Efficient and practical catalyst-free-like dehydrative N-alkylation of amines and sulfinamides with alcohols initiated by aerobic oxidation of alcohols under air

Article abstract of DOI:10.1016/j.tet.2015.11.016

We developed simple and practical N-alkylation reactions of amines and sulfinamides with primary and secondary alcohols by using only catalytic amounts of air as the initiator without adding any external catalysts. This method has advantages of simple conditions, easy operation, and comparatively wider scope of substrates, providing an efficient and green catalyst-free-like alcohol-based dehydrative N-alkylation method. Mechanistic studies revealed that air initiated the reactions by aerobic oxidation of the alcohols to the key initiating aldehydes or ketones in the presence of bases.

Full text of DOI:10.1016/j.tet.2015.11.016

Accepted Manuscript
Efficient and Practical Catalyst-Free-Like Dehydrative N-Alkylation of Amines and
Sulfinamides with Alcohols Initiated by Aerobic Oxidation of Alcohols under Air
Xiaohui Li, Shuangyan Li, Qiang Li, Dong Xu, Yang Li, Xiaochun Yu, Qing Xu
PII:
S0040-4020(15)30200-3
10.1016/j.tet.2015.11.016
TET 27272
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 July 2015
Revised Date: 4 November 2015
Accepted Date: 12 November 2015
Please cite this article as: Li X, Li S, Li Q, Xu D, Li Y, Yu X, Xu Q, Efficient and Practical Catalyst-Free-
Like Dehydrative N-Alkylation of Amines and Sulfinamides with Alcohols Initiated by Aerobic Oxidation of
Alcohols under Air, Tetrahedron (2015), doi: 10.1016/j.tet.2015.11.016.
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ACCEPTED MANUSCRIPT
Efficient and Practical Catalyst-Free-Like Dehydrative N-Alkylation of Amines and Sulfinamides with
Alcohols Initiated by Aerobic Oxidation of Alcohols under Air
Xiaohui Li, Shuangyan Li, Qiang Li, Xu Dong, Yang Li, Xiaochun Yu, and Qing Xu*
[O] (air)
N
O
R3
R3
R4
OH
R2
R3
R1
Initiation
NH2
R1
or
OH
NH2
or
R1
R2
O
R1
or
R1
R2
R1
R N
R N
O
S
initiated by aerobic alcohol oxidation under air
no external catalysts required
N
S
H
H
NH2
R3
NH2
+ H2O
We developed simple and practical N-alkylation reactions of amines and sulfinamides with primary and
secondary alcohols by using only catalytic amounts of air as the initiator without adding any external catalysts.
This method has advantages of simple conditions, easy operation, and comparatively wider scope of substrates,
providing an efficient and green catalyst-free-like alcohol-based dehydrative N-alkylation method. Mechanistic
studies revealed that air initiated the reactions by aerobic oxidation of the alcohols to the key initiating
aldehdyes or ketones in the presence of bases.
1

ACCEPTED MANUSCRIPT
Efficient and Practical Catalyst-Free-Like Dehydrative N-Alkylation of
Amines and Sulfinamides with Alcohols Initiated by Aerobic Oxidation
of Alcohols under Air
Xiaohui Li, Shuangyan Li, Qiang Li, Xu Dong, Yang Li, Xiaochun Yu, and Qing Xu*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, P. R. China
Abstract: We developed simple and practical N-alkylation reactions of amines and sulfinamides
with primary and secondary alcohols by using only catalytic amounts of air as the initiator
without adding any external catalysts. This method has advantages of simple conditions, easy
operation, and comparatively wider scope of substrates, providing an efficient and green
catalyst-free-like alcohol-based dehydrative N-alkylation method. Mechanistic studies revealed
that air initiated the reactions by aerobic oxidation of the alcohols to the key initiating aldehdyes
or ketones in the presence of bases.
Keywords: alcohols; N-alkylation; amines; aerobic alcohol oxidation; catalyst-free-like
1. Introduction
Organonitrogen compounds such as amines and amides are key structures in natural
products, bioactive molecules, and pharmaceuticals.1 Therefore, developing efficient, practical,
and green C-N construction methods for the synthesis of amine and amide derivatives is one of
the major topics in synthetic chemistry. In comparison with other methodologies, transition metal
(TM)-catalyzed anaerobic dehydrogenative N-alkylation of amines and amides with alcohols,
namely the borrowing hydrogen or hydrogen autotransfer methodology (Scheme 1A),2 has
recently become a useful way to obtain the versatile amine and amide derivatives, mostly due to
the green features of the readily available alcohols and their advantages over the organohalides
* Corresponding author. Tel: +86-13857745327; Fax: +86-577-86689302; email: qing-xu@wzu.edu.cn
2

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and carbonyl compounds.2-3 In previous studies, we accidentally observed that air could greatly
facilitate an Rh-catalyzed dehydrative N-alkylation reaction of sulfonamides and alcohols,4
which subsequently led to the development of air-promoted TM-catalyzed aerobic dehydrative
N- and C-alkylation reactions (Scheme 1B),5 aerobic imination reactions,6 and the proposal of an
interesting relay race mechanism for these reactions.4-6 Two major advantages of these aerobic
methods are that 1) no inert atmosphere protection is necessary, and thus the reactions can be
readily performed under air and 2) since air can greatly promote the reactions, ligand-free TM
salts even non-noble metals such as Cu and Mn could be directly used as the catalysts,4,5
avoiding the use of capricious ligands to active the TM catalysts and the thermally unfavorable
anaerobic dehydrogenative alcohol activation process.2 Based on these findings and supported by
the literature such as the cross-dehydrogenative coupling (CDC) reactions,7 multi-step
N-alkylation reactions,8 and TM-catalyzed aerobic oxidation of alcohols,9 we proposed that there
should be more efficient and green alternatives for alcohol activation10 in addition to the
anaerobic dehydrogenation strategy.2 Indeed, we later found that addition of aldehydes11 or
organohalides12 could be new ways for alcohol activation and developed TM-free aldehyde- or
organohalides-catalyzed N-, C-, and O-alkylation methods for amides, amines, and primary and
secondary alcohols (Scheme 1C). In addition, certain substrates were also found to take effect in
alcohol activation, leading to catalyst-free autocatalyzed dehydrative C- and N-alkylation of
methyl ketones and certain heteroaryl amines (Scheme 1D).13,14
Although above TM-free methods have their own advantages, the aldehyde- or
organohalide-catalyzed methods require the use of respective aldehydes or organohalides
corresponding to the alcohols11,12 and the autocatalyzed methods are restrained to certain
substrates.13 Therefore, more general methods are still highly desirable in the field, which
reasonably became our long-term targets and part of our projects. Recently the groups of Zhao,
Xia, and Adimurthy independently reported transition metal-free N-alkylation reactions under
aerobic conditions.15 However, in Zhao’s method, a mixture of O2 and argon was required to
initiate the reaction, which is not so practical in operation;15a whereas, Xia’s method requires a
o
very harsh condition (≥220 C) and air’s role in the reaction was not identified.15b On the other
hand, in our own studies on N-alkylation reactions of certain heteroarylamines, we have
observed that air was not required in the reactions so that they could occur under catalyst-free
3

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conditions,13b,14 and therefore Adimurthy’s reaction having almost the same scope of substrates15c
might also proceed via an alternative mechanism other than the one they proposed. All these
reports prompted us to report more of our own findings in this area. Herein we report air-initiated
catalyst-free-like dehydrative N-alkylation reactions of amines and sulfinamides with primary
and secondary alcohols, which provides a simple and efficient, practical and green alkylation
method for synthesis of the useful amine and sulfonamide derivatives without using any external
catalysts14 (Scheme 1E).
A. TM-Catalyzed Anaerobic Borrowing Hydrogen or Hydrogen Autotransfer Methodology
(TM = Ru, Ir, etc.; Nu = N, C)
R2
O
R2
R1 Nu
cat. TM/L, base
under N2 or Ar
R2-Nu
Nu
R1
reduction
R1 OH
R1
[MH] or [MH2]
condensation
dehydrogenative activation
- H2O
B. Air-Promoted TM-Catalyzed Dehydrative Alkylation Methods
(TM = Rh, Ru, Ir, Pd, Mn, Cu; Nu = N, C)
R2
O
R1 OH
base
R2-Nu
Nu
cat. TM, ligand-free
R2
R1 Nu
R1 OH
R1
under air
aerobic oxidative activation
condensation
R1
cat. TM
- H2O
C. Aldehyde- or Organohalide-Catalyzed TM-Free Dehydrative Alkylation Methods
OH
OH
cat. R1CHO
under air or N2
- H2O
R2
R2-NH2
HO R2
R1
OH
+
R1
N
or
R2
or
R2
R1
H
CH3
cat. R1-X or R2-X
O
R1 O H
R1
R2
+
under air
- H2O
D. Catalyst-Free Substrate-Autocatalyzed Dehydrative Alkylation Methods
(X = O, Nu = CH; or X = N, Nu = N)
XH
Nu R1
X
catalyst-free
autocatalyzed
NuH2
under air or N2
X
R1
OH
+
or
Nu R1
H
R
R
R
H
- H2O
E. Air-Initiated Catalyst-Free-Like Dehydrative N-Alkylation Reaction (This Work):
OH
N
R3
R3
R4
R1
OH
R2
R3
or
NH2
NH2
R1
R2
R1
R1
or
under air
R N
R N
O
S
initiated by air
no external catalyst
N
S
H
H
NH2
R3
NH2
- H2O
Scheme 1. Alcohol-Based Dehydrative Alkylation Methods.
4

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2. Results and Discussion
In previous studies,11a we observed that certain non-metal oxidants could also be used to
initiate the N-alkylation of sulfonamides with alcohols, which we gradually realized could
become a useful protocol potentially more general than the aldehyde-catalyzed method. Since air
can promote the TM-catalyzed alkylation reactions4,5,16,17 and we and other groups have also
noticed the base’s effect in aerobic alcohol oxidation18 and corresponding synthetic
applications,19 it occurred to us that air alone may also be a good promoter for the TM-free
N-alkylation reactions. This hypothesis, if achieved, can colligate the advantages of both
air-promoted TM-catalyzed4,5 and aldehyde-catalyzed11 methods, and thus lead to
catalyst-free-like N-alkylation reactions without using both TM catalysts and the corresponding
aldehydes.14 With these in mind, we initially investigated the reactions of benzyl alcohol (1a) and
11a
benzenesulfonamide (2a) with their best base K2CO3 under air (eq. 1). Contrary to our
expectation, no reaction occurred at all. This may be due to the weak basicity and consequently
weak activity of K2CO3 in aerobic oxidation of alcohols18 (vide infra for comparison). We also
investigated K2CO3-MOH (M = Na, K, Cs) bi-base systems for the reaction, but they were not
effective, either.19,20
air (10-50 mL, ca. 5~25 mol% O2)
Ph
NHSO2Ph
3a
no reaction
PhSO2NH2
OH +
Ph
(1)
K2CO3 (20 mol%)
135 oC, 24 h
1a
2a
Despite of these failed attempts, we continued to investigate other amines and amides such
as anilines, a class of substrates incapable of undergoing autocatalyzed N-alkylation reaction.13b
Thus, when the above aerobic protocol was applied to aniline (4a) using CsOH as the base, the
reaction readily afforded a good yield of the target amine 5a in a high selectivity, without
detecting the possible imine byproduct 5a’ (Table 1, run 1). On the contrary, when redistilled
pure 1a (100% purity without aldehyde contaminant, as confirmed by GC analysis) was used
instead of commercial 1a in control reactions under nitrogen,22 no reaction or only trace amount
of 5a was detected in the presence of usual bases such as LiOH, NaOH, KOH, or CsOH (run 2).
5

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These contrastive results clearly revealed the great facilitation effect of air on this N-alkylation
reaction. Base screening under air showed that, while the reactions of other bases generated
lower yields of 5a and varied amounts of byproduct 5a’ (runs 3-5), the reaction of CsOH could
give a high 90% isolated yield of 5a with the highest selectivity of >99/1 (run 6). These results
showed that CsOH is the most effective base for the reaction. Less loadings of CsOH (run 7) and
lower temperatures led to lower yields of 5a, but more loadings of CsOH and higher
o
temperatures (run 8) gave no much better results. Thus, running the reaction at 130 C for 24 h
with 30 mol% of CsOH are the best conditions for the reaction of 1a and 4a (run 6).
Table 1. Condition Screening for Air-Initiated Catalyst-Free-Like N-Alkylation of Aniline with
Benzyl Alcohol.a,14
base, atm., T, 24 h
Ph N
Ph N
5a'
Ph NH2
Ph
+
OH
Ph
Ph
H
- H2O
1a
5a
4a
b
run
1
base (mol%)
CsOH·H2O (50)
MOH (50)
atm., T
5a
%
5a/
5a’c
air, 140 oC
N2, 100-150 oC
air, 130 oC
air, 130 oC
air, 130 oC
air, 130 oC
air, 130 oC
air, 150 oC
79
>99/1
--
2d
NDe/trace
3
LiOH (30)
NDe
<1/99
90/10
92/8
4
NaOH (30)
40
5
KOH (30)
50
6
CsOH·H2O (30)
CsOH·H2O (10)
CsOH·H2O (30)
90
>99/1
44/56
>99/1
7
27
8
92
a Unless otherwise noted, the neat mixture of commercial 1a (3 mmol, 1.5 equiv.), 4a (2 mmol),
and a base was sealed in a 20 mL Schlenk tube under air or N2 and then heated and monitored by
b
c
d
TLC/GC-MS. Isolated yields based on 4a. Determined by GC-MS. Redistilled 1a of 100%
purity was used. M = Li, Na, K, Cs. e Not detected.
6

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Table 2. Air-Initiated Catalyst-Free-Like N-Alkylation of Anilines with Primary Alcohols.a,14
CsOH.H2O
air, 150 oC, 24 h
R2 NH2
R1
R1
+
OH
R2
N
H
5
4
1
- H2O
b
run
1
R1 (
1
)
R2 (
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4
)
CsOH (mol%)
5%
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
Ph
20
20
20
20
20
20
30
30
30
10
30
30
20
30
5b: 93
5c: 83
2
3
5d: 69
5e: 93
4
5
5f: 96
6
5g: 75
5h: 50
5i: 90
7
8
9
5j: - (complex)
5k: 87
5l: 90
10
11
12
13
14
4-MeC6H4
4-MeC6H4
2-MeC6H4
3-MeOC6H4
4-ClC6H4
4-MeC6H4
Ph
5m: 75
5n: 92
5o: 95
Ph
Ph
15
Ph
30
5p: 90
a The neat mixture of commercial 1 (3.0 mmol, 1.5 equiv.), 4 (2.0 mmol), and CsOHꢀH2O (10-30
o
b
mol%) was sealed under air in a 20 mL Schlenk tube and then heated at 150 C for 24 h.
Isolated yields based on 4.
The above method were then applied to different anilines and benzylic alchols to extend the
scope of the air-initiated N-alkylation method. As shown in Table 2, slightly different to
unsubstituted 1a and 4a (Table 1), the reactions of both substituted benzylic alcohols and
o
substituted anilines require a higher temperature of 150 C to achieve good results. Besides,
many reactions could use less loadings of CsOH (10-20 mol%) but still maintaining high
reaction efficiencies to give good to high yields of the products. Thus, most of the substrates,
7

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including the more bulky 2-substitued ones (Table 2, runs 3, 6, 12, 15) and the ones with the
reactive Cl group (runs 8, 14), gave good to high isolated yields of the target products under
similar conditions. The 2-substituted benzylic alcohols and anilines (runs 3, 6, 12) generally gave
slightly lower yields of the products than the corresponding 3- or 4-substituted ones (runs 1, 2, 4,
5, 10, 11), most possibly due to the steric hindrance of the 2-positioned groups. In the cases of
chlorobenzylic alcohols (runs 7-9), even though we tried many conditions, the reaction of
4-chlorobenzylic alcohol still gave a relatively lower yield of the product (run 7); what is more,
2-chlorobenzylic alcohol gave a complex reaction mixture that is difficult to purify the observed
low yield of the target product in the mixture (run 9). This is most possibly due to the potential
aromatic nuleophilic substitution (SNAr) reactions occurred with the in situ generated
intermediates 2- and 4-chlorobenzaldehydes23 during the initial aerobic alcohol oxidation step
(see mechanism section), which led to consumption of the base and the intermediate aldehydes
and then incomplete conversion of the reactants and lower reaction efficiency as observed. We
also investigated some benzylic alcohols bearing electron-withdrawing groups (EWGs) such as
the nitro, formyl, and acetyl groups under similar conditions. However, complex reactions
occurred and gave mixtures of low yields of the products and unidentified byproducts, most
possibly due to the reactive nature and possible side-reactions of these EWGs under the basic
conditions.24,25 In addition, we also tried many times the reactions of aliphatic alcohols with
anilines to extend the scope of the method, but they were not efficient even under harsher
reaction conditions like higher temperatures and more loadings of bases, giving only trace yields
of the target products.26
With these satisfactory results in hand, N-alkylation reactions of aminopyridines, another
class of lowly active substrates in autocatalytic reaction,13b were then investigated. As shown in
Table 3, the reaction of 1a and 2-aminopyridine 6a under air readily afforded a moderate yield of
target 7a at 135 oC in the presence of 50 mol% NaOH (run 1). In this reaction, the same with our
previous observation,11a NaOH was found to be the best base for 2-aminopyridine. The reaction
o
was more efficient at 150 C, giving a high yield of 7a (run 2). A higher loading of NaOH did
not improve the product yield very much (run 3), but a lower loading could lead to obvious drop
in product yield (run 4). Besides, the reactions using pure 1a still gave good yields of the product
(runs 5-6). These results showed that air was very efficient to promote the reactions in the
8

ACCEPTED MANUSCRIPT
absence of aldehdyes (known contaminants in commercial alcochols).5c,11a In great contrast,
another control reaction using pure 1a under nitrogen was ineffective at all,22 clearly revealing
again the facilitation effect of air on the reaction.
Table 3. Condition Screening for Air-Initiated Catalyst-Free-Like N-Alkylation of
2-Aminopyridine with Benzyl Alcohol.a,14
NaOH, atm., T, 24 h
Ph
OH
+
N
N
Ph
N
6a
NH2
- H2O
1a
H
7a
b
run
1
NaOH (mol%)
atm., T
7a
72
89
90
77
80
69
%
50
50
80
30
50
30
50
air, 135 oC
air, 150 oC
air, 150 oC
air, 150 oC
air, 150 oC
air, 150 oC
N2, 150 oC
2
3
4
5c
6c
7c
≤ 5
a The neat mixture of commercial 1a (3 mmol, 1.5 equiv.), 6a (2 mmol), and NaOH was sealedin
a 20 mL Schlenk tube under air or N2 and then heated and monitored by TLC/GC-MS. b Isolated
yields based on 6a. Selectivities for 7a are all >99% since no imine byproduct was observed by
GC-MS analysis. c Redistilled 1a of 100% purity was used.
9

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Table 4. Air-Initiated Catalyst-Free-Like N-Alkylation of Heteroarylamines with Primary
Alcohols.a,14
NaOH (50 mol%)
air, 150 oC, 24 h
- H2O
R1
OH
+
R2
NH2
R2
N
R1
Cl
N
N
H
1
6, 8
7, 9
(2)
(3)
(1)
N
N
N
H
N
N
N
N
Ph
H
H
Cl
7b, 88%
7c, 91%
7a, 89%
(4)
(6)
(5)
N
N
H
N
N
H
N
H
OMe
Br
Me
7f, 90%
7d, 85%
7e, 95%
(7)
(9)
(8)
OMe
N
N
H
N
N
H
N
N
H
7g, 84%
7h, 77%
7i, 81%
(10)
(11)
(12)
Cl
N
N
H
N
N
H
N
N
Ph
H
N
N
7l, 42%
7j, 86%
7k, 65%
(13)b
(14)b
Ph
N
N
N
NH
N
H
Ph
N
H
Ph
S
9a
(15)c 64%
(16)d ≤ 5% (N2)
7m, 86%
7n, 84%
(17)c
Ph
(18)c
Ph
Me
N
OMe
N
S
NH
S
NH
9c, 50%
9b, 50%
a
Unless otherwise noted, see run 2 of Table 3 for conditions. Isolated yields of 7 and 9 were
based on 6 and 8, respectively. b CsOHꢀH2O (30 mol%). c LiOHꢀH2O (50 mol%). d Redistilled 1a
of 100% purity was used under nitrogen.
10

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As shown in Table 4, the above method was also applied to other heteroarylamines and
alcohols. Thus, benzylic alcohols, including the more bulky ortho-substiuted ones (runs 3, 7, 8)
and those with reactive halogen groups (runs 2-4, 10), all reacted efficiently with
2-aminopyridines to give good to high yields of the target products (runs 1-10). For reactions
using heteroarylmethanols as the alkylating reagents, they were less efficient and gave lower
yields of the target products (runs 11-12). The same protocol was also applicable to 3- and
4-aminopyridines, but in these cases NaOH was found to be an ineffective base. Subsequent base
screening showed that CsOH is a much better base, giving good yields of the target products
under
similar
conditions
(runs
13-14).
Another
heteroarylamine
such
as
2-amino-4-phenylthiazole (8) was also investigated. A detailed base and condition screening
showed that LiOH is a more suitable base.20 Thus, the reaction of 8 with primary alcohols
afforded moderate yields of target 9 in the presence of 50 mol% LiOH (runs 15, 17, 18). In
contrast, the same reaction under nitrogen using pure 1a was rather ineffective, giving only trace
amounts of 9a (run 16).22 These contrastive results (runs 15-16) also revealed the facilitation
effect of air on the reaction of 2-amino-4-phenylthiazole.
We then continued to investigate the reactions of sulfinamides (Table 5), an analogue of
sulfonamides 2. Thus, the reaction of t-butanesulfinamide 10 and 1a under air gave 85% yield of
o
target 11a at 120 C in the presence of 100 mol% NaOH only (run 1). Temperature screening
showed that the reaction at 100 oC was still efficient, giving 11a in a slightly higher yield of 87%
(run 2). In contrast, the reaction under nitrogen gave only 47% yield of 11a (run 3).27 More
control reactions under nitrogen at higher temperatures (125-150 oC) did not give expected high
yields of the product (runs 4-5), but led to decrease of the product yield especially at 150 oC (run
5).27 This might be attributed to possible decomposition of 10 at high temperatures as obvious
color change was observed in these reactions. These contrastive results (runs 1-5) clearly
revealed the advantages of performing the reactions under air, such as simpler and easier
operation of the reactions, milder conditions like air atmosphere and lower temperatures, more
efficient reactions, and higher yields of the products. The aerobic reaction of 1a and 10 was also
attempted in a shorter reaction time, at a lower temperature, or using a lower loading of NaOH,
but these reactions were less efficient and gave lower yields of 11a (runs 6-8). Therefore, the
11

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best condition for the reaction is simply heating the mixture of 1a and 10 under air at 100 oC for
12 h (run 2). These optimized conditions were then applied to other primary alcohols (Table 6),
including the more bulky ones (runs 3, 7, 8) and those with reactive halogen groups (runs 2-4),
all giving good to high yields of the target products.
Table 5. Condition Screening for Air-initiated Catalyst-Free-Like N-Alkylation of
t-Butanesulfinamide with Benzyl Alcohol.a,14
O
S
O
S
NaOH, atm., T, t
- H2O
Ph
OH
+
NH2
N
Ph
H
1a
11a
10
b
run
1
NaOH (mol%)
atm., T, t
11a%
100
100
100
100
100
100
100
50
air, 120 oC, 12 h
air, 100 oC, 12 h
N2, 100 oC, 12 h
N2, 125 oC, 12 h
N2, 150 oC, 12 h
air, 100 oC, 6 h
air, 80 oC, 12 h
air, 100 oC, 12 h
85
87
47
66
43
77
74
35
2
3c,27
4c,27
5c,27
6
7
8
a Unless otherwise noted, the neat mixture of commercial 1a (3 mmol, 1.5 equiv.), 10 (2 mmol),
and NaOH was sealed in a 20 mL Schlenk tube under air or N2 and then heated and monitored by
b
TLC/GC-MS. Isolated yields based on 10. Selectivities for 11a are all >99% since no imine
byproduct was observed by GC-MS analysis. c Redistilled 1a of 100% purity was used.
12

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Table 6. Air-Initiated Catalyst-Free-Like N-Alkylation of t-Butanesulfinamide with Primary
Alcohols.a,14
O
S
O
S
NaOH (100 mol%)
R1
OH
NH2
R1
+
N
air, 100 oC, 12 h
- H2O
H
1
10
11
O
S
Cl
O
S
(1)
(4)
(2)
O
(3)
S
N
N
H
Ph
N
H
H
Cl
11a, 87%
11b, 94%
11c, 72%
(5)
(8)
(6)
O
O
S
O
S
S
N
N
H
N
H
H
Me
OMe
Br
11d, 92%
11e, 88%
11f, 89%
(9)
(7)
O
O
OMe
O
S
S
N
H
S
N
H
N
H
11i, 70%
11h, 74%
11g, 90%
a See run 2 of Table 5 for conditions. Isolated yields of 11 were based on 10.
Based on above successful results, the more challenging N-alkylation reactions of secondary
alcohols were then investigated. Although secondary alcohols were seldom used in basic
dehydrative alkylation reactions,2 the literature has shown that they could be oxidized by air to
ketones in the presence of bases,18 indicating they are also potential alkylating reagents under
aerobic conditions. As shown in Table 7, the reaction of 2-aminopyridine (6a) and secondary
benzohydrol (12a) was initially investigated under the optimized conditions (50 mol% NaOH,
o
150 C, under air) for the reaction of 6a and primary alcohols (run 1). However, no reaction
occurred at all. Other bases were then screened (runs 2-5), showing that base is crucial for the
reaction, with KOH and CsOH being much better bases than others. CsOH is in comparison the
best base (run 5), giving the highest 93% isolated yield of the target 13a. Further condition
o
screening showed that the reaction was also efficient at 130 C (run 6) and with a lower loading
of 12a (run 7). In contrast, the same reaction under nitrogen did not occur at all (run 8), revealing
13

ACCEPTED MANUSCRIPT
again the great facilitation effect of air on the reaction. The reaction was further investigated
under conditions using lower loadings of 12a and CsOH or at lower temperatures, but only lower
yields of 13a were obtained.20
Table 7. Condition Screening for Air-Initiated Catalyst-Free-Like N-Alkylation of
2-Aminopyridine with Benzohydrol.a,14
Ph
OH
base, atm., T, t
- H2O
+
N
N
Ph
Ph
Ph
12a
N
NH2
H
6a
13a
b
run
1
base (mol%)
NaOH (50)
t-BuONa (50)
KOH (50)
atm., T, t
13a%
air, 150 oC, 24 h
air, 150 oC, 24 h
air, 150 oC, 24 h
air, 150 oC, 24 h
air, 150 oC, 24 h
air, 130 oC, 24 h
air, 130 oC, 24 h
N2, 130 oC, 24 h
NDc
NDc
83
2
3
4
t-BuOK (50)
CsOH (30)
CsOH (30)
CsOH (30)
CsOH (30)
18
5
93
6
94
7d
92
8d
NDc
a
Unless otherwise noted, the neat mixture of 6a (1 mmol), 12a (1.5 mmol, 1.5 equiv.), and a
base was sealed in a 20 mL Schlenk tube under air or N2 and then heated and monitored by
b
TLC/GC-MS. Isolated yields based on 6a. Selectivities for 13a are all >99% since no imine
byproduct was observed by GC-MS analysis. c Not detected. d 1.3 equiv. 12a.
The optimized conditions (Table 7, run 7) were then applied to other amines and secondary
alcohols. As shown in Table 8, both unsubstituted and substituted aminopyridines readily reacted
with diarylmethanols to give moderate to high yields of the target products under similar
conditions (runs 1-6). The reactions of 2-amino-5-chloropyridine and 4-aminopyridine were less
o
effective and require a higher temperature of 150 C (runs 4-6). Moreover, the product yield of
2-amino-5-chloropyridine was not high under the neat conditions (run 4), which is possibly due
to the higher viscosity of the reaction mixture owning to the higher boiling point of the substrate.
14

ACCEPTED MANUSCRIPT
Thus, addition of small amounts of solvent toluene (0.5 mL) readily improved the product yield
to a high yield of 86% (run 5).
The same N-alkylation protocol could also be applied to anilines for the synthesis of secondary
alkylanilines. As shown in Table 8, aniline 4a was firstly treated with 12a under air in the
presence of better bases KOH or CsOH (runs 7-8).20 Anilines were found to be less reactive than
2-aminopyridine and require a higher temperature of 150 oC. Thus, the reaction using KOH gave
only a moderate yield of the target 14a (59%); while the reaction using CsOH afforded a high
90% isolated yield of 14a. Similar to previous results, the reactions under nitrogen were not
effective at all, only trace amounts of 14a could be detected using both KOH and CsOH (run
9).20 The optimized conditions (run 8) were then applied to other anilines and secondary alcohols.
As shown in Table 8, most substituted anilines and secondary alcohols, including those with
reactive Cl groups (runs 12-14) and sterically more bulky ones (runs 14, 20), readily afforded
good to high yields of the target products under similar conditions (runs 10-20). Due to the
presence of an ortho-methyl moiety to give an obvious steric effect, the reactions of 2-methyl
benzohydrol (run 11) and 2-methylaniline (run 17) were slow and afforded only low yields of the
products in long time.
15

ACCEPTED MANUSCRIPT
Table 8. Air-Initiated Catalyst-Free-Like N-Alkylation of Amines with Secondary Alcohols.a,14
H
OH
CsOH.H2O (30 mol%)
N
R2
R1
R1 NH2
+
R2
R3
air, 130-150 oC, 24-28 h
R3
4, 6
12
- H2O
13, 14
(3)
(2)
Ph
(1)
Cl
Me
Ph
Ph
N
N
N
N
Ph
H
N
N
Ph
H
H
Me
130 oC, 24 h
13b, 89%
130 oC, 24 h
13a, 92%
130 oC, 24 h
13c, 81%
Ph
Ph
(6)
N
Ph
Ph N
Ph
N
N
Ph
H
N
Ph
H
150 oC, 28 h
H
150 oC, 24 h
(4) 13d, 52%
(5)b 13d, 86%
150 oC, 24 h
(7) 14a, 59% (KOH)c
(8) 14a, 90%
(9) 14a, ≤ 5 (N2)d
13e, 85%
(10)
(13)
Ph
Ph Me
(11)
(12)
Cl
Ph
Ph N
Ph N
H
H
N
Ph
H
Me
150 oC, 28 h
14b, 87%
150 oC, 28 h
14c, 26%
150 oC, 28 h
14d, 82%
(15)e
Cl
(14)
(17)
Cl
Me
Ph
Ph
Ph
N
H
Ph
N
H
Ph
N
H
Ph
150 oC, 28 h
14f, 74%
150 oC, 28 h
150 oC, 28 h
14e, 81%
14g, 84%
(16)
OMe
Ph
Me
(18)e
Me
Ph
Ph
N
H
Ph
N
H
Ph
N
H
Ph
150 oC, 3 d
14i, 58%
150 oC, 28 h
150 oC, 35 h
14j, 95%
14h, 85%
(19)e
(20)
Ph
EtO
Ph
N
Ph
H
N
Ph
H
150 oC, 28 h
150 oC, 28 h
14l, 92%
14k, 90%
16

ACCEPTED MANUSCRIPT
a
b
See the Supporting Information for detailed conditions. Isolated yields based on 4 or 6.
c
d
e
Toluene (0.5 mL) and 50 mol% CsOHꢀH2O. 30 mol% KOH. Under nitrogen. 40 mol%
CsOHꢀH2O.
As to the mechanism of these air-induced dehydrative N-alkylation reactions, the contrastive
results of the reactions under air and under nitrogen clearly revealed the great facilitation effect
of air on the alcohol-based dehydrative N-alkylation reactions. Since the reaction conditions are
very simple, we initially thought that base alone should catalyze the oxidation of alcohols under
air to give carbonyl compounds as the initiating step.18 However, to our surprise, in a control
reaction under the standard conditions (Table 1, run 6) but without the addition of aniline 4a, no
target benzaldehyde 15a was detected after heating pure primary alcohol 1a with CsOH (30
mol% if based on 2 mmol 4a, which was not added in the reaction) under air in a 20 mL tube at
o
130 C for 24 h (eq. 2).20 This result, based on our following findings (vide infra), was most
possibly due to the absence of an amine and not adequate air in the reaction tube.
CsOH.H2O (0.6 mmol, 20 mol%)
(30 mol% if based on not added 4a)
Ph
15a
not detected
Ph
1a
3 mmol
OH
O
(2)
air (20 mL), 130 oC, 24 h
17

ACCEPTED MANUSCRIPT
Table 9. Aniline-Assisted CsOH-Mediated Aerobic Oxidation of Benzyl alcohol.a
PhNH2 (4a)
CsOH.H2O (10 mol%)
toluene, air baloon, 80 oC, 24 h
Ph
Ph
N
16a
Ph
OH
Ph
O
15a
1a
d
e
run
1f
2
4a (mol%)b
1a% (unreacted)c
15a
%
16a%
-
~99.6-99.1
~91
~0.4-0.9
~5
-
~10
~20
~50
~4 (40)
~13(65)
~4(86)
3
~82
~5
4
~36
~21
a
The mixture of pure 1a (3 mmol, 100% purity as confirmed by GC), 4a, and CsOHꢀH2O (10
mol%) in toluene (0.5 mL) in a 100 mL Schlenk tube adapted with an air balloon was heated at
o
b
80 C for 24 h and then monitored by TLC/GC-MS. 4a (mol% to 1a) was added using a
c
d
microsyringe. Calculated based on GC analysis and the yields of 15a and 16a. GC yields
based on 1a. e GC yields based on 1a (the yields in parenthesis were based on 4a added). f Three
parallel reactions were carried out to give close results of <1% yield of 15a.
On the other hand, we observed that addition of 4a could facilitate the oxidation of 1a by air to
give 15a and the condensation product imine 16a19 under a condition milder than that of the
alkylation reactions. Thus, as shown in Table 9, no obvious oxidation of pure 1a was initially
observed with CsOH alone in the absence of 4a (run 1), giving <1% yield of 15a. Differently,
when 10 mol% of aniline 4a was added, the reaction readily afforded ca. 5% 15a and 4% 16a
(run 2, based on 1a) under the same conditions, which equals to 9% conversion of primary
alcohol 1a to 15a (90% if based on the added 10 mol% 4a). Similarly, ca. 5% 15a and 13% 16a
(equals to 18% conversion of 1a to 15a) were observed when 20 mol% 4a was added (90%
based on 4a), and ca. 21% 15a and 43% 16a (equals to 64% conversion of 1a to 15a) were
observed when 50 mol% 4a was added (128% based on 4a). Therefore, it could be concluded
that in the reactions of primary alcohols, amines participated in the aerobic alcohol oxidation
step to facilitate the generation of the important initiating aldehydes.
In the case of secondary alcohols, different to above reactions of primary alcohols but similar
to the known reports,18 we found base alone could mediate the oxidation of benzohydrol 12a to
benzophenone 17a under air.20 Thus, under identical conditions with the N-alkylation reaction of
18

ACCEPTED MANUSCRIPT
6a and 12a (Table 7, run 7, albeit without 6a), 12a readily afforded 19% isolated yield of 17a
under air in the presence of CsOH (eq. 3, run 1). In contrast, no ketone formation was observed
at all when the same reaction was conducted under nitrogen (run 2). This result could account for
the reason why the reactions of secondary alcohols were also not effective under nitrogen (Table
7, run 8, and Table 8, run 9).
CsOH.H2O (0.3 mmol, 23 mol%)
(30 mol% if based on not added 6a)
O
OH
Ph
(3)
Ph
Ph
Ph
130 oC, 24 h
17a
12a
1.3 mmol
1) air (20 mL tube), 19% isolated
2) N2, not detcted (GC and TLC)
Based on above results, a plausible mechanism was proposed for the present convenient and
practical air-initiated catalyst-free-like N-alkylation of amines and sulfinamides with alcohols.
As shown in Scheme 2, the reaction was initiated by aerobic oxidation of the alcohols to
aldehdydes or ketones (step i). This step could be achieved via either an amine-facilitated
process in case of primary alcohols (the upper process) or a lone base-mediated process in case
of secondary alcohols (the under process). Then dehydrative condensation of amines and the
carbonyl compounds readily occurred to give imine intermediates (step ii), which were then
reduced by the alcohols to give product amines via a transition metal-free MPV-O process with
regeneration of the carbonyl compounds (step iii).11a The carbonyl compounds were then
recycled and further acted as the catalysts in the reactions to finish the reaction cycle (step iv).
Since the initial carbonyl compounds generated from the aerobic alcohol oxidation reaction (step
i) can be regenerated in the later MPV-O process (step iii), only a small amount of air is adequate
to initiate and complete the whole reaction.5,11 Indeed, in a 20 mL reaction tube, there is only ca.
10 mol% O2 to a standard 2 mmol reaction.28
19

ACCEPTED MANUSCRIPT
(i)
OH
R2
R2 = H, RNH2, base, air
(iv)
O
O
R1
or: R2 ≠ H, base, air
R1
R2
R1
R2
R2
R1
MPV-O process
R N
R1
MA
H
(iii)
RNH2
R2
(ii)
O
base
OH
R2
R1
R2
N
R2
H
R
R1
H2O
R1
MA = Cs, Na, etc.
R N
Scheme 2. Proposed Mechanism for Air-Initiated Catalyst-Free-like N-Alkylation of Amines
and Sulfinamides with Alcohols.
3. Conclusion
In summary, we have developed a catalyst-free-like dehydrative N-alkylation method for amines
and sulfinamides with primary and secondary alcohols by using only catalytic amounts of air as
the initiator without adding any external catalysts. In comparison with known N-alkylation
methods, this method has advantages of simple and practical conditions, easy operation, efficient
and green reactions, and comparatively wider scope of the substrates. Mechanistic studies
revealed that air initiated the reactions by aerobic oxidation of the alcohols to the key aldehyde
or ketone intermediates in the presence of bases, in which amines were interestingly found to
facilitate the more demanding aerobic oxidation of the primary alcohols. Further extension and
more synthetic applications of the method are underway.
4. Experimental Section
Typical procedure for air-initiated catalyst-free-like N-alkylation of anilines with primary
alcohols. The mixture of benzyl alcohol (1a, 0.3244 g, 3.0 mmol, 1.5 equiv.), aniline (4a, 0.1863
g, 2.0 mmol), and CsOH·H2O (0.1007 g, 0.6 mmol, 30 mol%) was sealed under air in a 20 mL
Schlenk tube and then stirred at 130 oC for 24 h. After completion, the reaction was monitored by
TLC and/or GC-MS (96% GC conversion) and the crude product was purified by column
chromatography using ethyl acetate and petroleum ether as the eluent. The target product 5a was
20

ACCEPTED MANUSCRIPT
obtained in 90% isolated yield.
Typical Procedure for air-initiated catalyst-free-like N-alkylation of amines with secondary
alcohols. The mixture of benzhydrol (1b, 0.2395 g, 1.3 mmol, 1.3 equiv.), 2-aminopyridine (6a,
0.0941 g, 1.0 mmol), and CsOH·H2O (0.0504 g, 0.3 mmol, 30 mol%) was sealed under air in a
o
20 mL Schlenk tube and then stirred at 130 C for 24 h. After completion, the reaction was
monitored by TLC and/or GC-MS (95% GC conversion) and the crude product was purified by
column chromatography using ethyl acetate and petroleum ether as eluent. The target product
13a was obtained in 92% isolated yield.
Acknowledgements
We thank ZJNSF for Distinguished Young Scholars (LR14B020002), NNSFC (20902070), and
580 Overseas Talents Program of Wenzhou City for financial support.
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D.; Michalik, D.; Thurow, K.; Deng, Y.; Beller, M. Angew. Chem. Int. Ed. 2009, 48, 5912 ;
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23

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19. (a) Xu, J.; Zhuang, R.; Bao, L.; Tang, G.; Zhao, Y. Green Chem. 2012, 14, 2384. (b) Donthiri,
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20. See Supporting Information for details.
21. The aldehyde-catalyzed (ref. 11a) or oxidant-initiated methods are in comparison more
suitable for N-alkylation of sulfonamides with alcohols.20
22. To avoid aldehyde contamination in commercial 1a that can lead to misguiding results (ref.
5c, 11a), redistilled pure 1a (100% purity as confirmed by GC) were used. The reactions
were then strictly degassed and heated under nitrogen.
23. 2- And 4-cholorobenzaldehydes are typical electron-withdrawing groups (formyl group in
this case)-substituted halobenzenes at the 2- and 4-positions, which can readily undergo
aromatic nuleophilic substitution (SNAr) reactions with nucleophiles in the presence of bases.
See: (a) Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273. (b) J. Zhu, Synlett 1997, 133.
(c) Theil, F. Angew. Chem. Int. Ed. 1999, 38, 2345. (d) Sawyer, J. S. Tetrahedron 2000, 56,
5045. (e) Liu, C.; Zang, X.; Yu, B.; Yu, X.; Xu, Q. Synlett 2011, 1143. (f) Jia, X.; Yu, L.; Liu,
J.; Xu, Q.; Sickert, M.; Chen, L.; Lautens, M. Green Chem. 2014, 16, 3444.
24. Nitro is a reactive group that can be reduced by alcohols or other reducing reagents to give a
variety of products. See: (a) Blaser, H.-U.; Steiner, H.; Studer, M. ChemCatChem 2009, 1,
210. (b) Kim, J. H.; Park, J. H.; Chung, Y. K.; Park, K. H. Adv. Synth. Catal. 2012, 354, 2412.
(c) Wu, M.; Hu, X.; Liu, J.; Liao, Y.; Deng, G.-J. Org. Lett. 2012, 14, 2722. In the presence
of 2- or 4-positioned electron-withdrawing groups, nitro can also undergo SNAr reactions
with nucleophiles as a leaving group. See: (d) Beck, J. R. Tetrahedron 1978, 34, 2057. (e)
Kondoh, A.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006, 62, 2357. (f) Yu, X.; Li, B.; Yu,
B.; Xu, Q. Chin. Chem. Lett. 2013, 24, 605.
25. Carbonyl groups can also react with alcohols via MPV-O processes to give transfer
hydrogenated hydroxylmethyl compounds. See ref 11 and 13 and references cited therein.
26. When new Schlenk tubes/stirring bars or old ones that had not been used in transition metal
catalyzed reactions were used, we found the reactions were not effective and gave only trace
yields of the target products. In great contrast, when old Schlenk tubes/stirring bars that had
been used in transition metal catalyzed reactions were used in the same N-alkylation
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ACCEPTED MANUSCRIPT
reactions, we found improved low to moderate yields of the products could be obtained. We
later conclude that it is most possibly the transition metal contaminants in the reaction
tubes/stirring bars worked to improve the reactions and the product yields. However, these
results were hard to reproduce and thus not included in this work.
27. According to our previous hypothesis and findings (ref. 13b), sulfonamide t-BuSONH2 10,
structurally belong to the substrates having RY(=X)NuH2 unit, should be potentially reactive
compounds under autocatalyzed N-alkylation conditions. Therefore, it may oxidize alcohols
to aldehydes (via the MPV-O redox process, see the scheme below or in ref 13b) and then
initiate the reaction. Therefore, the autocatalyzed N-alkylation mechanism could not be
excluded in reactions of sulfonamides. Since only moderate yields of target product 11a were
obtained under N2 (Table 5, run 3-5) and the reaction still require air’s initiation to ensure
completion, it indicates that the autocatalyzed process is not effective enough and the
reaction should also proceed via the air-initiated mechanism (vide infra).
R1
O
MA
R1
OH
MA
O
+
initiation
step
X
Y
+
X
Y
XH
Y
R1
R
H
H
H2Nu
R
NuH2
H
R
NuH2
MPV-O processes
28. A 20 mL Schlenk tube contains 20 mL air, in which there is ca. 0.2 mmol O2, ca. 10 mol% to
a standard 2 mmol reaction. See also ref. 5 for related discussions.
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