Boron-Catalyzed N-Alkylation of Arylamines and Arylamides with Benzylic Alcohols

Article abstract of DOI:10.1021/acs.joc.9b02816

A sustainable boron-based catalytic approach for chemoselective N-alkylation of primary and secondary aromatic amines and amides with primary, secondary, and tertiary benzylic alcohols has been presented. The metal-free protocol operates at low catalyst loading, tolerates several functional groups, and generates H₂O as the sole byproduct. Preliminary mechanistic studies were performed to demonstrate the crucial role of boron catalyst for the activation of the intermediate dibenzyl ether and to identify the rate-determining step.

Full text of DOI:10.1021/acs.joc.9b02816

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Article
Boron-Catalyzed N-Alkylation of Arylamines
and Arylamides with Benzylic Alcohols
Murali Mohan Guru, Pradip Ramdas Thorve, and Biplab Maji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02816 • Publication Date (Web): 05 Dec 2019
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Page 1 of 13
The Journal of Organic Chemistry
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Boron-Catalyzed N-Alkylation of Arylamines and Arylamides with
Benzylic Alcohols
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Murali Mohan Guru, Pradip Ramdas Thorve, and Biplab Maji*
Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur-741246 (India)
R2
R1
R2NHAr2
R
N
B(C6F5)3 (1-2 mol %)
Ar1
Ar2
Amine (1/2) N-alkylation
33 examples
up to 92% yield
R1
R
OH
R3NHSO2Ar3
R2
R1
Ar1
B(C6F5)3 (2 mol %)
R
N
(1/2/3
Amide (1/2) N-alkylation
Ar1
15 examples
up to 90% yield
SO2Ar3
Renewable feedstock
Low catalyst loading
No base or ligand
Wide substrate scope
ABSTRACT: A sustainable boron-based catalytic approach for chemoselective N-alkylation of primary and secondary aromatic
amines and amides with primary, secondary, and tertiary benzylic alcohols have been presented. The metal-free protocol operates at
low catalyst loading, tolerates several functional groups and generates H2O as the sole by-product. Preliminary mechanistic studies
were performed to demonstrate the crucial role of boron catalyst for the activation of the intermediate dibenzyl ether and to identify
the rate-determining step.
INTRODUCTION
Similar to N-alkylamines, the N-alkyl amides has also
attracted much attention due to their extensive applications in
pharmaceutical, biological, and chemical industry.7 In
particular, the N-alkyl sulfonamides, a sub-class of amide are
commonly employed as cannabinoid receptor 2 inverse
agonist,8 inhibitors of Mycobacterium tuberculosis9 and
secreted frizzled-related protein-1 (sFRP-1) inhibitors (Figure
1b).10 Due to the several limitations of classical approaches for
the synthesis of N-alkyl sulfonamides,11 the widely accepted
methodologies involve borrowing hydrogen catalysis in the
presence of transition metal12 and Lewis-13 or Brønsted-acid14
catalyzed direct substitution of alcohol by nitrogen
nucleophiles. Despite the development of these remarkable
atom economical processes, often their green credentials are
somehow limited due to the use of (i) toxic noble metals, (ii)
capricious ligands and bases, (iii) high reaction temperature,
(iv) the use of excess amines or alcohols, (v) highly reactive
and non-renewable feedstock. Nevertheless, with the
increasing trend to follow up the principles of green
chemistry, it is highly attractive to develop a metal-free green
and sustainable chemical process for N-alkylation reaction
using renewable resources.15
The N-alkylation of amines through carbon-nitrogen bond
formation1 has become an efficient approach for the
construction of a plethora of N-alkyl amines, which are
essential motifs in pharmaceuticals, agrochemicals, and
natural products (Figure 1a).2 Among the state-of-the-art
synthetic methods, the traditional protocols involved a non-
catalytic reaction of amines with alkyl halides, tosylates or
triflates, which are limited due to their toxicity, poor
chemoselectivity, over-alkylation, and generation of
stoichiometric waste.3 In comparison to the classical approach,
the more appealing strategies for C–N bond formation
involved transition-metal-catalyzed reductive amination of
carbonyl compounds,4 hydroamination of alkenes and
alkynes,5 borrowing hydrogen methodologies using alcohols
or amines.1b,6
F
a.
O
O
NH
N
tBu
N
N
N
N
Me
H2N
NHCO2Et
In recent years, the main group element boron has emerged
as an alternative catalyst due to their excellent reactivity and
selectivity for a wide range of transformations.16-11 Recently,
the boron-catalyzed hydroamination of alkynes,17 and
reductive N-alkylation of amines with carbonyls in the
presence of H2 or hydrosilanes (Scheme 1a) have been
demonstrated for the diversification of amines.18 Conversely,
in the pursuit of more sustainable developments, the use of
widely available primary alcohols as alkylating agent under
metal-free conditions remain unexplored.19 While the
manuscript in preparation, Chan et al. reported B(C6F5)3-
Butenafine
Retigabin
(Anticonvulsant)
Piribedil
(Piperazine dopamine agonist)
(Antimycotic agent)
O
O
b.
O
O
Ph
S
S
N
NHBz
HN
PhO2S
S
MeO
NEt2
O
O
O2N
NO2
Me
Cannabinoid receptor 2
inverse agonist
Mycobacterium tuberculosis
inhibitor
Secreted frizzled related
protein-1 inhibitors
Figure 1. Selected bioactive N-alkylated (a) amines, and (b)
sulfonamides
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catalyzed N-alkylation of anilines with secondary alcohols decreased significantly when 0.5 mol% of catalyst was used
1
2
3
4
5
6
7
8
(Scheme 1b). The reaction proceeded in nitromethane solvent
via the intermediacy of a carbocation in the presence of higher
loading of catalyst.20 However, the formation of a carbocation
from primary alcohols is challenging,21 and the scope of
primary alcohols with amines under metal and base free
conditions have not been explored to date. As the carbocations
generated from primary alcohols are strong Lewis acid, the
alkylation should occur selectively at the nitrogen site of the
anilines that requires less reorganization evergy.21c Besides,
the N-benzylation of sulfonamide with alcohols under metal-
free conditions could only be achieved either in a non-catalytic
pathway using more than stoichiometric boron reagent22 or in
the presence of a catalytic combination of boric acid/oxalic
acid where electron-rich benzylic alcohols are not productive
(Scheme 1c).23 In continuation of our recent finding of the
catalytic transformation of aromatic amines in the presence of
B(C6F5)3-catalyst,24 herein we report a boron-catalyzed N-
alkylation of aromatic amines and amides with primary and
hindered benzylic alcohols (Scheme 1d). The reaction operates
at a catalyst loading of 1-2 mol% and tolerates functional
groups like carbonyl, cyano, carboxylic acid, halogens, nitro,
etc. and produces water as the sole by-product thereby making
the process highly environmentally benign.
(entry 9). Other boron catalysts were not efficient for this
reaction (entries 10-11). A controlled reaction confirmed that
molecular sieve has a crucial role in the improvement of
product yield (entry 12).
Table 1. Optimization for N-alkylation of secondary aryl
amines.a
Me
N
Me
9
B(C6F5)3 (1 mol %)
MeO
+
N
toluene, 110 °C
4 Å MS, 24 h
- H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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59
60
OH
H
MeO
1a
2a
3a
entry
deviation from standard condition
yield (%)b
1
2
3
none
92 (88)c
75
benzene
chlorobenzene
56
4
5
6
7
1,4-dioxane
12
n.r.
58
90
acetonitrile
90 °C temperature
120 °C temperature
8
2 mol % B(C6F5)3
0.5 mol % B(C6F5)3
1 mol % BPh3
93
63
n.r.
33
78
9
10
11
12
5 mol % BF3•Et2O
without 4Å MS
a Reaction conditions: 1a (0.375 mmol), 2a (0.25 mmol), B(C6F5)3
(1 mol %), and 4Å molecular sieve (30 mg) in 0.5 mL of solvent
for 24h at appropriate temperature. b NMR yield using mesitylene
as an internal standard. c Yield obtained after column purification.
n.r. = no reaction.
(a) Metal-free reductive N-alkylation of carbonyl compounds
R1
R
Ar
R1
R
Ar
H
N
O
O
[H]
Borane catalyst
N
N
or
+
R1
Ar
R
H
R
OH
H
(b) Borane-catalyzed N-alkylation of aniline with secondary benzylic alcohol
H
H
R
R
Only secondary alcohol
High catalyst loading
B(C6F5)3 (10 mol %)
nitromethane, 120 °C
Ar1
+
N
Ar2
N
With the optimized conditions in hand, the scope for the N-
alkylation reaction of secondary aromatic amines with primary
and secondary alcohols was examined (Table 2). When p-
anisyl alcohol 1a was reacted with N-benzyl anilines having
electron-donating (-OMe) and withdrawing (-Cl) groups, the
corresponding N-alkylated compounds 3b and 3c have
obtained in 83% and 77% yields, respectively. Similarly, the
piperonyl alcohol and 9-anthracene methanol smoothly
afforded 3d (76%) and 3e (92%). The heteroaryl alcohol and
trimethoxy substituted benzyl alcohol were also furnished 3f
and 3g in high to excellent yields. In contrast, benzyl alcohols
having moderate electron-withdrawing substituents (Cl, F) on
the aromatic rings delivered 3h and 3i in moderate yields, and
the presence of strong electron-withdrawing -CF3 or -NO2
groups completely shut down the reaction, thus indicating a
strong electronic influence of the ring substituent on its
reactivity, vide infra. Importantly, the hindered secondary
alcohols with different secondary amines were also equally
useful under the optimized reaction condition to give 3l and
3m in 65-80% yields.
Ar1
OH
H
Ar2
(c) Metal-free N-benzylation of sulfonamides with alcohols
BF3OEt2 (1.2 equiv)
R1
R
Non-catalytic N-benzylation
R1
R
Ar1
N
+
N
SO2R
Boronic acid (10 mol %)
Oxalic acid (10 mol %)
Ar1
OH
SO2R
H
Incompatable with electron
rich benzylic alcohols
(d) This work: B(C6F5)3 catalyzed N-alkylations of amines and amides with benzylic alcohols
R2
R3
or
R3
R1
R
Ar1
R2
or
Ar2
R1
R1
R
Ar1
B(C6F5)3 (1-2 mol %)
Ar1
N
+
R
N
Ar2
N
SO2Ar3
N
R, R1, R2, R3 = H, alkyl, Ar
SO2Ar3
OH
H
H
(1°/ 2°/3)
(1°/2°)
Ar2NHR2
or
ArNHXAr3
B(C6F5)3
Ar1
O
B(C6F5)3
R1
R
- B(C6F5)3
R
Ar1
R1
Low catalyst loading
Wide substrate scope
Single catalyst for both amines and amide N-alkylation
Large functional group tolerance
Scheme 1. Boron-catalyzed N-alkylation of amines and
amides.
RESULTS AND DISCUSSION
Table 2. B(C6F5)3-catalyzed N-alkylation of secondary
anilines with benzylic alcohols.a
At the onset of our study, the N-alkylation reaction of p-
anisyl alcohol 1a with N-methyl aniline 2a was investigated
(Table 1). To our delight, the N-alkylated product 3a was
detected in 92% NMR yield by employing 1 mol% of
B(C6F5)3 at 110 °C in toluene after 24 h in the presence of 4Å
molecular sieve (entry 1). The yield dramatically reduced on
moving from a non-polar to a polar solvent (entries 2-4) and in
acetonitrile, no reaction was observed (entry 5). A lower yield
was obtained when the temperature was reduced to 90 °C
(entry 6), whereas at a slightly higher temperature (120 °C) the
yield reduced to 90% (entry 7). The observed yield remains
almost similar even after 2 mol% catalyst loading (entry 8) but
2
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The Journal of Organic Chemistry
R4
R2
Table 4. To note, in all cases studied, the formation of the bis-
alkylated product was not observed. The reaction of 1a with
halo substituted anilines delivered mono-alkylated compounds
5b-d in 82-87% yields. It is noteworthy to mention that the
benzylamines having carboxyl or cyano groups are present in
many bioactive compounds,2a,25 and, in general, these
functional groups are often sensitive under reductive
alkylation conditions in the presence of H2 or hydrosilane.10
Pleasingly, the reaction of 1a with aromatic amines 4e-g
having substituents like -CN, -COPh and -COOH could
readily be tolerated under the present reaction conditions to
give desired compound 5e-g in 71-84% yields. The p-OMe
substituted electron-rich aniline was also alkylated with 1a to
yield 5h (83%).
Similarly, the ortho substituent on aniline did not affect the
formation of 5i (84%). The heteroaryl alcohol showed good
reactivity to produce 5j in 71% yield. Halogen substituents on
the alcohol coupling partner were also tolerated to deliver 5k
and 5l in moderate yields. The parent benzyl and naphthyl
alcohols underwent the alkylation reaction smoothly to afford
the targeted products 5m-o in good yields. Notably, the
secondary alcohols were also equally useful under this
condition to furnish 5p-r in 62-78% yields. Similarly, the
hindered tertiary alcohol provided 5s in 52% yield at lower
reaction temperature. Interestingly, for tertiary alcohol having
a vinyl group attached to the 3° carbon center, migration of the
double bond took place to deliver the linear allyl amine 5t in
79% yield.
H
R2
R
OH
R
N
B(C6F5)3 (1 mol %)
1
2
3
4
5
6
7
8
+
N
R3
toluene, 110 °C
4 A° MS, 24 h
R3
R1
R4
R1
1 (1°/ 2°/3 )
2
3
Me
N
Bn
Bn
N
Bn
N
N
O
O
MeO
MeO
OMe MeO
Cl
OMe
3a
3b
3c
3d
(76%)
(88%)
(83%)
N
(77%)
Bn
Me
N
R
N
N
9
MeO
MeO
10
11
12
13
14
15
16
17
S
OMe
OMe
Cl
3h
OMe
3e
3f
3g
(92%)
R
(81%)
(90%)
(42%)
[R = 4-OMePh]
Bn
N
Me
Bn
N
N
Me
N
R
OMe
Me
Cl
F
OMe
3i
3j
3l
3m
(80%)
(45%) [R = 4-OMePh] R = CF3; (0%)
(65%)
18
19
20
21
22
23
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25
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31
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60
3k
= NO2;
(0%)
aReaction condition: Table 1, entry 1. Yields are given in
parenthesis.
Subsequently, we have realized the challenge associated
with the selective mono-alkylation of primary amines with
primary alcohols. The difficulty lies not only in the generation
of the primary electrophile but also in the selectivity step as
the product secondary amine has higher nucleophilicity than
the starting aniline.21 To best of our knowledge, selective
mono-alkylation of aniline with primary alcohol is unknown
under metal-free conditions.
To test the viability of selective mono-alkylation of primary
amines with primary alcohols, alcohol 1a, and aniline 4a were
selected as the model substrates (Table 3). When the 1a and
4a were treated under the optimized condition of Table 1, only
62% yield of 5a was observed (entry 1). Pleasingly, with 2
mol% of catalyst loading, the yield was improved to 84%
(entry 2). Further increase in catalyst loading or reaction
temperature leads to lower yields of 5a with the formation of
bis-alkylated products (entries 3-4). Besides, the use of excess
amine was not adequate to improve the yield of 5a (entry 5).
Table 4. B(C6F5)3-catalyzed selective mono-N-alkylation of
anilines with benzylic alcohols.a
R2
H
R3
H
R2
R
OH
R
N
B(C6F5)3 (2 mol %)
+
R3
N
toluene, 120 °C
4 Å MS, 36 h
R1
H
R1
1 (1°/ 2°/3°)
4
5
H
H
N
H
H
N
N
N
Br
Cl
R3
Cl
CN
MeO
MeO
MeO
MeO
R3 = Me;
= Cl;
(81%)
(87%)
(86%)
(82%)
5a
5b
5c
5d
5e
(74%)
H
N
H
H
N
H
N
N
CO2H
Me
COPh
O
Table 3. Optimization for monoalkylation of aniline with
primary alcohol.a
MeO
O
MeO
Cl
OMe
MeO
5f
5h
5i
(84%)
(88%)
(83%)
5g
(71%)
H
N
H
N
H
N
H
N
H
N
H
H
B(C6F5)3 (2 mol %)
S
N
Me
+
MeO
toluene, 120 °C
4 Å MS, 36 h
R1
Br
OH
R3
Cl
OMe
(38%)
4a
MeO
1a
entry
5a
Me
R1 = 4-Cl;
= 3-F;
R3 = Cl;
= Br;
5m
(80%)
5n
(76%)
5k
5j
(71%)
H
5o
(72%)
yield (%)b
5l
(43%)
deviation from standard condition
Ph
Ph
H
N
Ph
Ph
Me
Me
H
H
1
2
3
Table 1, entry 1
none
62
84 (81)c
73d
N
N
N
Ph
3 mol % B(C6F5)3
70d
4
5
130 °C temperature
OMe
Me
Me
Me
Me
51
1a
4a
and 1.5 equiv
1.0 equiv
b
5r
(78%)
5p
5q
5s
(52%)
(62%)
(69%)
a
Reaction conditions: 1a (0.375 mmol), 4a (0.25 mmol),
H
N
B(C6F5)3 (2 mol %), and 4Å molecular sieve (30 mg) in 0.5 mL of
conditiona
Ph
Ph
H
H
b
c
+
OH
N
OMe
toluene. NMR yield using mesitylene as an internal standard.
Ph
Ph
d
Yield after column purification.
detected in 10% NMR yield.
Bis-alkylated product also
OMe
5t
(79%)
a
Reaction condition: Table 3, entry 2. Yields are given in
parenthesis. bReaction temperature 80 °C.
After finding the optimum condition, we have then explored
the scope for selective mono-alkylation of anilines 4 with
different benzylic alcohols 1, and results are summarized in
3
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Further, we are interested to extend the scope for this metal-
free C-N coupling protocol for the N-alkylation of amides. To
our delight, with mol% of B(C6F5)3 loading, the
1
2
3
4
5
6
7
8
1
Table 6. B(C6F5)3-catalyzed selective mono-N-alkylation of
amides with benzylic alcohols.a
monoalkylation of p-toluenesulfonamide 6a with p-
methoxybenzyl alcohol 1a afforded 7a in 37% yield (Table 5,
entry 1). When the reaction time was prolonged to 48 h the
yield of the monoalkylated product was increased to 60%
(entry 2). The yield could be improved (entry 3) by applying 2
mol% of B(C6F5)3 at 110 °C. Although, a further increase in
catalyst loading or reaction temperature leads to decrease in
product yield of 7a with the formation of bis-alkylated product
(entries 4-5). Gratifyingly, yield of 7a was improved to 93%
when chlorobenzene was used as solvent (entry 6). However,
detrimental effect was observed as benzene or 1,4-dioxane
were used as solvent (Table 5, entries 7-8). The change in
stoichiometry between 1a and 6a does not significantly alter
the yield (entry 9).
R3
R2
R2
R3
B(C6F5)3 (2 mol %)
R
N
R
+
N
SO2Ar
R1
chlorobenzene, 110 °C
4 Å MS, 48 h
SO2Ar
OH
1 (1°/ 2°/3)
H
R1
6
(1/2)
7
H
H
H
H
N
MeO
N
N
N
9
Ts
Ts
Ts
Ts
I
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
MeO
Me2N
7b
7d
(78%)
7a
7c
(64%)
(90%)
N
(82%)
H
H
H
H
R
N
N
N
Ts
Ts
Ts
Ts
S
7h
7i
R = Me;
R = Et;
(77%)
(76%)
7g
(79%)
7e
(75%)
7f
(72%)
Ts
N
Table 5. Optimization for monoalkylation of sulfonamide
with benzyl alcohol.a
H
N
H
Ph
Ph
N
N
Ts
Cl
Ts
MeO
H
N
OMe
7j
7k
7l
(84%)
(68%)
(84%)
H
B(C6F5)3 (2 mol %)
Ts
iPr
iPr
+
N
Ts
MeO
chlorobenzene, 110 °C
4 Å MS, 48 h
OH
O
S
H
6a
MeO
1a
7a
O
H
iPr
N
TsNH2
H
yield (%)b
N
OH
Ph
Ph
Ph
Ph
entry
deviation from standard condition
conditiona
N
N
Ts
Ph
1
2
B(C6F5)3 (1 mol %)
B(C6F5)3 (1 mol %), 48 h
in toluene solvent
37
60
Ts
Ph
Ph
7o
MeO
OMe
3
4
5
6
81
71c
73c
93 (90)d
7m
(73%)
b
(67%)
7n
(71%)
B(C6F5)3 (3 mol %), in toluene solvent
aReaction condition: Table 5, entry 6. Yields are given in
parenthesis. bIn DCE solvent at 120 °C.
in toluene solvent at 120 C
none
7
8
in benzene solvent
80
45
91
In order to probe the mechanistic cycle for the metal-free N-
alkylation reaction, several experimental pieces of evidence
have been depicted in Scheme 2. At first, when benzyl alcohol
1a was stirred in toluene at room temperature in the presence
of boron-catalyst, dibenzyl ether 8a was formed in 82% yield
(Scheme 2a). To see whether 8a is an intermediate in the
catalytic cycle or not, the stoichiometric reaction of 4a with 8a
afforded 5a in 35% yield after 8 h under the standard
conditions (Scheme 2a). Again, the stoichiometric reaction of
8a and B(C6F5)3 in C6D6 at room temperature lead to the
formation of 9a (B(C6F5)3 adduct of 8a) in 9a:8a > 95:5 ratio
(Scheme 2b). Whereas, in our recent report,24 we have studied
the equilibrium between 4a and 10a (B(C6F5)3 adduct of 4a) to
give 10a:4a 80:20 (Scheme 2b). Also, a mixture of 4a, 8a,
and B(C6F5)3 in benzene showed 10a:9a 92:8 (Scheme 2b).
The above equilibrium studies highlight the reversibility of the
Lewis acid-base adduct of B(C6F5)3 with aniline and dibenzyl
ether intermediate, and availability of the catalyst for alcohol
activation. Further, the Hammett correlation study was
performed to examine the electronic effect of arene
substituents on both the alcohols and anilines (Scheme 2c).
After varying the electronic groups on the aryl-ring of 1, a
large ρ = –2.92 was found which probably indicates the
accumulation of positive charge on the benzylic carbon of
alcohol in the rate-determining step (RDS). In contrast, an
insignificant electronic influence of the substituents on the
aromatic ring of aniline 2 was observed (ρ = –0.09).
in 1,4-dioxane solvent
1a 6a
and 1.2 equiv
9
1.0 equiv
a
Reaction conditions: 1a (0.25 mmol), 6a (0.25 mmol), B(C6F5)3
(2 mol %), and 4Å molecular sieve (30 mg) in 0.5 mL of
b
chlorobenzene. NMR yield using mesitylene as an internal
c
standard. Bis-alkylated product also detected in 15% NMR
yield. d Yield after column purification.
With the optimum conditions in hand, we have explored the
scope and limitation of the boron catalyzed alkylations of
amides. Initially, differently substituted alcohols were reacted
with p-toluenesulfonamide 6a, and the results were
summarized in Table 6. To note in all cases studied bis-
alkylated product was not detected. Benzyl alcohols with
different substituents at o-, m-, or p-position readily reacted
with 6a to furnish 7b-d in 64-82% yields. Similarly, the
naphthyl, anthracenyl and thiophenyl methanol produced the
N-alkylated sulfonamide 7e-g in 72-79% yields. The reaction
could also be extended to secondary alcohols, and the products
7h-k were obtained in moderate to excellent yields. The N-
sulfonyl hydrazones can also be alkylated selectively at the sp3
nitrogen with 1a to afford 7l and 7m in 84% and 73% yields,
respectively. The hindered trityl alcohol also reacted at
slightly higher temperature in DCE solvent to yield 7n (71%)
and similar migration of double bond also observed for the
vinyl group containing tertiary alcohol to selectively afford the
linear amide 7o in 67% yield.
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The Journal of Organic Chemistry
(a) B(C6F5)3-Catalyzed ether formation from benzylic alcohol and subsequent reaction with aniline
4a
CONCLUSION
(1.0 equiv)
1
2
3
4
5
6
7
8
B(C6F5)3 (2 mol %)
B(C6F5)3 (2 mol %)
2
MeO
In summary, we have developed a metal-free protocol for
catalytic N-alkylation of primary and secondary aromatic
amines and amides with readily available benzylic alcohols
under mild conditions. This method is useful for direct
functionalization of amines and amides even in the presence of
sensitive functional groups like cyano, carboxylic acid, and
carbonyl that are often difficult to survive under metal-
catalyzed reductive amination process. Mechanistic
experiments suggest the formation of an ether adduct which
decomposes to the product in the rate-determining step. This
protocol could show future perspectives for the development
of amine functionalization in a green and sustainable pathway.
O
5a
(35%)
toluene, 120 °C
OMe
4 Å MS, 8 h
OH
toluene, rt, 2 h
1a
MeO
8a
(82%)
(b) Equlibrium studies
9a
B(C6F5
)
3
B(C6F5
)
3
8a
Ar
O
Ar
C6D6, r.t.
9a
(9a:8a  95:5)
9
4a
10a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
H
B(C6F5
)
3
Me
N
B(C6F5)
3
Me
N
C6D6, r.t.
H
4a
10a
(10a:4a  80:20)
EXPERIMENTAL SECTION
General Information
All reactions were performed under a dry and oxygen free
argon atmosphere by using Schlenk techniques or in a
glovebox under argon atmosphere. 1H, 13C NMR, 11B
(BF3.OEt2 reference) and 19F (CFCl3 reference) spectra were
B(C6F5
)
3
4a
8a
9a
10a
9a
+
10a
4a
8a
+
C6D6, r.t.
(10a:9a  92:8)
(c) Hammett analysis
CH2OH
recorded on
a Bruker-AVANCE500 or JEOL-ECS400
NH2
1
spectrometer. The H NMR and 13C NMR chemical shifts
were presented relative to tetramethylsilane (TMS) or residual
solvent peak as an internal standard. Mass spectral analyses
were done in Bruker micrOTOF-Q II Spectrometer. Perkin–
Elmer FT–IR Spectrometer was used for FT-IR spectra. Dry
solvents were freshly prepared and degassed by freeze-pump-
thaw cycles, prior to use. Anilines, benzylic alcohols, amides,
boron compounds and other chemicals were purchased from
Sigma-Aldrich, Alfa-Aesar, Acros Organics, and Avra
Synthesis and used without further purification. Secondary
aryl amines were prepared according to the previous report.27
Representative procedure for B(C6F5)3-catalyzed N-
alkylation of secondary aromatic amines 2 with benzylic
alcohols 1.
B(C6F5)3 (2 mol %)
B(C6F5)3 (2 mol %)
4 Å MS, 10 h
5
5
1a
+
4h
+
toluene, 120 °C
4 Å MS, 10 h
X = p-OMe, p-Me,
H, p-Cl, m-Br
X = p-OMe, p-Me,
H, p-Cl, m-F
1
4
X
X
OMe
0.8
0.8
Me
0.3
0.4
OMe
Me
H
H
Cl
Br
0
-0.4
-0.8
-0.5
-0.3
-0.1
0.1
0.3
0.5
-0.5
-0.3
-0.1
0.1
0.3
0.5
-0.2
Cl
-0.7
log (kX/kH) = -2.92σ + 0.01
F
log (kX/kH) = -0.09σ + 0.006
R² = 0.99
R² = 0.97
-1.2
-1.2
Scheme 2. Mechanistic studies for the B(C6F5)3-catalyzed N-
alkylation reaction.
Based upon the above experimental results and previous
reports,13a,26 a plausible reaction mechanism is shown in
Scheme 3. At first, amine forms a reversibly Lewis adduct 10
with B(C6F5)3.24 Alcohol 1 in the presence of B(C6F5)3 catalyst
quickly delivers dibenzyl ether 8, which could furnish an
adduct 9 with B(C6F5)3 through the oxygen center. Later, the
adduct 9 could break into carbocation 11 and intermediate 12
in a rate-limiting step. However, an alternative reaction path
for the formation of carbocation 11 directly from alcohol in
the presence of Lewis acid cannot be ruled out.14c,20 The
carbocation 11 could then be intercepted instantaneously by
the aniline 2 or 4 or amide 6 to affords N-alkylated products 3
or 5 or 7 with the regeneration of B(C6F5)3 catalyst. The
intermediate 12, on the other hand immediately transforms
into 8 in the presence of 1.
30 mg of activated 4Å molecular sieve (powdered) was
taken in an oven dried 15 mL Schlenk tube. Benzyl alcohol 1a
(51.8 mg, 0.375 mmol, 1.5 equiv), N-methylaniline 2a (26.8
mg, 0.25 mmol, 1.0 equiv), and B(C6F5)3 catalyst (1.3 mg,
0.0025 mmol, 1 mol %) dissolved in 0.5 mL of toluene was
then added in that tube under argon. The solution was then
stirred at 110 °C (oil bath temperature) for 24 h under argon
atmosphere. Upon completion, the solvent was removed under
reduced pressure and the crude residue was purified by silica
gel column chromatography using hexane/ethyl acetate as
eluent to afford 3a as colorless liquid.
N-(4-Methoxybenzyl)-N-methylaniline (3a).28 Analytical
TLC on silica gel, 100:0 hexane/ethylacetate Rf = 0.50; Yield
88% (50 mg, 0.22 mmol). 1H NMR (400 MHz,
CHLOROFORM-D) δ 7.21-7.16 (m, 2H), 7.12 (d, J = 8.5 Hz,
2H), 6.81 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.3 Hz, 2H), 6.67 (t,
J = 7.3 Hz, 1H), 4.43 (s, 2H), 3.75 (s, 3H), 2.94 (s, 3H). 13C
{1H} NMR (126 MHz, CDCl3) δ 158.6, 149.9, 130.9, 129.1,
128.0, 116.5, 114.0, 112.5, 56.0, 55.3, 38.3. IR (neat / cm-1):
3026, 2945, 1601, 1538, 1336, 1224, 1034, 857, 683. HRMS
(ESI+): calculated for C15H17NONa [M + Na]+ : 250.1208;
found: 250.1215.
R1 Ar1
H2O
R1
Ar1
O
fast
fast
B(C F )
+
8
6
5
3
R2
R1
Ar2
N
H2O
Ar1
R2
B(C6F5)3
H
R1 Ar1
OH
1
2
4
6
or or
Ar2
N
Ar1
R1
B(C6F5)3
R1
Ar1
O
H
H
10
O
B(C6F5)3
B(C6F5)3
9
3
5
7
or or
12
N-Benzyl-4-methoxy-N-(4-methoxybenzyl)aniline
(3b).
R2
R2
slow
Analytical TLC on silica gel, 19:1 hexane/ethylacetate Rf =
0.40; Yield 83% (69.2 mg, 0.2075 mmol). 1H NMR (500
MHz, CDCl3) δ 7.35 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 8.0 Hz,
3H), 7.21 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.81
(d, J = 8.9 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 4.56 (s, 2H), 4.53
(s, 2H), 3.83 (s, 3H), 3.77 (s, 3H). 13C{1H} NMR (126 MHz,
Ar2
10
N
H
B(C6F5)3
+
Ar
fast
Ar1
NH
R1
2
B(C6F5)3
11
2
4
6
or or
Scheme 3. Proposed mechanism for borane-catalyzed N-
alkylation.
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The Journal of Organic Chemistry
Page 6 of 13
CDCl3) δ 158.5, 151.7, 143.9, 139.0, 130.8, 128.5, 128.1, 4H), 6.86 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 6.71
1
2
3
4
5
6
7
8
126.9, 126.7, 114.8, 114.7, 113.9, 55.7, 55.2, 55.0, 54.6. IR
(neat / cm-1): 2938, 2830, 1595, 1234, 1157, 1033, 838, 698.
(d, J = 8.9 Hz, 2H), 4.46 (s, 4H), 3.80 (s, 3H), 3.74 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 158.6, 152.0, 143.6,
137.6, 132.4, 130.5, 128.6, 128.4, 128.2, 115.2, 114.7, 113.9,
55.7, 55.2, 54.8, 54.4. IR (neat / cm-1): 2933, 2834, 1611,
1515, 1489, 1244, 1173, 1035, 810. HRMS (ESI+): calculated
for C22H22ClNO2Na [M + Na]+ : 390.1237; found: 390.1229.
N-(3-Fluorobenzyl)-4-methoxy-N-(4-methoxybenzyl)aniline
(3i). Analytical TLC on silica gel, 19:1 hexane/ethylacetate Rf
HRMS (ESI+): calculated for C22H23NO2Na [M + Na]+
356.1626; found: 356.1620.
:
N-Benzyl-4-chloro-N-(4-methoxybenzyl)aniline
(3c).
Analytical TLC on silica gel, 19:1 hexane/ethylacetate Rf =
1
0.60; Yield 77% (65.0 mg, 0.1925 mmol). H NMR (500
MHz, CDCl3) δ 7.35 (t, J = 7.7 Hz, 2H), 7.28 (d, J = 7.0 Hz,
1H), 7.23 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.11
(d, J = 8.8 Hz, 2H), 6.89 (d, J = 7.7 Hz, 2H), 6.67 (d, J = 8.1
Hz, 2H), 4.62 (s, 2H), 4.59 (s, 2H), 3.82 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 158.7, 147.7, 138.2, 129.9, 129.0,
128.7, 127.8, 127.0, 126.6, 121.5, 114.1, 113.8, 55.3, 54.3,
53.9. IR (neat / cm-1): 3064, 3030, 2852, 1598, 1506, 1448,
1400, 1321, 1319, 1178, 1093, 816, 731, 693. HRMS (ESI+):
calcd for C21H20ClNONa [M + Na]+ : 360.1131; found
360.1130.
1
= 0.25; Yield 45% (38.6 mg, 0.105 mmol). H NMR (500
9
MHz, CDCl3) δ 7.29 – 7.25 (m, 1H), 7.17 (d, J = 8.3 Hz, 2H),
7.03 (d, J = 7.6 Hz, 1H), 7.00 – 6.89 (m, 2H), 6.87 (d, J = 8.4
Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.72 (d, J = 9.0 Hz, 2H),
4.49 (s, 4H), 3.80 (s, 3H), 3.74 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 163.2 (d, J = 245.9 Hz), 158.6, 152.0, 143.6,
142.1 (d, J = 6.5 Hz), 130.5, 130.0 (d, J = 8.2 Hz), 128.2,
122.5 (d, J = 2.3 Hz), 115.0, 114.7, 114.0, 113.8 (d, J = 18.1
Hz), 113.6 (d, J = 17.4 Hz), 55.7, 55.2, 54.9, 54.6. IR (neat /
cm-1): 2938, 2834, 1617, 1520, 1177, 1036, 812, 786, 689.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(Benzo[d][1,3]dioxol-5-ylmethyl)-N-benzyl-4-
methoxyaniline (3d). Analytical TLC on silica gel, 19:1
hexane/ethylacetate Rf = 0.35; Yield 76% (65.9 mg, 0.19
mmol). 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.21 (m, 5H),
6.82 – 6.69 (m, 7H), 5.94 (s, 2H), 4.54 (s, 2H), 4.47 (s, 2H),
3.75 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 151.8, 147.9,
146.4, 143.7, 138.9, 132.9, 128.5, 127.0, 126.8, 119.9, 114.9,
114.7, 108.2, 107.5, 100.9, 55.7, 55.1, 55.0. IR (neat / cm-1):
3028, 2900, 2832, 1515, 1488, 1443, 1243, 1039, 937, 812,
736, 697. HRMS (ESI+): calcd for C22H21NO3Na [M + Na]+ :
370.1419, found 370.1421.
N-(Anthracen-9-ylmethyl)-N-benzyl-4-methoxyaniline (3e).
Analytical TLC on silica gel, 19:1 hexane/ethylacetate Rf =
0.50; Yield 92% (92.8 mg, 0.23 mmol). 1H NMR (400 MHz,
CHLOROFORM-D) δ 8.41 (s, 1H), 8.25 (d, J = 9.4 Hz, 2H),
8.02 – 7.93 (m, 2H), 7.47 – 7.38 (m, 4H), 7.09 – 7.00 (m, 5H),
6.93 – 6.84 (m, 4H), 5.34 (s, 2H), 4.18 (s, 2H), 3.80 (s, 3H).
13C{1H} NMR (101 MHz, CHLOROFORM-D) δ 152.7,
144.6, 139.8, 131.5, 131.3, 129.0, 128.8, 127.9, 127.1, 126.2,
125.9, 124.9, 124.6, 117.0, 114.7, 55.6, 52.9, 47.8. IR (neat /
cm-1): 3053, 2931, 2832, 1511, 1452, 1244, 1038, 813, 731.
HRMS (ESI+): calcd for C29H25NONa [M + Na]+ : 426.1834,
found 426.1845.
HRMS (ESI+): calcd for C22H22FNO2Na [M + Na]+
374.1532, found 374.1536.
:
N-Benzyl-4-chloro-N-(1-(p-tolyl)ethyl)aniline
(3l).
Analytical TLC on silica gel, 100:0 hexane/ethylacetate Rf =
1
0.30; Yield 65% (54.6 mg, 0.1625 mmol). H NMR (500
MHz, CDCl3) δ 7.32 – 7.26 (m, 2H), 7.23 – 7.19 (m, 5H), 7.15
(d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 8.7
Hz, 2H), 5.19 (q, J = 7.0 Hz, 1H), 4.50 (d, J = 17.4 Hz, 1H),
4.39 (d, J = 17.4 Hz, 1H), 2.35 (s, 3H), 1.59 (d, J = 7.0 Hz,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 147.8, 139.6, 139.3,
136.7, 129.3, 128.8, 128.4, 126.7, 126.6, 126.4, 121.9, 115.4,
57.2, 50.3, 21.0, 18.7. IR (neat / cm-1): 3026, 2976, 2924,
1597, 1497, 1449, 1245, 805, 731. HRMS (ESI+): calcd for
C22H22ClNNa [M + Na]+ : 358.1338, found 358.1351.
N-Benzhydryl-N-methylaniline (3m): Analytical TLC on
silica gel, 49:1 hexane/ethylacetate Rf = 0.60; Yield 80% (54.7
mg, 0.20 mmol). 1H NMR (500 MHz, CDCl3) δ 7.49 – 7.27
(m, 12H), 6.92 (d, J = 8.1 Hz, 2H), 6.85 (t, J = 7.2 Hz, 1H),
6.31 (s, 1H), 2.86 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
150.2, 140.7, 129.1, 128.7, 128.4, 127.2, 116.8, 113.0, 67.0,
34.5. IR (neat / cm-1): 3061, 3026, 1598, 1504, 1319, 1105,
990, 748, 699. HRMS (ESI+): calcd for C20H19NNa [M + Na]+
: 296.1415, found 296.1410.
N-Phenyl-N-(thiophen-2-ylmethyl)aniline (3f). Analytical
TLC on silica gel, 100:0 hexane/ethylacetate Rf = 0.40; Yield
Representative procedure for B(C6F5)3-catalyzed N-
alkylation of Primary aromatic amines 4 with benzylic
alcohols 1.
1
81% (53.7 mg, 0.2025 mmol). H NMR (500 MHz, CDCl3) δ
7.27 (t, J = 7.9 Hz, 4H), 7.16 (d, J = 5.0 Hz, 1H), 7.09 (d, J =
7.8 Hz, 4H), 7.02 – 6.90 (m, 4H), 5.12 (s, 2H). 13C{1H} NMR
(126 MHz, CDCl3) δ 147.6, 142.8, 129.3, 126.7, 124.7, 124.1,
121.7, 121.0, 51.8. IR (neat / cm-1): 3060, 3030, 1594, 1501,
1453, 1367, 1105, 1030, 748, 730, 696. HRMS (ESI+): calcd
for C17H15NSNa [M + Na]+ : 288.0823, found 288.0821.
30 mg of powdered 4Å molecular sieve was taken in an
oven dried 15 mL Schlenk tube. In that tube, benzyl alcohol
1a (51.8 mg, 0.375 mmol, 1.5 equiv), aniline 4a (26.8 mg,
0.25 mmol, 1.0 equiv), B(C6F5)3 catalyst (2.5 mg, 0.005 mmol,
2 mol %) and toluene (0.5 mL) were added under argon and
the tube was sealed, stirred at 120 °C (oil bath temperature)
for 36 h. Upon completion, the solvent was removed under
reduced pressure and the crude residue was purified by silica
gel column chromatography using hexane/ethylacetate as
eluent to afford 5a as colorless liquid.
N-Methyl-N-(3,4,5-trimethoxybenzyl)aniline
(3g).
Analytical TLC on silica gel, 19:5 hexane/ethylacetate Rf =
0.30; Yield 90% (64.7 mg, 0.225 mmol). 1H NMR (500 MHz,
CDCl3) δ 7.24 (t, J = 8.0 Hz, 2H), 6.79 (d, J = 8.2 Hz, 2H),
6.74 (t, J = 7.3 Hz, 1H), 6.48 (s, 2H), 4.46 (s, 2H), 3.85 (s,
3H), 3.81 (s, 6H), 3.00 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 153.4, 150.0, 136.7, 134.9, 129.1, 116.8, 112.7,
103.4, 60.8, 57.2, 56.0, 38.4. IR (neat / cm-1): 3060, 3029,
1598, 1502, 1454, 1106, 751, 730, 696. HRMS (ESI+): calcd
for C17H21NO3Na [M + Na]+ : 310.1419, found 310.1422.
N-(4-Chlorobenzyl)-4-methoxy-N-(4-methoxybenzyl)aniline
(3h). Analytical TLC on silica gel, 19:1 hexane/ethylacetate Rf
N-(4-Methoxybenzyl)-4-methylaniline (5a).29 Analytical
TLC on silica gel, 19:1 hexane/ethylacetate Rf = 0.50; Yield
81% (46.0 mg, 0.2025 mmol). 1H NMR (500 MHz, CDCl3) δ
7.29 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.1 Hz, 2H), 6.88 (d, J =
8.7 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 4.24 (s, 2H), 3.81 (s,
4H), 2.24 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 158.8,
146.0, 131.6, 129.7, 128.8, 126.7, 114.0, 113.0, 55.3, 48.1,
20.4. IR (neat / cm-1): 2963, 2839, 1611, 1513, 1242, 1179,
1
= 0.30; Yield 42% (38.6 mg, 0.105 mmol). H NMR (500
MHz, CDCl3) δ 7.27 (d, J = 8.2 Hz, 2H), 7.17 (t, J = 8.2 Hz,
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1028, 814. HRMS (ESI+): calcd for C15H17NONa [M + Na]+ :
110.2, 55.5, 47.1. IR (neat / cm-1): 3046, 2997, 2933, 2834,
1709, 1611, 1515, 1244, 1173, 1034, 809. HRMS (ESI+):
calcd for C15H14ClNO3Na [M + Na]+ : 314.0560; found
314.0575.
1
2
3
4
5
6
7
8
250.1208, found 250.1211.
4-Chloro-N-(4-methoxybenzyl)aniline (5b).30 Analytical
TLC on silica gel, 19:1 hexane/ethylacetate Rf = 0.40; Yield
1
87% (53.9 mg, 0.2175 mmol). H NMR (400 MHz, CDCl3) δ
4-Methoxy-N-(4-methoxybenzyl)aniline (5h).30 Analytical
TLC on silica gel, 9:1 hexane/ethylacetate Rf = 0.40; Yield
7.25 (d, J = 7.0 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.86 (d, J =
8.7 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H), 4.21 (s, 2H), 3.97 (brs,
1H), 3.79 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 159.0,
146.7, 130.9, 129.0, 128.7, 122.0, 114.1, 113.9, 55.3, 47.8. IR
(neat / cm-1): 3413, 2957, 2932, 2836, 1601, 1505, 1512, 1247,
1177, 1034, 815, 506. HRMS (ESI+): calcd for C14H14ClNONa
[M + Na]+ : 270.0662, found 270.0670.
1
83% (50.5 mg, 0.2075 mmol). H NMR (500 MHz, CDCl3) δ
7.29 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.79 (d, J =
8.8 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 4.21 (s, 2H), 3.78 (m,
7H). 13C{1H} 13C NMR (101 MHz, CHLOROFORM-D) δ
158.8, 152.1, 142.5, 131.6, 128.8, 114.9, 114.1, 114.0, 55.8,
55.3, 48.7. IR (neat / cm-1): 3010, 2997, 1588, 1534, 1230,
1101, 1035, 780. HRMS (ESI+): calcd for C15H17NO2Na [M +
Na]+ : 266.1157; found 266.1149.
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3,5-Dichloro-N-(4-methoxybenzyl)aniline (5c): Analytical
TLC on silica gel, 49:1 hexane/ethylacetate Rf = 0.35; Yield
1
86% (60.6 mg, 0.2150 mmol). H NMR (400 MHz, CDCl3) δ
N-(Benzo[d][1,3]dioxol-4-ylmethyl)-2-methylaniline (5i):
Analytical TLC on silica gel, 19:1 hexane/ethylacetate Rf =
7.23 (d, J = 9.3 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.65 (s, 1H),
6.46 (s, 2H), 4.19 (d, J = 5.1 Hz, 2H), 4.09 (brs, 1H), 3.80 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 159.1, 149.6, 130.0,
128.8, 117.2, 114.2, 111.0, 55.3, 47.4. IR (neat / cm-1): 2933,
2836, 1593, 1511, 1452, 1247, 1177, 1114, 820, 799. HRMS
(ESI+): calcd for C14H13Cl2NONa [M + Na]+ : 304.0272; found
304.0269.
1
0.50; Yield 84% (50.6 mg, 0.21 mmol). H NMR (500 MHz,
CDCl3) δ 7.14 – 7.09 (m, 2H), 6.90 (s, 1H), 6.87 (d, J = 7.9
Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.70 (t, J = 7.7 Hz, 1H),
6.63 (d, J = 8.0 Hz, 1H), 5.96 (s, 2H), 4.30 (s, 2H), 3.83 (brs,
1H), 2.18 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 147.9,
146.7, 145.9, 133.4, 130.0, 127.1, 121.9, 120.6, 117.2, 110.0,
108.3, 108.0, 101.0, 48.1, 17.5. IR (neat / cm-1): 3000, 2933,
2835, 1513, 1488, 1244, 1172, 1034, 811. HRMS (ESI+):
calcd for C15H15NO2Na [M + Na]+ : 264.1000, found
264.1005.
3-Bromo-N-(4-methoxybenzyl)aniline (5d). Analytical TLC
on silica gel, 49:1 hexane/ethylacetate Rf = 0.40; Yield 82%
1
(59.8 mg, 0.205 mmol). H NMR (500 MHz, CDCl3) δ 7.27
(d, J = 8.0 Hz, 2H), 7.01 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.5
Hz, 2H), 6.82 (d, J = 7.8 Hz, 1H), 6.78 (s, 1H), 6.53 (d, J = 8.2
Hz, 1H), 4.23 (s, 2H), 4.01 (brs, 1H), 3.81 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 159.0, 149.4, 130.7, 130.5, 128.8,
123.3, 120.2, 115.4, 114.1, 111.5, 55.3, 47.6. IR (neat / cm-1):
3411, 3000, 2931, 2835, 1595, 1511, 1418, 1359, 1323, 1301,
1245, 1174, 1102, 1067, 1033, 985, 809, 762, 682, 518.
3-Bromo-N-(thiophen-2-ylmethyl)aniline (5j). Analytical
TLC on silica gel, 100:0 hexane/ethylacetate Rf = 0.50; Yield
1
71% (47.6 mg, 0.1775 mmol). H NMR (500 MHz, CDCl3) δ
7.30 – 7.20 (m, 1H), 7.04 – 6.69 (m, 3H), 6.91 – 6.78 (m, 2H),
6.58 (d, J = 8.0 Hz, 1H), 4.49 (s, 2H), 4.11 (brs, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ 148.8, 142.0, 130.5, 126.9, 125.3,
124.8, 123.2, 120.8, 115.7, 111.8, 43.2. IR (neat / cm-1): 2933,
2830, 1594, 1455, 1360, 1033, 748, 694. HRMS (ESI+): calcd
for C11H10BrNSNa [M + Na]+ : 289.9615, found 289.9610.
N-(4-Chlorobenzyl)-4-methoxyaniline (5k).30 Analytical
TLC on silica gel, 19:1 hexane/ethylacetate Rf = 0.40; Yield
HRMS (ESI+): calcd for C14H14BrNONa [M + Na]+
314.0156; found 314.0162.
:
4-((4-Methoxybenzyl)amino)benzonitrile (5e). Analytical
TLC on silica gel, 49:1 hexane/ethylacetate Rf = 0.40; Yield
1
74% (44.1 mg, 0.185 mmol). H NMR (400 MHz, CDCl3) δ
1
7.39 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.88 (d, J =
8.6 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 4.55 (brs, 1H), 4.27 (d, J
= 5.3 Hz, 2H), 3.79 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3)
δ 159.1, 151.1, 133.6, 129.7, 128.6, 120.4, 114.2, 112.3, 98.8,
55.2, 46.9. IR (neat / cm-1): 2997, 2935, 2832, 2222, 1518,
1249, 1172, 1036, 811. HRMS (ESI+): calculated for
C15H14N2ONa [M + Na]+ : 261.1004; found: 261.1012.
38% (26.1 mg, 0.095 mmol). H NMR (500 MHz, CDCl3) δ
7.31 (s, 4H), 6.79 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.9 Hz, 2H),
4.27 (s, 2H), 3.75 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
152.3, 142.1, 138.2, 132.7, 128.70, 128.65, 114.9, 114.1, 55.7,
48.5. IR (neat / cm-1): 3063, 3032, 1601, 1498, 1319, 816, 730.
HRMS (ESI+): calcd for C14H14ClNONa [M + Na]+
270.0662, found 270.0670.
:
(2-((4-Methoxybenzyl)amino)phenyl)(phenyl)methanone
N-(3-Fluorobenzyl)-4-methoxyaniline (5l).31 Analytical TLC
(5f). Analytical TLC on silica gel, 19:1 hexane/ethylacetate Rf
= 0.50; Yield 88% (69.8 mg, 0.22 mmol). 1H NMR (500 MHz,
CDCl3) δ 8.96 (brs, 1H), 7.64 (d, J = 7.1 Hz, 2H), 7.57 – 7.42
(m, 4H), 7.41 – 7.29 (m, 3H), 6.91 (d, J = 8.6 Hz, 2H), 6.78
(d, J = 8.5 Hz, 1H), 6.57 (t, J = 7.5 Hz, 1H), 4.45 (d, J = 5.4
Hz, 2H), 3.81 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
199.3, 158.8, 151.5, 140.4, 135.4, 134.9, 130.7, 130.5, 129.0,
128.4, 128.0, 117.4, 114.1, 114.0, 111.9, 55.2, 46.4. IR (neat /
cm-1): 2931, 2830, 1725, 1615, 1585, 1513, 1242, 1032, 818,
on silica gel, 19:1 hexane/ethylacetate Rf = 0.35; Yield 43%
1
(24.9 mg, 0.1075 mmol). H NMR (500 MHz, CDCl3) δ 7.31
(dd, J = 13.9, 7.7 Hz, 1H), 7.17 – 7.10 (m, 2H), 6.97 (t, J = 8.3
Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.7 Hz, 2H),
4.31 (s, 2H), 3.86 (brs, 1H), 3.76 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 163.1 (d, J = 246.0 Hz), 152.3, 142.6 (d, J =
6.9 Hz), 142.0, 130.0 (d, J = 8.2 Hz), 122.8 (d, J = 2.8 Hz),
114.9, 114.2 (d, J = 21.4 Hz), 114.1, 113.9 (d, J = 21.1 Hz),
55.7, 48.6. IR (neat / cm-1): 2997, 2831, 1589, 1514, 1179,
917, 685. HRMS (ESI+): calcd for C14H14FNONa [M + Na]+ :
254.0957, found 254.0952.
783. HRMS (ESI+): calcd for C21H19NO2Na [M + Na]+
340.1313; found 340.1301.
:
4-Chloro-2-((4-methoxybenzyl)amino)benzoic acid (5g).
Analytical TLC on silica gel, 4:1 hexane/ethylacetate Rf =
0.30; Yield 71% (51.8 mg, 0.1775 mmol). 1H NMR (500
MHz, THF-d8) δ 8.43 (brs, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.25
(d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 1.7
Hz, 1H), 6.51 (dd, J = 8.5, 1.8 Hz, 1H), 4.35 (d, J = 5.1 Hz,
2H), 3.74 (s, 3H). 13C{1H} NMR (126 MHz, THF-d8) δ 170.4,
160.3, 153.2, 141.2, 134.4, 131.6, 129.3, 115.4, 115.0, 112.0,
N-Benzyl-4-chloroaniline (5m).32 Analytical TLC on silica
gel, 49:1 hexane/ethylacetate Rf = 0.50; Yield 80% (43.5 mg,
1
0.2 mmol). H NMR (500 MHz, CDCl3) δ 7.48 – 7.47 (m,
4H), 7.43 – 7.40 (m, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.67 (d, J =
8.8 Hz, 2H), 4.43 (s, 2H), 4.18 (brs, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 146.6, 138.9, 129.0, 128.7, 127.4, 127.3,
122.1, 113.9, 48.3. IR (neat / cm-1): 3063, 3028, 1601, 1502,
1450, 1323, 1175, 1120, 1089, 817, 734, 700. HRMS (ESI+):
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calcd for C13H12ClNNa [M + Na]+ : 240.0556, found
N-(3,3-diphenylallyl)-4-methoxyaniline (5t). Analytical TLC
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2
3
4
5
6
7
8
240.0547.
on silica gel, 19:1 hexane/ethylacetate Rf = 0.20; Yield 79%
(62.3 mg, 0.1975 mmol). 1H NMR (400 MHz,
CHLOROFORM-D) δ 7.41 – 7.34 (m, 4H), 7.28 – 7.19 (m,
7H), 6.76 (d, J = 9.0 Hz, 2H), 6.55 (d, J = 8.8 Hz, 2H), 6.19 (t,
J = 6.6 Hz, 1H), 3.79 (d, J = 6.7 Hz, 2H), 3.73 (s, 3H).
13C{1H} NMR (101 MHz, CHLOROFORM-D) δ 152.2,
144.0, 142.1, 142.0, 139.3, 129.7, 128.5, 128.3, 128.1, 127.5,
126.6, 126.5, 114.8, 114.4, 55.8, 44.2. IR (neat / cm-1): 2929,
1634, 1511, 1234, 1032, 818, 755, 699. HRMS (ESI+): calcd
for C22H21NONa [M + Na]+ : 338.1521; found 338.1519.
Large scale synthetic procedure for B(C6F5)3-catalyzed
N-benzylation of p-toluidine (4a) with p-methoxybenzyl
alcohol (1a).
In an oven dried 100 mL Schlenk tube 300 mg of powdered
4Å molecular sieve was taken. In that tube, benzyl alcohol 1a
(518.1 mg, 03.75 mmol, 1.5 equiv), aniline 4a (267.9 mg, 2.5
mmol, 1.0 equiv), B(C6F5)3 catalyst (25.6 mg, 0.05 mmol, 2
mol %) and toluene (50 mL) were added under argon and the
tube was sealed, stirred at 120 °C (oil bath temperature) for 48
h. Upon completion, the solvent was removed under reduced
pressure and the crude residue was purified by silica gel
column chromatography using hexane/ethylacetate as eluent to
afford 5a in 76% yield (431.5 mg, 1.9 mmol).
N-Benzyl-4-bromoaniline (5n).33 Analytical TLC on silica
gel, 49:1 hexane/ethylacetate Rf = 0.50; Yield 76% (49.8 mg,
1
0.19 mmol). H NMR (400 MHz, CHLOROFORM-D) δ 7.35
– 7.34 (m, 4H), 7.31 – 7.27 (m, 1H), 7.24 (d, J = 8.6 Hz, 2H),
6.50 (d, J = 8.6 Hz, 2H), 4.29 (s, 2H), 4.07 (brs, 1H). 13C{1H}
NMR (101 MHz, CHLOROFORM-D) δ 147.0, 138.8, 131.9,
128.7, 127.3, 114.4, 109.1, 48.2. IR (neat / cm-1): 3064, 3030,
2857, 1598, 1500, 1322, 1179, 1068, 810, 730, 694. HRMS
(ESI+): calcd for C13H12BrNNa [M + Na]+ : 284.0051, found
284.0042.
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4-Chloro-N-(naphthalen-2-ylmethyl)aniline
(5o).34
Analytical TLC on silica gel, 49:1 hexane/ethylacetate Rf =
1
0.10; Yield 72% (49.8 mg, 0.18 mmol). H NMR (400 MHz,
CHLOROFORM-D) δ 7.82 – 7.77 (m, 4H), 7.47 – 7.43 (m,
3H), 7.09 (d, J = 8.9 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 4.45 (s,
2H), 4.16 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.7,
136.4, 133.5, 132.8, 129.1, 128.5, 127.73, 127.70, 126.2,
125.9, 125.9, 125.5, 122.2, 114.0, 48.6. IR (neat / cm-1): 3429,
3054, 2963, 1599, 1504, 1402, 1313, 1262, 1178, 1095, 855,
813, 750, 621. HRMS (ESI+): calcd for C17H14ClNNa [M +
Na]+ : 290.0712, found 290.0720.
4-Methyl-N-(1-phenylethyl)aniline (5p).35 Analytical TLC
on silica gel, 49:1 hexane/ethylacetate Rf = 0.40; Yield 62%
(32.8 mg, 0.155 mmol). 1H NMR (500 MHz, CDCl3) δ 7.50 –
7.35 (m, 5H), 7.29 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 8.2 Hz,
2H), 6.52 (d, J = 8.3 Hz, 2H), 4.54 (q, J = 6.7 Hz, 1H), 3.97
(brs, 1H), 2.27 (s, 3H), 1.58 (d, J = 6.7 Hz, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 145.4, 145.0, 129.5, 128.6, 126.7,
126.3, 125.8, 113.4, 53.6, 25.0, 20.3. IR (neat / cm-1): 2938,
2834, 1615, 1588,1518, 1250, 819, 783. HRMS (ESI+): calcd
for C15H17NNa [M + Na]+ : 234.1259, found 234.1245.
Representative procedure for B(C6F5)3-catalyzed N-
alkylation of amide 6 with benzylic alcohol 1.
In an oven dried 15 mL Schlenk tube 30 mg of powdered
4Å molecular sieve was taken. Benzyl alcohol 1a (34.5 mg,
0.25 mmol, 1.0 equiv), amide 6a (42.8 mg, 0.25 mmol, 1.0
equiv), B(C6F5)3 catalyst (2.5 mg, 0.005 mmol, 2 mol %) and
chlorobenzene (0.5 mL) were then added under argon. The
tube was sealed, stirred at 110 °C (oil bath temperature) for 48
h. Upon completion, the solvent was removed under reduced
pressure and the crude residue was purified by flash column
chromatography to afford 7a.
4-Methyl-N-(1-(p-tolyl)ethyl)aniline (5q). Analytical TLC
on silica gel, 99:1 hexane/ethylacetate Rf = 0.35; Yield 69%
1
(38.9 mg, 0.1725 mmol). H NMR (500 MHz, CDCl3) δ 7.33
N-(4-Methoxybenzyl)-4 methylbenzenesulfonamide (7a).36
Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf =
0.35; Yield 90% (65.6 mg, 0.225 mmol). 1H NMR (400 MHz,
CHLOROFORM-D) δ 7.71 (d, J = 8.3 Hz, 2H), 7.26 (d, J =
8.2 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H),
4.98 (t, J = 6.0 Hz, 1H), 4.01 (d, J = 6.1 Hz, 2H), 3.73 (s, 3H),
2.40 (s, 3H). 13C{1H} NMR (101 MHz, CHLOROFORM-D) δ
159.1, 143.3, 136.8, 129.6, 129.2, 128.3, 127.1, 113.9, 55.2,
46.6, 21.4. IR (neat / cm-1): 2933, 2867, 1599, 1462, 1410,
1235, 1098, 987, 828, 663. HRMS (ESI+): calcd for
C15H17NO3SNa [M + Na]+ : 314.0827; found 314.0820.
N-(4-(Dimethylamino)benzyl)-4-methylbenzenesulfonamide
(7b). Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf
(d, J = 7.8 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 8.0
Hz, 2H), 6.52 (d, J = 8.1 Hz, 2H), 4.51 (q, J = 6.6 Hz, 1H),
3.94 (brs, 1H), 2.40 (s, 3H), 2.27 (s, 3H), 1.56 (d, J = 6.7 Hz,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 145.1, 142.4, 136.2,
129.5, 129.2, 126.2, 125.7, 113.4, 53.3, 25.0, 21.0, 20.3. IR
(neat / cm-1): 2949, 2831, 1615, 1584, 1513, 1246, 1037, 822,
782. HRMS (ESI+): calcd for C16H19NNa [M + Na]+
248.1415; found 248.1407.
:
N-Benzhydryl-4-methylaniline (5r).28 Analytical TLC on
silica gel, 100:0 hexane/ethylacetate Rf = 0.30; Yield 78%
(53.3 mg, 0.195 mmol). 1H NMR (500 MHz, CDCl3) δ 7.50 –
7.36 (m, 8H), 7.33 (d, J = 6.9 Hz, 2H), 7.01 (d, J = 7.4 Hz,
2H), 6.55 (d, J = 7.0 Hz, 2H), 5.55 (s, 1H), 4.19 (brs, 1H),
2.29 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 145.1,
143.1, 129.6, 128.7, 127.4, 127.2, 126.8, 113.5, 63.3, 20.3. IR
(neat / cm-1): 2997, 2934, 2834, 1615, 1584, 1513, 1241, 1032,
1
= 0.20; Yield 82% (62.4 mg, 0.205 mmol). H NMR (400
MHz, CHLOROFORM-D) δ 7.76 (d, J = 8.3 Hz, 2H), 7.31 (d,
J = 8.1 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.7 Hz,
2H), 4.46 (t, J = 5.6 Hz, 1H), 4.01 (d, J = 5.8 Hz, 2H), 2.92 (s,
6H), 2.44 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 150.4,
143.3, 137.0, 129.7, 129.0, 127.2, 123.6, 112.5, 47.0, 40.5,
21.5. IR (neat / cm-1): 2922, 2804, 1616, 1524, 1327, 1159,
1094, 810, 661. HRMS (ESI+): calcd for C16H20N2O2SNa [M +
Na]+ : 327.1143; found 327.1135.
783. HRMS (ESI+): calcd for C20H19NNa [M + Na]+
296.1415; found 296.1417.
:
4-Methoxy-N-tritylaniline (5s).20 Analytical TLC on silica
gel, 19:1 hexane/ethylacetate Rf = 0.50; Yield 52% (47.5 mg,
1
0.13 mmol). H NMR (400 MHz, CHLOROFORM-D) δ 7.39
– 7.27 (m, 6H), 7.28 – 7.24 (m, 6H), 7.22 – 7.18 (m, 3H), 6.50
(d, J = 8.9 Hz, 2H), 6.30 (d, J = 8.9 Hz, 2H), 4.75 (brs, 1H),
3.63 (s, 3H). 13C{1H} NMR (101 MHz, CHLOROFORM-D) δ
151.7, 145.5, 140.0, 129.2, 127.8, 126.7, 117.2, 113.7, 71.6,
55.4. IR (neat / cm-1): 3026, 2999, 1510, 1490, 1447, 1247,
1237, 1034, 820, 701. HRMS (ESI+): calcd for C26H23NONa
[M + Na]+ : 388.1677; found 388.1670.
N-(3-Iodobenzyl)-4-methylbenzenesulfonamide
(7c).
Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf =
1
0.45; Yield 64% (62.0 mg, 0.16 mmol). H NMR (400 MHz,
CHLOROFORM-D) δ 7.71 (d, J = 8.2 Hz, 2H), 7.55 (d, J =
7.8 Hz, 1H), 7.43 (s, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.16 (d, J =
7.8 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 4.66 (d, J = 5.7 Hz, 1H),
4.07 (d, J = 6.3 Hz, 2H), 2.43 (s, 3H). 13C{1H} NMR (126
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The Journal of Organic Chemistry
MHz, CDCl3) δ 143.8, 138.6, 137.0, 136.9, 136.8, 130.3, 4.82 (d, J = 6.9 Hz, 1H), 4.28 (q, J = 7.2 Hz, 1H), 2.45 (s, 3H),
129.8, 127.13, 127.06, 94.4, 46.5, 21.6. IR (neat / cm-1): 2922,
2850, 1641, 1634, 1323, 1153, 658. HRMS (ESI+): calcd for
C14H14INO2SNa [M + Na]+ : 409.9688; found 409.9675.
N-(4-Bromo-2-methoxybenzyl)-4-methylbenzenesulfonamide
(7d). Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf
1.96 – 1.77 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 144.9, 142.9, 140.7, 137.7, 129.3, 128.4,
127.4, 127.1, 126.5, 59.8, 30.6, 21.4, 10.4. IR (neat / cm-1):
2922, 2855, 1599, 1455, 1319, 1310, 1162, 670. HRMS
(ESI+): calcd for C16H19NO2SNa [M + Na]+ : 312.1034; found
312.1031.
1
2
3
4
5
6
1
= 0.25; Yield 78% (72.2 mg, 0.195 mmol). H NMR (400
MHz, CHLOROFORM-D) δ 7.60 (d, J = 8.2 Hz, 2H), 7.19 (d,
J = 8.1 Hz, 2H), 6.93 (s, 2H), 6.81 (s, 1H), 5.08 (t, J = 6.5 Hz,
1H), 4.09 (d, J = 6.6 Hz, 2H), 3.72 (s, 3H), 2.40 (s, 3H).
13C{1H} NMR (101 MHz, CHLOROFORM-D) δ 157.7,
143.3, 137.2, 130.9, 129.4, 127.0, 123.5, 113.8, 55.5, 43.4,
21.5. IR (neat / cm-1): 2927, 2856, 1595, 1489, 1462, 1400,
1329, 1160, 1030, 814, 730, 663. HRMS (ESI+): calcd for
C15H16BrNO3SNa [M + Na]+ : 391.9932; found 391.9931.
4-Methyl-N-(naphthalen-2-ylmethyl)benzenesulfonamide
(7e).12a Analytical TLC on silica gel, 9:1 hexane/ethylacetate
Rf = 0.45; Yield 75% (58.3 mg, 0.1875 mmol). 1H NMR (400
MHz, CHLOROFORM-D) δ 7.77 – 7.74 (m, 4H), 7.59 (s,
2H), 7.47 – 7.44 (m, 2H), 7.31 – 7.27 (m, 4H), 4.68 (t, J = 6.2
Hz, 2H), 4.28 (d, J = 6.3 Hz, 4H), 2.40 (s, 5H). 13C{1H} NMR
(126 MHz, CDCl3) δ 143.6, 137.0, 133.6, 133.2, 132.9, 129.7,
128.6, 127.73, 127.66, 127.2, 126.7, 126.4, 126.2, 125.6, 47.5,
21.5. IR (neat / cm-1): 2922, 2855, 1629, 1603, 1323, 1162,
813, 733. HRMS (ESI+): calcd for C18H17NO2SNa [M + Na]+
: 334.0878; found 334.0865.
N-(Anthracen-9-ylmethyl)-4-methylbenzenesulfonamide(7f).
Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf =
0.40; Yield 72% (65.1 mg, 0.18 mmol). 1H NMR (500 MHz,
CDCl3) δ 8.43 (s, 1H), 8.00 – 7.97 (m, 2H), 7.96 – 7.92 (m,
2H), 7.84 (d, J = 8.2 Hz, 2H), 7.47 – 7.45 (m, 4H), 7.35 (d, J =
8.0 Hz, 2H), 5.06 (d, J = 5.4 Hz, 2H), 4.54 (s, 1H), 2.50 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 143.7, 136.4, 131.4,
130.2, 129.8, 129.2, 128.7, 127.5, 126.8, 125.9, 125.2, 123.2,
39.5, 21.6. (s). IR (neat / cm-1): 2922, 2850, 1633, 1336, 1158,
1094, 729, 670. HRMS (ESI+): calcd for C22H19NO2SNa [M +
Na]+ : 384.1034; found 384.1023.
N-(1-(3-Chlorophenyl)ethyl)-4-methylbenzenesulfonamide
(7j). Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf =
0.40; Yield 68% (52.7 mg, 0.17 mmol). 1H NMR (500 MHz,
CDCl3) δ 7.59 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H),
7.10 (d, J = 4.8 Hz, 2H), 7.05 – 7.01 (m, 1H), 6.98 (s, 1H),
5.42 (s, 1H), 4.47 – 4.39 (m, 1H), 2.38 (s, 3H), 1.38 (d, J = 6.9
Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 144.0, 143.3,
137.4, 134.2, 129.7, 129.4, 127.4, 127.0, 126.4, 124.4, 53.2,
23.4, 21.4. IR (neat / cm-1): 2978, 2927, 1598, 1576, 1435,
1327, 1161, 1092, 965, 814, 665. HRMS (ESI+): calcd for
C15H16ClNO2SNa [M + Na]+ : 332.0488; found 332.0495.
7
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N-Benzhydryl-4-methylbenzenesulfonamide
(7k).40
Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf =
0.30; Yield 84% (70.9 mg, 0.21 mmol). 1H NMR (500 MHz,
THF) δ 7.54 (d, J = 7.8 Hz, 2H), 7.45 (s, 1H), 7.17 – 7.08 (m,
11H), 5.59 (s, 1H), 2.59 – 2.24 (m, 1H), 2.32 (s, 3H). 13C{1H}
NMR (126 MHz, THF) δ 143.1, 142.9, 140.8, 130.0, 129.1,
128.7, 128.0, 127.9, 62.1, 21.5. IR (neat / cm-1): 3058, 2986,
2922, 1599, 1493, 1450, 1162, 936, 810. HRMS (ESI+): calcd
for C20H19NO2SNa [M + Na]+ : 360.1034; found 360.1022.
N-(4-Methoxybenzyl)-N'-(4-methoxybenzylidene)-4-
methylbenzenesulfonohydrazide (7l). Analytical TLC on silica
gel, 4:1 hexane/ethylacetate Rf = 0.30; Yield 84% (89.1 mg,
0.21 mmol). 1H NMR (400 MHz, CHLOROFORM-D) δ 7.80
(d, J = 8.3 Hz, 2H), 7.71 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.31
(d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 6.83 (dd, J = 8.9,
2.2 Hz, 4H), 4.63 (s, 2H), 3.77 (d, J = 12.3 Hz, 6H), 2.41 (s,
3H). 13C{1H} NMR (101 MHz, CHLOROFORM-D) δ 161.4,
159.0, 150.7, 143.9, 134.2, 129.5, 129.2, 128.6, 128.3, 127.6,
126.6, 55.3, 55.2, 52.5, 21.6. IR (neat / cm-1): 2927, 2838,
1607, 1510, 1353, 1247, 1166, 1030, 742, 657. HRMS (ESI+):
calcd for C23H24N2O4SNa [M + Na]+ : 447.1354; found
447.1362.
4-Methyl-N-(thiophen-2-ylmethyl)benzenesulfonamide
(7g).37 Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf
1
= 0.35; Yield 79% (52.8 mg, 0.1975 mmol). H NMR (500
MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0 Hz,
2H), 7.20 (d, J = 5.0 Hz, 1H), 6.90 – 6.87 (m, 1H), 6.86 (d, J =
3.1 Hz, 1H), 4.67 (s, 1H), 4.34 (d, J = 6.0 Hz, 2H), 2.44 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 143.7, 138.9, 136.8,
129.8, 127.2, 126.9, 126.5, 125.8, 42.1, 21.5. IR (neat / cm-1):
2918, 2850, 1599, 1421, 1323, 1157, 1090, 1039, 813, 665.
2,4,6-Triisopropyl-N-(4-methoxybenzyl)-N'-(4-
methylbenzylidene)benzenesulfonohydrazide (7m). Analytical
TLC on silica gel, 19:1 hexane/ethylacetate Rf = 0.25; Yield
73% (95.0 mg, 0.1825 mmol). 1H NMR (400 MHz,
CHLOROFORM-D) δ 7.43 (s, 1H), 7.32 (d, J = 8.6 Hz, 2H),
7.27 (d, J = 8.1 Hz, 2H), 7.18 (s, 2H), 7.04 (d, J = 8.0 Hz, 2H),
6.87 (d, J = 8.6 Hz, 2H), 5.13 (s, 2H), 4.26 (dq, J = 13.6, 6.8
Hz, 2H), 3.77 (s, 3H), 2.90 (dq, J = 13.7, 6.9 Hz, 1H), 2.28 (s,
3H), 1.30 – 1.25 (m, 18H). 13C{1H} NMR (101 MHz,
CHLOROFORM-D) δ 158.9, 153.3, 151.7, 141.7, 139.7,
131.7, 129.0, 128.2, 127.0, 126.8, 123.7, 114.3, 55.2, 47.9,
34.2, 29.9, 24.9, 23.6, 21.3. IR (neat / cm-1): 2960, 2931, 2867,
1615, 1599, 1514, 1459, 1247, 1166, 903, 733, 581. HRMS
(ESI+): calcd for C31H40N2O3SNa [M + Na]+ : 543.2657; found
543.2667.
4-Methyl-N-tritylbenzenesulfonamide (7n). Analytical TLC
on silica gel, 9:1 hexane/ethylacetate Rf = 0.30; Yield 71%
(73.4 mg, 0.1775 mmol). 1H NMR (400 MHz,
CHLOROFORM-D) δ 7.33 – 7.28 (m, 6H), 7.19 – 7.13 (m,
9H), 7.05 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 5.76
(brs, 1H), 2.31 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
143.2, 142.1, 139.4, 129.2, 128.80, 127.7, 127.1, 126.5, 72.6,
21.4. IR (neat / cm-1): 2920, 1636, 1597, 1494, 1400, 1316,
HRMS (ESI+): calcd for C12H13NO2S2Na [M + Na]+
290.0285; found 290.0280.
4-Methyl-N-(1-phenylethyl)benzenesulfonamide
:
(7h).38
Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf =
1
0.40; Yield 77% (53.0 mg, 0.1925 mmol). H NMR (400
MHz, CHLOROFORM-D) δ 7.62 (d, J = 8.3 Hz, 2H), 7.20 –
7.15 (m, 5H), 7.12 – 7.09 (m, 2H), 5.16 (s, 1H), 4.46 (p, J =
7.0 Hz, 1H), 2.38 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H). 13C{1H}
NMR (101 MHz, CHLOROFORM-D) δ 143.1, 142.0, 137.6,
129.4, 128.5, 127.4, 127.0, 126.1, 53.6, 23.5, 21.4. IR (neat /
cm-1): 3033, 2978, 2927, 1599, 1497, 1455, 1327, 1162, 1090,
962, 814, 665. HRMS (ESI+): calcd for C15H17NO2SNa [M +
Na]+ : 298.0878; found 298.0865.
4-Methyl-N-(1-phenylpropyl)benzenesulfonamide
(7i).39
Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf =
1
0.40;Yield 76% (55.0 mg, 0.19 mmol). H NMR (400 MHz,
CHLOROFORM-D) δ 7.63 (d, J = 8.2 Hz, 2H), 7.36 (s, 1H),
7.25 (d, J = 2.7 Hz, 2H), 7.20 (s, 2H), 7.11 – 7.08 (m, 2H),
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Page 10 of 13
1160, 1152, 1023, 697. HRMS (ESI+): calcd for
NMR was measured at room temperature. Now, 5.1 mg of
C26H23NO2SNa [M + Na]+ : 436.1347; found 436.1365.
B(C6F5)3 (0.01 mmol) was added to the NMR tube and after
1h at room temperature the reaction mixture was analyzed by
1H NMR again to obtain 10a:4a 80:20.
Recation procedure for equilibrium studies in a mixture
of 4a, 8a and B(C6F5)3.
In a J-Young NMR tube, ether 8a (2.6 mg, 0.01 mmol),
aniline 4a (2.7 mg, 0.016 mmol) and B(C6F5)3 (5.1 mg, 0.01
mmol) were dissolved in 0.6 mL of benzene-d6 under argon.
After 1h at room temperature the reaction mixture was
analyzed by 1H NMR again to obtain 10a:9a 92:8.
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4
5
6
7
8
N-(3,3-Diphenylallyl)-4-methylbenzenesulfonamide
(7o).
Analytical TLC on silica gel, 9:1 hexane/ethylacetate Rf =
0.20; Yield 67% (60.9 mg, 0.1675 mmol). 1H NMR (500
MHz, CDCl3) δ 7.68 (d, J = 8.1 Hz, 2H), 7.34 – 7.22 (m, 8H),
7.12 – 6.99 (m, 4H), 5.91 (t, J = 7.0 Hz, 1H), 4.46 – 4.45 (m,
1H), 3.66 (t, J = 6.5 Hz, 2H), 2.41 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 145.5, 143.4, 141.2, 138.4, 137.1, 129.7,
129.5, 128.4, 128.2, 127.8, 127.7, 127.4, 127.2, 123.2, 42.4,
21.5. IR (neat / cm-1): 2921, 1598, 1443, 1321, 1158, 1092,
758, 701. HRMS (ESI+): calcd for C22H21NO2SNa [M + Na]+ :
386.1191; found 386.1185.
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Experimental procedure for Hammett analysis by
varying alcohol with aniline.
Reaction procedure for B(C6F5)3-catalyzed formation of
dibenzyl ether 8a from alcohol 1a.
In five different 15 mL Schlenk tubes, p-anisidine (30.8 mg,
0.25 mmol, 1.0 equiv), B(C6F5)3 catalyst (2.5 mg, 0.005 mmol,
2 mol %) were added with 30 mg of 4Å molecular sieve. Next,
0.5 mL toluene solution of alcohol p-methoxybenzyl alcohol,
p-methybenzyl alcohol, benzyl alcohol, p-chlorobenzyl
alcohol and m-fluorobenzyl alcohol (0.375 mmol, 1.5 equiv)
was slowly added in the five different Schlenk tubes
respectively. Now, the Schlenk tubes containing the reaction
mixture were heated at 120 °C (oil bath temperature) for 10 h
under argon. The solvent was removed under reduced pressure
and the corresponding NMR yield of N-alkylated product from
Schlenk tube 1-5 was found as 60%, 30%, 10%, 2% and 1%,
respectively (average of three independent runs). The ratio of
the reaction rate was determined from the ratio of the yields of
corresponding product to draw Hammett plot.
In a 15 mL Schlenk tube alcohol 1a (51.8 mg, 0.375 mmol)
and B(C6F5)3 catalyst (3.8 mg, 0.0075 mmol, 2 mol %) were
dissolved in 0.5 mL of toluene. Then the solution was stirred
at room temperature under argon atmosphere for 2 h. The
solvent was removed under reduced pressure and the crude
residue was purified by flash column chromatography to
obtain 8a as a colorless liquid in 82% yield (39.7 mg, 0.1538
mmol).
4,4'-(Oxybis(methylene))bis(methoxybenzene) (8a).41 1H
NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.5 Hz, 2H), 6.91 (d, J
= 8.6 Hz, 2H), 4.48 (s, 2H), 3.82 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 159.2, 130.5, 129.4, 113.8, 71.4, 55.3. GCMS.
calcd for C20H19N: (m/z) = 258.13; found 258.13.
Procedure for B(C6F5)3-catalyzed reaction of dibenzyl
ether 8a with aniline 4a.
Experimental procedure for Hammett analysis by
varying aniline with an alcohol.
In a 15 mL Schlenk tube 10 mg of powdered 4Å molecular
sieve was taken. Next, ether 8a (37.7 mg, 0.15 mmol), aniline
4a (16.1 mg, 0.15 mmol and B(C6F5)3 catalyst (1.5 mg, 0.003
mmol, 2 mol %) in 0.25 mL of toluene was added. Then the
solution was stirred at 120 °C (oil bath temperature) under
argon atmosphere for 8 h. The solvent was removed under
reduced pressure and the crude residue was purified by flash
column chromatography to obtain 5a as a colorless liquid in
35% yield (11.9 mg, 0.0525 mmol).
In five different 15 mL Schlenk tubes, p-anisidine, p-
toluidine, aniline, p-chloroaniline and m-bromoaniline (0.25
mmol, 1.0 equiv) was dissolved in 0.5 mL toluene. Now,
B(C6F5)3 catalyst (2.5 mg, 0.005 mmol, 2 mol %), p-
methoxybenzyl alcohol (51.8 mg, 0.375 mmol, 1.5 equiv) and
30 mg of 4Å molecular sieve were added in each of the five
different Schlenk tubes. Now, the Schlenk tubes containing
the reaction mixture were heated at 120 °C (oil bath
temperature) for 10 h under argon. The solvent was removed
under reduced pressure and the yield of the corresponding N-
alkylated product was found as 60%, 58%, 55%, 53% and
52%, respectively (average of three independent runs). The
ratio of the reaction rate was determined from the ratio of the
yields of corresponding product to draw Hammett plot.
Recation procedure for equilibrium studies in between
8a and 9a (B(C6F5)3 adduct of 8a).
In a J-Young NMR tube, ether 8a (2.6 mg, 0.01 mmol) was
1
dissolved in 0.6 mL of benzene-d6 under argon and H NMR
was measured at room temperature. Now, 5.1 mg of B(C6F5)3
(0.01 mmol) was added to the NMR tube and after 1h at room
temperature the reaction mixture was analyzed by 1H NMR
again to obtain 9a:8a > 95:5.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Now the solvent was evaporated by taking the reaction
mixture from the NMR tube to a round bottom flask under
argon. The crude residue was washed with cold hexane (1 mL)
to get 9a.
NMR spectra (PDF)
1
9a. H NMR (500 MHz, C6D6) δ 7.18 (d, J = 8.6 Hz, 4H),
AUTHOR INFORMATION
Corresponding Author
* Email: bm@iiserkol.ac.in
Homepage: http://biplabmaji.wixsite.com/iiserkol
6.78 (d, J = 8.6 Hz, 4H), 4.30 (d, J = 8.4 Hz, 4H), 3.30 (s, 6H).
13C{1H} NMR (126 MHz, C6D6) δ 160.3, 148.4 (d, J = 241.3
Hz), 140.7 (d, J = 251.7 Hz), 137.6 (d, J = 246.7 Hz), 130.2,
130.1, 114.4, 71.7, 54.9. 19F NMR (471 MHz, C6D6) δ -134.42
(dd, J = 23.2, 7.3 Hz), -155.65 (t, J = 20.7 Hz), -163.05 (td, J
= 23.7, 8.7 Hz). 11B{1H} NMR42 (161 MHz, C6D6) δ 1.5.
Author Contributions
HRMS (ESI+): calculated for C34H19BF15O3 [M + H]+
771.1188; found: 771.1207.
:
The manuscript was written through the contributions of all
authors. All authors have approved the final version of the
manuscript.
Procedure for equilibrium studies in between 4a and 10a
(B(C6F5)3 adduct of 4a).
Notes
In a J-Young NMR tube, aniline 4a (1.1 mg, 0.01 mmol)
The authors declare no competing financial interest.
1
was dissolved in 0.6 mL of benzene-d6 under argon and H
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The Journal of Organic Chemistry
Receptor 2 Inverse Agonists and Osteoclast Inhibitors: Discovery,
Optimization, and Biological Evaluation. J. Med. Chem. 2013, 56,
2045-2058.
(9) Malwal, S. R.; Sriram, D.; Yogeeswari, P.; Konkimalla, V. B.;
Chakrapani, H. Design, Synthesis, and Evaluation of Thiol-Activated
Sources of Sulfur Dioxide (SO2) as Antimycobacterial Agents. J.
Med. Chem. 2012, 55, 553-557.
ACKNOWLEDGMENT
We thank IISER Kolkata for financial support. M.M.G. thanks
SERB (PDF/2017/000028) for the NPDF fellowship and P.R.T.
thanks UGC for a research fellowship.
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