a heterogeneous
catalyst, was obviously less effective than other homo-
geneous Pd precursors, giving lower yield of the prod-
uct in longer time (Table 1, run 12). However, since Pd
nanoparticles may also be generated from the homoge-
neous Pd precatalysts, an alternative way of nano-Pd-
catalyzed reaction cannot be excluded completely at
present.[17]
(mol%)
1
2
Pd(OAc)2
50, —
50, —
air, 120 ℃, 2 h 44
Pd(OAc)2
N2, 120 ℃, 4 h
air, r.t., 24 h
48 h
air, r.t., 24 h
48 h
4
24
33
25
37
2
3
4
Pd(OAc)2
0, —
Pd(OAc)2
50, —
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
50, —
N2, r.t., 48 h
0, PPh3 (7.5)
50, PPh3 (7.5)
0, PPh3 (7.5)
N2, r.t., 48 h
N2, r.t., 48 h
N2, 120 ℃, 4 h
2
1
2
50, PPh3 (7.5)
50,
PhSO2NH2 (25)
50, —
N2, 120 ℃, 4 h
air, r.t., 24 h
48 h
2
1
2
10 Pd(OAc)2
11 PdCl2
12 PdCl2
air, 120 ℃, 2 h 31
air, 120 ℃, 2 h 25
0, —
air, r.t., 24 h
48 h
air, r.t., 24 h
48 h
21
30
10
12
13 PdCl2
14 PdCl2
50, —
0, —
15 Pd(PPh3)2Cl2 50, —
air, 120 ℃, 4 h 24
air, r.t., 24 h
48 h
21
29
16 Pd(PPh3)2Cl2 50, —
a
Absolute 1a (freshly distilled from CaH2 under vacuum and
stored under nitrogen, 100% purity as confirmed by GC) was
used. Reactions at room temperature were stirred in open air.
Reactions at 120 ℃ were heated in a sealed 50 mL Schlenk tube.
b
Reactions under nitrogen used degassed substrates. GC yields
based on 1a.
MeOH, air, r.t.
Pd(OAc)2
+
PyNH2
Contrary to above results, the efficient aerobic oxi-
dation at room temperature was inhibited greatly by the
absence of air when the reaction was conducted under
nitrogen (run 5), even when heated at 120 ℃ (run 2).
In addition, the anaerobic dehydrogenation reactions in
the presence of a phosphine ligand PPh3 were also inef-
fective under nitrogen either at room temperature (runs
6, 7) or at heating (runs 8, 9). These results revealed
again air’s great promoting effect in the rate-limiting
aldehyde generation step by Pd-catalyzed aerobic oxi-
dation[18] and the clear inhibition of the alcohol oxida-
tion/aldehyde formation by the absence of air.
(4 equiv.)
Pd(OAc)(PyNH) +
minor
Pd(PyNH)2
major
+
Pd(OAc)(PyNH)(PyNH2)
major
+
Pd(PyNH)2(PyNH2)
minor
(1)
+
Pd(OAc)(PyNH)(PyNH2)2
minor
Then, the individual reactions in Scheme 1b were
studied. First step of the reaction, the Pd-catalyzed
aerobic alcohol oxidation (Scheme 1b, step i), is a
well-established process in the literature.[18] As shown
in Table 3, this reaction could also be easily confirmed.
Thus, various Pd catalysts were found active to oxidize
Chin. J. Chem. 2012, XX, 1—11
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Yu et al.
FULL PAPER
On the other hand, the effective aerobic oxidation at
room temperature (runs 3, 4) was greatly inhibited by
the addition of sulfonamide 2a under the same condition
(run 10). This result also consists well with the general
metal catalyst deactivation by the strong ligating am-
ides/amines[14] as we recently discovered and pointed
out.[11b]
The second step of the reaction, the dehydrative
condensation of amides/amines with aldehydes (Scheme
1b, step ii), is another standard organic reaction[19] that
usually occurs under mild conditions. According to the
borrowing hydrogen concept,[5-10] transition metal cata-
lysts do not affect this step. Whereas, in present reac-
tions, Pd catalysts were found to promote the condensa-
tion step in considerable degrees,[16] even greater than
those promoted by the Rh catalysts.[11b] This result is
also consistent with our previous findings and supports
Crabtree’s prediction again that coordination of the in-
termediate aldehyde with the electrophilic metal centers
should increase the electrophilicity of the carbonyl car-
bon and thus enhance the nucleophilic attack by the
amides/amines.[5b]
optimized condition, there is only ca. 6.3 mol% O2
(21% V/V in 20 mL sealed Schlenk tube containing 20
mL air) to a 3 mmol reaction.
Moreover, condensation of aldehydes with amines
followed by reduction of the intermediate imines to al-
kylated amines (Scheme 1b, steps ii—iv) is in fact a
reductive amination reaction well-studied in the litera-
ture.[4] Different to the literature methods using gas hy-
drogen or metal borohydrides as the reducing reagents,[4]
the present reaction uses the alcohol as the reducing
reagents that can be converted to the reactant aldehyde
in the transfer hydrogenation step (step iii). Thus, for-
mation or addition of only catalytic amounts of the
starting aldehyde should be enough for an efficient re-
action. This hypothesis, consistent with the results ob-
tained from the reactions in the condition optimization
section and those using only catalytic amounts of alde-
hyde or imine as the initiators (Table 4), can also be
another support to our mechanistic proposal.
Table 4 Additive effect of the Pd-catalyzed N-alkylation reac-
tiona
Worth noting is that, based on above findings in the
aerobic alcohol oxidation and dehydrative condensation
steps, by careful optimizing the reaction conditions and
by carrying out the reactions under excess amounts of
air, we also developed a direct and mild Pd-catalyzed
aerobic oxidative synthesis of imines from alcohols and
amines.[20] This is a further proof that supports our
above hypothesis on the reaction path of the aerobic
reactions and the final mechanistic conclusions (Scheme
1b, especially steps i and ii).
Pd(OAc)2 (y mol%)
+
Ph
OH PhSO2NH2
Ph
NHSO2Ph
3aa
K2CO3 (z mol%)
additive, N2, 135 oC, 24 h
1a
2a
(x equiv.)
Yield of
3aa/%
Run x, y, z
Additive/mol%
1
2
3
4
5
1.3, 1, 10
PhCHO (10)
94
1.3, 1, 10
1.3, 1, 10
1.2, 1, 20
1.5, 1, 20
1.5, 1, 20
PhSO2N＝CHPh 5aa (9)
TEMPO (20)
PPh3 (5)
72
92
trace
trace
trace
The last step of the reaction, the Pd-catalyzed trans-
fer hydrogenation (Scheme 1b, step iii) could also be
easily confirmed under the standard reaction condition.
In the literature, palladiums have been known as good
catalysts in hydrogenation and transfer hydrogenation
reactions.[21] In our hands, the efficient transfer hydro-
genation of the intermediate imine 5aa to product amide
3aa by alcohol 1a could not only be confirmed at a
lower temperature of 100 ℃, the regeneration of quan-
titative amounts of 4a in this step was also clearly con-
pyridine (3)
6
a
bipyridine (1.5)
Reactions monitored by TLC and/or GC-MS. GC yields based
on 2a.
During the research, we have noticed that the an-
aerobic reactions using commercial 1a that contains
trace aldehyde as the impurity[13] were more effective
than those of the absolute 1a (Table 1, run 10). Indeed,
as shown in Table 4, addition of 10 mol% of 4a could
promote an inefficient reaction greatly to give high yield
of the product under the anaerobic condition (run 1).
Similarly, the intermediate imine 5aa (run 2) that can
generate the aldehyde via transfer hydrogenation (eq. 2)
and TEMPO (run 3), an alcohol oxidation co-catalyst
that can directly oxidize the alcohols to the aldehydes,[22]
were also good initiators for the anaerobic reaction. In
addition, comparing these results with those of the con-
densation, transfer hydrogenation and the condition op-
timization reactions, it can be concluded that the alcohol
activation/aldehyde generation step (Scheme 1b, step i)
is the rate-limiting step of the whole process and is the
only step that requires air for a more effective alcohol
activation/oxidation to aldehydes. Therefore, air (Tables
1—3) or other oxidants (Table 4) that are potential can-
1
firmed by H NMR spectroscopic analysis (eq. 2).[16]
We then deduce, the regenerated aldehyde may be recy-
cled (via step iv) in next condensation reaction, thus
furnishing the consumed aldehyde (previously gener-
ated in aerobic alcohol oxidation in step i) in the cata-
lytic cycle. As a result, only catalytic amount of the air
was required for the generation of the catalytic amount
of aldehyde for an efficient reaction. Indeed, under the
Pd(OAc)2 (1 mol%)
PhCH2OH
+
PhSO2N=CHPh
K2CO3 (20 mol%)
N2, 100 oC
1a
5aa
+
PhCHO PhSO2NHCH2Ph
(2)
4a
3aa
t
GC (NMR) yield/%
4a/3aa (NMR)
6 h 3aa: 60 (60) 4a: 48 (64) 1.07/1.00
8 h 3aa: 69 (71) 4a: 45 (64)
0.90/1.00
6
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—11

Palladium-Catalyzed N-Alkylation of Amides and Amines with Alcohols
didates to afford the aldehydes are all good initiators to
ensure an efficient reaction. In comparison, using air is
the most convenient, practical, efficient, economic and
green protocol.
ligands under the anaerobic conditions, revealing that
they are not typical borrowing hydrogen catalysts in the
reaction. Possibly for this reason, they had not been
used as effective N-alkylation catalysts in the past. On
the contrary, by employing the aerobic relay race meth-
odology, homogeneous Pd catalysts are found to be very
active catalysts for the N-alkylation of various am-
ides/amines with alcohols, leading to a potentially gen-
eral and advantageous ligand-free Pd-catalyzed aerobic
N-alkylation method. To our knowledge, this is the first
successful and efficient homogeneous Pd-catalyzed
N-alkylation reaction of amides and amines with alco-
hols that proceeds via the aerobic relay race mechanism.
Further extension and applications of the Pd-catalyzed
aerobic method are also in progress.[20]
Contrary to above results, attempts to promote the
Pd-catalyzed anaerobic reactions by adding ligands,
which is a typical strategy in the borrowing hydrogen
methodology, failed. For example, PPh3, pyridine and
bipyridine, the frequently adopted ligands in Pd-cata-
lyzed reactions,[3,12,18,21] showed no catalyst activating
capacity at all (Table 4, runs 4—6). Even in the pres-
ence of excess 1a, a smooth anaerobic reaction (Table 1,
run 4) was also inhibited by these ligands in different
degrees, which was also the case with the reactions us-
ing various Pd catalysts.[16] That the ligands could not
activate the Pd catalysts and that Pd catalyst alone is
also ineffective catalyst under anaerobic conditions may
account for that homogeneous Pd catalysts had not been
successfully used in N-alkylation reactions in the past.[5]
These results also differ greatly to the efficient, ligand-
assisted Rh-, Ru- and Ir-catalyzed anaerobic N-alkyla-
tion reactions that were held to proceed via the well-
documented borrowing hydrogen mechanism,[5-11] but,
on the other hand, may demonstrate that, like Cu cata-
lysts,[11d,11e] homogeneous palladiums are not typical
borrowing hydrogen catalysts in the N-alkylation reac-
tions of alcohols and amines.
Regarding that all the individual reactions in path b
of Scheme 1 are well-documented processes in the lit-
erature,[4,18-21] and their occurrence proved as above and
in our related aerobic imination reaction,[20] it can be
assumed that the Pd-catalyzed aerobic N-alkylation re-
action should proceed via the new relay race mechanism
(Scheme 1b). Thus, possibly because Pd is not a typical
borrowing hydrogen transition metal and due to a deac-
tivation by the strong ligating amides/amines, anaerobic
dehydrogenative alcohol activation to aldehydes was the
rate-limiting step in the Pd-catalyzed N-alkylation reac-
tion. Then, air or other additives can be employed to
facilitate this aldehyde generation step as a more effec-
tive alcohol activation process. Once the catalytic
amount of aldehyde 4 was generated via either routes,
the reaction can circulate itself to complete under a mild
condition with 4 being continuously regenerated in
quantitative amount (step iii) and recovered (step iv) in
the catalytic cycle, because, on the other hand, conden-
sation and transfer hydrogenation (steps ii and iii) can
still be very efficient even at lower temperatures (such
as 100 ℃). The findings in the present Pd-catalyzed
N-alkylation reaction are also new proofs supporting our
recent proposal,[11] extending the catalyst scope of the
aerobic relay race methodology.
Experimental
General methods
Substrates and catalysts are all purchased. In reac-
tions carried out under air, substrates and catalysts were
used as purchased without further purification and de-
gassing. In reactions under N2 and mechanistic studies,
unless otherwise noted, absolute alcohols (1) and alde-
hydes (4) were used. Absolute alcohols (1) were ob-
tained by distillation from CaH2 under vacuum and
stored under nitrogen in a Schlenk flask. Its purity
(100%) was confirmed by GC analysis. Aldehydes were
also distilled and stored under nitrogen in a Schlenk
flask. Reactions were carried out in sealed Schlenk
tubes and monitored by TLC and/or GC-MS. GC-MS
and MS analyses were performed on a Shimadzu
GCMS-QP2010 Plus spectrometer (EI). GC yields of
the products were calculated, based on the integrations
of the peaks of the products and reactants, according to
the ratios of the product/(product＋reactant). Products
were purified by column chromatography on silica gel
using petroleum ether and ethyl acetate as the eluent. 1H
and 13C NMR spectra were recorded on a Bruker
1
Avance-III 500 instrument (500 MHz for H and 125.4
MHz for 13C NMR spectroscopy) or a Bruker Avance
1
300 instrument (300 MHz for H and 75 MHz for 13C
NMR spectroscopy). Unless otherwise noted, CDCl3
1
was used as the solvent. Chemical shift values for H
and 13C NMR were referred to internal Me4Si (δ 0).
LC-MS analysis of the in situ generated homogeneous
Pd complexes from Pd(OAc)2 and an amine was ob-
tained from an Esquire HCT (ESI) apparatus using
methanol as the solvent.
Typical procedure for Pd-catalyzed aerobic
N-alkylation of amides/amines with alcohols
The mixture of benzenesulfonamide 2a (0.471 g, 3.0
mmol), Pd(OAc)2 (0.0034 g, 0.015 mmol, 0.5 mol%),
and K2CO3 (0.041 g, 0.3 mmol, 10 mol%) in benzyl
alcohol 1a (0.4 mL, 4.0 mmol, 1.33 equiv.) was stirred
at 135 ℃ under air in a sealed 20 mL Schlenk tube and
monitored by TLC and/or GC-MS. The reaction was
Conclusions
In conclusion, unlike Rh, Ru and Ir catalysts, homo-
geneous Pd catalysts are found unable to catalyze the
N-alkylation reactions even in the presence of various
Chin. J. Chem. 2012, XX, 1—11
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7

Yu et al.
FULL PAPER
then quenched with ethyl acetate and the product puri-
fied by column chromatography with ethyl acetate and
petroleum ether (60—90 ℃) as the eluent, giving
N-benzylbenzenesulfonamide 3aa in 87% isolated yield.
7.20—7.16 (m, 1H), 7.05 (dd, J＝7.5, 1.5 Hz, 1H), 6.81
—6.78 (m, 1H), 6.72 (d, J＝8.0 Hz, 1H), 5.13 (bt, J＝
6.0 Hz, 1H), 4.17 (d, J＝6.5 Hz, 2H), 3.73 (s, 3H). MS
(EI) m/z (%): 277 (5), 141 (4), 136 (100), 121 (15), 107
(11), 92 (9), 91 (24), 77 (29), 65 (8), 51 (10).
N-Benzyl-4-chlorobenzenesulfonamide (3ab)[6d]
White solid. 1H NMR (500 MHz, CDCl3) δ: 7.76 (d, J＝
8.5 Hz, 2H), 7.46 (d, J＝8.5 Hz, 2H), 7.31—7.24 (m,
3H), 7.19—7.17 (m, 2H), 4.94 (bt, J＝5.8 Hz, 1H), 4.15
(d, J＝6.0, 2H). MS (EI) m/z (%): 281 (0.2), 280 (0.25),
177 (4), 112 (6), 111 (16), 107 (8), 106 (100), 104 (16),
91 (17), 79 (17), 77 (14), 75 (10).
Typical procedure for corresponding anaerobic re-
actions
The mixture of benzenesulfonamide 2a (0.157 g, 1.0
mmol), Pd(OAc)2 (0.0112g, 0.05 mmol, 5 mol%), and
K2CO3 (0.138 g, 1.0 mmol, 1.0 equiv.) was degassed
under vacuum and refilled with nitrogen for 3-5 times,
and then absolute benzyl alcohol 1a (0.6 mL, 6.0 mmol,
6 equiv., 100% purity as confirmed by GC analysis) was
added under nitrogen and the tube was then sealed and
heated at 120 ℃. Trace product was detected as moni-
tored by TLC. In cases variant equivalents of 1a and/or
other catalysts were used, trace or no product may be
detected with large amount of the substrates remained
unreacted.
N-Benzyl-2-chlorobenzenesulfonamide
(3ac)[8f]
White solid. 1H NMR (500 MHz, CDCl3) δ: 8.10—8.08
(m, 1H), 7.52—7.47 (m, 2H), 7.42—7.39 (m, 1H), 7.26
—7.24 (m, 3H), 7.20—7.18 (m, 2H), 5.25 (b, 1H), 4.12
(d, J＝6.5 Hz, 2H). MS (EI) m/z (%): 281 (0.1), 280
(0.2), 177 (4), 159 (4), 111 (14), 106 (100), 104 (16), 91
(18), 79 (18), 77 (18), 75 (11), 51(10).
N-Benzylbenzenesulfonamide (3aa)[8f]
White
N-Benzyl-p-toluenesulfonamide (3ad)[6d] White
solid. 1H NMR (500 MHz, CDCl3) δ: 7.76 (d, J＝8.0 Hz,
2H), 7.31—7.23 (m, 5H), 7.20—7.18 (m, 2H), 4.78 (bt,
J＝6.0 Hz, 1H), 4.12 (d, J＝6.0 Hz, 2H), 2.44 (s, 3H).
MS (EI) m/z (%): 261 (0.1), 260 (0.17), 157 (2), 107 (9),
106 (100), 92 (14), 91 (41), 79 (16), 77 (11), 51(5).
N-(4-Chlorobenzyl)-p-toluenesulfonamide (3bd)[8f]
White solid. 1H NMR (500 MHz, CDCl3) δ: 7.74 (d, J＝
8.0 Hz, 2H), 7.32—7.13 (m, 6H), 4.61 (b, 1H), 4.10 (d,
J＝6.5 Hz, 2H), 2.44 (s, 3H). MS (EI) m/z (%): 295
(0.09), 157 (4), 142 (31), 140 (100), 139 (10), 125 (11),
113 (7), 92 (19), 91 (37), 77 (12), 65 (16).
1
solid. H NMR (500 MHz, CDCl3) δ: 7.86—7.83 (m,
2H), 7.57—7.54 (m, 1H), 7.49—7.46 (m, 2H), 7.26—
7.20 (m, 3H), 7.18—7.16 (m, 2H), 5.15 (b, 1H), 4.11 (d,
J＝6.5 Hz, 2H). MS (EI) m/z (%): 246 (0.27), 143 (4),
141 (3), 125 (5), 106 (100), 104 (12), 91 (14), 79 (22),
78 (15), 77 (42), 51 (18).
N-(4-Chlorobenzyl)benzenesulfonamide (3ba)[23]
White solid. 1H NMR (500 MHz, CDCl3) δ: 7.87 (d, J＝
7.5 Hz, 2H), 7.62—7.59 (m, 1H), 7.54—7.51 (m, 2H),
7.26—7.24 (m, 2H), 7.14 (d, J＝8.5 Hz, 2H), 4.65 (b,
1H), 4.13 (d, J＝6.5 Hz, 2H). MS (EI) m/z (%): 281
(0.15), 280 (0.14), 142 (31), 141(13), 140 (100), 138
(14), 125 (19), 113 (8), 89 (6), 78 (14), 77 (46).
N-(3-Chlorobenzyl)-p-toluenesulfonamide (3cd)[8f]
White solid. 1H NMR (300 MHz, CDCl3) δ: 7.70 (d, J＝
8.1 Hz, 2H), 7.26 (d, J＝7.9 Hz, 2H), 7.17—7.07 (m,
4H), 5.38 (bt, J＝5.8 Hz, 1H), 4.07 (d, J＝6.2 Hz, 2H),
2.41(s, 3H). MS (EI) m/z (%): 295 (0.56), 157 (3), 155
(5), 142 (31), 140 (100), 125 (7), 113 (7), 91 (43),
108( 2), 91 (43), 77 (11), 65 (18).
N-(3-Chlorobenzyl)benzenesulfonamide (3ca)[24]
White solid. 1H NMR (500 MHz, CDCl3) δ: 7.85—7.83
(m, 2H), 7.59—7.56 (m, 1H), 7.51—7.48 (m, 2H),
7.20—7.15 (m, 3H), 7.08 (d, J＝6.5 Hz, 1H), 5.21 (b,
1H), 4.11 (d, J＝6.5 Hz, 2H). MS (EI) m/z (%): 281
(0.69), 142 (32), 140 (100), 141(14), 125 (13), 113 (8),
78 (15), 77 (47), 51 (12).
N-(4-Methoxybenzyl)-p-toluenesulfonamide
1
(3ed)[27] White solid; H NMR (300 MHz, CDCl3) δ:
N-(4-Methylbenzyl)benzenesulfonamide (3da)[25]
White solid. 1H NMR (500 MHz, CDCl3) δ: 7.90—7.87
(m, 2H), 7.61—7.58 (m, 1H), 7.54—7.51 (m, 2H),
7.09—7.05 (m, 4H), 4.59 (b, 1H), 4.11 (d, J＝6.0 Hz,
2H), 2.31 (s, 3H). MS (EI) m/z (%): 261 (0.6), 143 (3),
120 (100), 118 (28), 105 (11), 93 (16), 91 (16), 77 (25),
65 (6), 51 (7).
7.74 (d, J＝8.2 Hz, 2H), 7.29 (d, J＝8.1 Hz, 2H), 7.09
(d, J＝8.5 Hz, 2H), 6.78 (d, J＝8.6 Hz, 2H), 4.89 (bt,
J＝5.7 Hz, 1H), 4.03 (d, J＝6.1 Hz, 2H), 3.76 (s, 3H),
2.43 (s, 3H). MS (EI) m/z (%): 291 (4), 155 (2), 137 (8),
136 (94), 135 (100), 134 (56), 121 (30), 109 (11), 108
(6), 91 (31), 77 (13), 65 (17).
N-Benzyl-o-toluenesulfonamide (3ae)[28] Colour-
N-(4-Methoxybenzyl)benzenesulfonamide (3ea)[26]
White solid. 1H NMR (500 MHz, CDCl3) δ: 7.76 (d, J＝
7.5 Hz, 2H), 7.50—7.47 (m, 1H), 7.41—7.38 (m, 2H),
7.20—7.16 (m, 1H), 7.06—7.04 (d, J＝7.5 Hz, 1H),
6.81—6.78 (m, 1H), 6.72—6.71 (d, J＝8.0 Hz, 1H),
5.17 (b, 1H), 4.17 (d, J＝6.5 Hz, 2H), 3.72 (s, 3H). MS
(EI) m/z (%): 277 (5), 141 (2), 136 (62), 135 (100), 134
(56), 121 (26), 109 (8), 93 (4), 77 (32), 51 (8).
1
less oil. H NMR (500 MHz, CDCl3) δ: 8.0 (d, J＝7.5
Hz, 1H), 7.48—7.45 (m, 1H), 7.33—7.15 (m, 7H), 4.7
(b, 1H), 4.12 (d, J＝6.0 Hz, 2H), 2.62 (s, 3H). MS (EI)
m/z (%): 261 (0.16), 157 (3), 155 (1), 107 (9), 106 (100),
92 (10), 91 (50), 77 (10), 65 (12).
N-Benzyl-4-methoxybenzenesulfonamide (3af)[6d]
White solid. 1H NMR (500 MHz, CDCl3) δ: 7.81 (d, J＝
8.5 Hz, 2H), 7.30—7.24 (m, 3H), 7.20—7.19 (m, 2H),
6.98 (d, J＝9.0 Hz, 2H), 4.65 (bt, J＝5.5 Hz, 1H), 4.12
(d, J＝6.5 Hz, 2H), 3.88 (s, 3H). MS (EI) m/z (%): 277
(3), 212 (1), 172 (4), 155 (13), 123 (19), 108 (24), 107
N-(2-Methoxybenzyl)benzenesulfonamide (3fa)[11b]
White solid. 1H NMR (500 MHz, CDCl3) δ: 7.78—7.76
(m, 2H), 7.50—7.47 (m, 1H), 7.42—7.38 (m, 2H),
8
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—11

Palladium-Catalyzed N-Alkylation of Amides and Amines with Alcohols
(18), 106 (100), 91 (14), 79 (11), 77 (22), 64 (6).
(EI) m/z (%): 184 (56), 183 (27), 182 (2), 154 (3), 127
(1), 116 (2), 107 (22), 106 (100), 91 (48), 79 (44), 78
(30), 65 (23).
N-Benzyl-2-naphthalenesulfonamide
(3ag)[6d]
White solid. 1H NMR (500 MHz, CDCl3) δ: 8.45 (s, 1H),
7.98—7.96 (m, 2H), 7.92 (m, J＝6.0 Hz, 1H), 7.84 (dd,
J＝9.0, 1.5 Hz, 1H), 7.68—7.61 (m, 2H), 7.26—7.18
(m, 5H), 4.77 (bt, J＝5.8 Hz, 1H), 4.18 (d, J＝6.0 Hz,
2H). MS (EI) m/z (%): 298 (2), 297 (10), 192 (6), 175
(2), 144 (8), 128 (48), 127 (56), 126 (10), 115 (8), 106
(100), 91 (16), 79 (11), 77 (18).
N-(4-Methylbenzyl)-(2-pyridyl)amine
(3dk)[10b]
White solid. 1H NMR (500 MHz, CDCl3) δ: 8.04—8.03
(m, 1H), 7.39—7.36 (m, 1H), 7.25—7.21 (m, 2H),
7.16—7.12 (m, 2H), 6.57—6.55 (m, 1H), 6.35—6.32
(m, 1H), 4.40 (d, J＝5.5 Hz, 2H), 2.33 (s, 3H). MS (EI)
m/z (%): 198 (99), 183 (13), 120 (100), 105 (70), 93
(15), 91 (10), 79 (27), 78 (23), 77 (15), 51 (6).
N-Benzylmethanesulfonamide (3ah)[8f]
White
1
solid. H NMR (500 MHz, CDCl3) δ: 7.40—7.31 (m,
5H), 4.62 (b, 1H), 4.33 (d, J＝6.0 Hz, 2H), 2.88 (s, 3H).
MS (EI) m/z (%): 185 (1), 184(0.4), 106 (100), 105 (18),
104 (44), 91 (28), 79 (29), 78 (12), 77 (20), 51 (11).
N-(2-Pyridylmethyl)benzenesulfonamide (3ga)[29]
N-(4-Methoxybenzyl)-(2-pyridyl)amine (3ek)[10b]
White solid. 1H NMR (500 MHz, CDCl3) δ: 7.37—7.34
(m, 2H), 7.29 (d, J＝9.0 Hz, 2H), 6.97—6.94 (m, 2H),
6.91 (d, J＝9.0 Hz, 2H), 4.99 (s, 2H), 4.62 (s, 1H), 3.81
(s, 3H). MS (EI) m/z (%): 214 (47), 199 (5), 183 (2),
136 (28), 121 (100), 107 (4), 105 (7), 91 (9), 78 (17), 77
(9), 51 (5).
1
Yellow solid. H NMR (500 MHz, CDCl3) δ: 8.45 (d,
J＝4.8 Hz, 1H), 7.86 (d, J＝7.5 Hz, 2H), 7.61—7.58 (m,
1H), 7.53—7.50 (m, 1H), 7.46—7.43 (m, 2H), 7.17—
7.14 (m, 2H), 6.00 (b, 1H), 4.27 (d, J＝5.3 Hz, 2H). MS
(EI) m/z (%): 248 (0.18), 184 (59), 183 (37), 141 (16),
107 (100), 92 (14), 78 (24), 77 (57), 51 (27).
N-Benzyl-(3-pyridyl)amine (3al)[7f] Yellow solid.
1H NMR (500 MHz, CDCl3) δ: 8.07 (d, J＝2.5 Hz, 1H),
7.96 (d, J＝4.5 Hz, 1H), 7.36—7.27 (m, 5H), 7.08—
7.05 (dd, J＝8.5, 5.0 Hz, 1H), 6.88—6.86 (dd, J＝8.5,
1.5 Hz, 1H), 4.34 (s, 2H), 4.20 (b, 1H). MS (EI) m/z (%):
184 (33), 183 (4), 92 (8), 91 (100), 78 (8), 77 (3), 65
(16), 51 (7).
N-(2-Thiophenylmethyl)-p-toluenesulfonamide
(3hd)[8f] Yellow solid. 1H NMR (300 MHz, CDCl3) δ:
7.74 (d, J＝8.2 Hz, 2H), 7.29 (d, J＝8.1 Hz, 2H),
7.17—7.16 (m, 1H), 6.87—6.84 (m, 2H), 5.14 (bt, J＝
5.8 Hz, 1H), 4.30 (d, J＝6.1 Hz, 2H), 2.42 (s, 3H). MS
(EI) m/z (%): 267 (0.7), 157 (2), 139 (5), 112 (100), 111
(17), 110 (13), 97 (21), 91 (31), 85 (22), 65 (18).
N-Benzyl-(4-pyridyl)amine (3am)[34] White solid.
1H NMR (500 MHz, CDCl3) δ: 8.19—8.18 (d, J＝4.5
Hz, 2H), 7.37—7.24 (m, 5H), 6.47—6.44 (m, 2H), 4.68
(b, 1H), 4.37—4.34 (m, 2H). MS (EI) m/z (%): 184 (50),
107 (8), 91 (100), 78 (8), 65 (13), 51 (8).
N-Benzylbenzamide (3ai)[30]
White solid. 1H
1
NMR (500 MHz, CDCl3) δ: 7.79 (d, J＝7.5 Hz, 2H),
7.50—8.48 (m, 1H), 7.43—7.40 (m, 2H), 7.35—7.27
(m, 5H), 6.53 (b, 1H), 4.63 (d, J＝5.5 Hz, 2H). MS (EI)
m/z (%): 211 (42), 210 (17), 134 (1), 106 (8), 105 (100),
91 (10), 79 (6), 77 (64), 51 (19).
N-Benzylaniline (3an)[35] Colourless oil. H NMR
(500 MHz, CDCl3) δ: 7.37—7.32 (m, 4H), 7.28—7.25
(m, 1H), 7.19—7.15 (m, 2H), 6.73—6.70 (m, 1H),
6.64—6.62 (m, 2H), 4.30 (s, 2H), 4.06 (br, 1H). MS (EI)
m/z (%): 183 (41), 182 (15), 106 (17), 104 (10), 92 (9),
91 (100), 77 (20), 65 (19), 51 (10).
N-Benzyl-(2-pyrimidyl)amine (3aj)[31]
White
1
solid. H NMR (500 MHz, CDCl3) δ: 8.22 (b, 2H),
7.37—7.26 (m, 5H), 6.52 (dd, J＝4.5, 5.0 Hz, 1H), 5.84
(b, 1H), 4.64 (d, J＝6.0 Hz, 2H). MS (EI) m/z (%): 186
(10), 185 (80), 184 (55), 157 (3), 144 (3), 129 (2), 108
(19), 106 (100), 91 (51), 81 (13), 80 (24), 79 (40), 77
(15), 65 (32), 53 (20).
N-(4-Methylbenzyl)aniline (3dn)[36] White solid.
1H NMR (500 MHz, CDCl3) δ: 7.25—7.24 (m, 2H),
7.18—7.14 (m, 4H), 6.73—6.70 (m, 1H), 6.65—6.63
(m, 2H), 4.27 (s, 2H), 2.34 (s, 3H). MS (EI) m/z (%):
197 (52), 106 (12), 105 (100), 91 (3), 77 (14), 65 (3), 51
(3).
N-(4-Chlorobenzyl)-(2-pyrimidyl)amine (3bj)[32]
White solid. 1H NMR (500 MHz, CDCl3) δ: 8.28 (d, J＝
5.0 Hz, 2H), 7.31—7.27 (m, 4H), 6.60 (dd, J＝5.0, 5.0
Hz, 1H), 5.52 (b, 1H), 4.61 (d, J＝6.0 Hz, 2H). MS (EI)
m/z (%): 219 (100), 184 (43), 140 (87), 125 (38), 108
(16), 90 (6), 89 (24), 80 (27), 77 (9), 53 (14).
N-(4-Methoxybenzyl)aniline (3en)[37] Yellow oil.
1H NMR (500 MHz, CDCl3) δ: 7.23 (d, J＝7.5 Hz, 2H),
7.15—7.11 (m, 2H), 6.84—6.82 (m, 2H), 6.69—6.63
(m, 1H), 6.57 (d, J＝7.5 Hz, 2H), 4.18 (s, 2H), 3.88 (b,
1H), 3.73 (s, 3H). MS (EI) m/z (%): 213 (27), 121 (100),
106 (3), 91 (5), 77 (9), 51 (2).
N-(4-Methylbenzyl)-(2-pyrimidyl)amine (3dj)[33]
White solid. 1H NMR (500 MHz, CDCl3) δ: 8.28 (d, J＝
5.0 Hz, 2H), 7.25 (d, J＝8.0 Hz, 2H), 7.14 (d, J＝8.0 Hz,
2H), 6.55 (dd, J＝5.0, 5.0 Hz, 1H), 5.42 (b, 1H), 4.60 (d,
J＝6.0 Hz, 2H), 2.34 (s, 3H). MS (EI) m/z (%): 199
(100), 184 (55), 120 (42), 108 (8), 105 (38), 93 (12), 91
(10), 79 (21), 77 (14), 53 (6).
N-Benzyl-4-methylaniline (3ao)[36] Yellow oil. 1H
NMR (500 MHz, CDCl3) δ: 7.37—7.31 (m, 4H), 7.27—
7.22 (m, 1H), 6.98 (d, J＝8.0 Hz, 2H), 6.56 (d, J＝8.5
Hz, 2H), 4.29 (s, 2H), 2.23 (s, 3H). MS (EI) m/z (%):
197 (69), 120 (23), 118 (7), 106 (5), 91 (100), 77 (7), 65
(15).
1
N-Benzyl-4-chloroaniline (3ap)[36] Yellow oil. H
N-Benzyl-(2-pyridyl)amine (3ak)[7a] White solid.
1H NMR (500 MHz, CDCl3) δ: 8.10 (d, J＝5.0 Hz, 1H),
7.42—7.26 (m, 6H), 6.60—6.58 (m, 1H), 6.37 (d, J＝
10.0 Hz, 1H), 4.95 (b, 1H), 4.51 (d, J＝6.0 Hz, 2H). MS
NMR (500 MHz, CDCl3) δ: 7.34—7.31 (m, 4H), 7.29—
7.25 (m, 1H), 7.11—7.08 (m, 2H), 6.55—6.52 (m, 2H),
4.28 (s, 2H). MS (EI) m/z (%): 217 (33), 180 (1), 140
(6), 111 (4), 91 (100), 77 (3), 65 (10).
Chin. J. Chem. 2012, XX, 1—11
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
9

Yu et al.
FULL PAPER
N-Benzylnaphthalen-1-amine (3aq)[38]
White
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When our work was previously considered by other journals (first
submitted on 10 June, 2011), Ramón and coworkers reported a
Pd-catalyzed N-alkylation method employing the hydrogen auto-
transfer process (submitted on 29 July 2011): Martínez-Asencio, A.;
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1
solid. H NMR (500 MHz, CDCl3) δ: 7.97 (b, 1H),
7.82—7.80 (m, 1H), 7.49—7.46 (m, 2H), 7.41—7.37
(m, 3H), 7.32—7.22 (m, 5H), 6.84 (b, 1H), 4.53 (s, 2H).
MS (EI) m/z (%): 233 (99), 156 (5), 142 (24), 127 (9),
144 (3), 115 (36), 91 (100), 89 (3), 77 (4), 65 (10).
Acknowledgement
We thank NNSFC (No. 20902070), SRF for ROCS
of SEM, NSF (No. Y4100579) and QJTP (No.
QJD0902004) of Zhejiang Province for financial sup-
port. X. Yu and Y. Xie thank the Opening Foundation
of Zhejing Provincial Top Key Disciplines (Nos.
100061200123 and 100061200134).
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