Selective catalytic Hofmann: N -alkylation of poor nucleophilic amines and amides with catalytic amounts of alkyl halides

Article abstract of DOI:10.1039/c6gc00938g

Using only catalytic amounts of alkyl halides in the reactions of poor nucleophilic amines/amides and alcohols led to a selective Hofmann N-alkylation reaction catalytic in alkyl halides, providing a practical and efficient method for the practical synthesis of mono- or di-alkylated amines/amides in high selectivities. This new method avoids the use of large amounts of bases, alkyl halides, and solvents, and generates water as the only byproduct. Preliminary mechanistic studies showed that alkyl halides are key intermediates/catalysts regeneratable in the reaction cycle.

Full text of DOI:10.1039/c6gc00938g

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DOI: 10.1039/C6GC00938G
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Selective Catalytic Hoffmann N‐Alkylation of Poor Nucleophilic
Amines and Amides with Catalytic Amounts of Alkyl Halides
Qing Xu,* Huamei Xie, Er‐Lei Zhang, Xiantao Ma, Jianhui Chen, Xiao‐Chun Yu and Huan Li
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Scheme 1. (a) Traditional Hoffmann N‐Alkylation Reaction and
(b) Catalytic Hoffmann N‐Alkylation Reaction.
Using only catalytic amounts of alkyl halides in the reactions of
poor nucleophilic amines/amides and alcohols led to a selective
Hoffmann N‐alkylation reaction catalytic in alkyl halides, providing
a practical and efficient method for practical synthesis of mono‐ or
di‐alkylated amines/amides in high selectivities. This new method
avoids the use of large amounts of bases, alkyl halides, and
solvents, and generates water as the only byproduct. Preliminary
mechanistic studies showed that alkyl halides are key
intermediates/catalysts regeneratable in the reaction cycle.
(a) Traditional Method (Multi-Step from
ROH)
(b) This Work: One-Step from ROH
and Waste-Free Catalytic Reaction
RR1NH or RR1R2N
yields & sel. up to 99%
R
+
NH2 R2NH
+
R N+X-
R
OH
R OH
R N
+
3
4
HX (?)
base·HX
base
MX
H2SO4
path b
path a
H2O
cat.
NH3
R1NH2
R1R2NH
R
R
R
R
X
X
X
X
RNH2·HX
R2NH·HX
RR1NH·HX
RR1R2N·HX
R
X
RNH2
R2NH
R3NH
Nitrogen‐containing compounds play important roles in all
fields of chemistry, among which amine and amide derivatives
are the most fundamental chemicals as they are usually the
starting materials for the synthesis of other useful
organonitrogen blocks. The reaction of ammonia/amines and
alkyl halides,1 namely the Hoffmann N‐alkylation reaction
discovered by A. W. Hoffmann in 1850,1a is included in all text
books as the basic method for amine derivative synthesis
(Scheme 1a).1c However, this method requires excess amounts
of the active and toxic alkyl halides, produces a mixture of
amines and ammonium salts as the byproducts, and is thus low
in selectivity and atom economy, which also resulted in tedious
product separation and purification problems. The Gabriel
reaction initiated by S. Gabriel in 1887 was later developed as a
more selective method for preparation of primary amines,1c,2
but the requirement of multi steps and large amounts of bases
and the production of large amounts of waste salts make the
method low in atom and reaction efficiency. More recently, Jung
and co‐workers developed a selective preparation of secondary
amines from primary amines using CsOH as the base3 by taking
advantage of the “Cesium Effect”.3,4 However, the method
requires pre‐activated 4Å molecular sieves, anhydrous solvents,
and excess amounts of alkyl halides and pre‐dried CsOH, and is
thus less practical from synthetic point of view.
R
X
R3N·HX
R4N+X-
catalytic in RX, high selectivities,
no base/solvent, sole byproduct H2O,
simple conditions, easy purification
Recently the reaction of amides and imines affording
Mannich‐type adducts, used to be stoichiometric in silicon
enolates, was made catalytic in trialkylsilyl triflate by the
Kobayashi group in 2011;5 while the Mitsunobu reaction was
also made catalytic in phosphine by Aldrich and co‐workers in
2015.6 To our knowledge, Hoffmann N‐alkylation reactions
catalytic in alkyl halides have not been described yet. Herein we
report an advance of the research by describing a selective
catalytic Hoffmann N‐alkylation reaction (Scheme 1b), in which,
by using only catalytic amounts of alkyl halides, the reactions of
primary and secondary amines/amides with primary and
secondary alcohols can produce mono‐ or di‐alkylated
amines/amides in high selectivities under transition metal‐,
base‐ and solvent‐free conditions, generating meanwhile water
as the only byproduct.
In the literature, dehydrative N‐alkylation reactions of
amines/amides with alcohols can be achieved mainly by the
transition metal‐catalyzed borrowing hydrogen and hydrogen
autotransfer methodology7 or Lewis/Brönsted acids‐ or
transition metal‐mediated/catalyzed direct nucleophilic
substitution reactions.8 The former method usually requires
noble metal catalysts to fulfill the anaerobic dehydrogenative
activation of the alcohols,7 whereas the latter one is mainly
limited to more active alcohols such as secondary arylmethanols,
allylic and propargylic alcohols.8 In the past few years, our group
also focused on dehydrative N‐ and C‐alkylation reactions9,10
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
Zhejiang 325035, P. R. China. E‐mail: qing‐xu@wzu.edu.cn; Fax: (+)‐86‐577‐
86689302; Tel: (+)‐86‐138‐57745327
Electronic Supplementary Information (ESI) available: Experimental details,
product characterization, details of the control experiments, and copies of 1H NMR,
13C NMR and HRMS spectra of the products. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
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using the greener alcohols as the alkylating reagents,7,8 giving 3a in a lower yield (run 8). Moreover, no VrieewacAtrtiioclne Ownlianes
DOI: 10.1039/C6GC00938G
especially that externally‐added aldehydes or ketones could be observed without the catalyst (run 9), revealing the significant
regenerated to work as the catalysts.10 Since alkyl halides can role of alkyl halides in the reaction.
also be produced from alcohols by halogenation,1c we
hypothesized that if alkyl halides can be regenerated in situ
from alcohols and then recycled to react with amines, a catalytic
Table 2. Catalytic N‐Alkylation of Primary and Secondary Amines
and Amides with Primary Alcohols.a
R1CH2Br (7.5 mol%)
under air, 160 oC, 24 h
- H2O
Hoffmann N‐alkylation reaction could possibly be achieved by
using only catalytic amounts of alkyl halides (Scheme 1b).
Although we have successfully developed an alkyl halides‐
catalyzed O‐alkylative etherification reaction of alcohols for
symmetrical and unsymmetrical dialkyl ether synthesis10e and
tried many times on the corresponding alkyl halide‐catalyzed N‐
alkylation reactions, these initial attempts failed. We thus
reckoned the reason that such a transformation have not be
realized so far since Hoffmann’s report1a is most probably
because the amine substrates and the alkylated amine products,
with the latter being more basic and more nucleophilic, may
readily transform the alkyl halides into corresponding
ammonium salts, and hence terminate the reaction (Scheme 1a).
R2
N
R1
R1
OH
R2-NH2
2
(1)b
+
H
1
3
H
N
H
N
H
Ph
Ph
Me
N
Ph
Ph
N
Ph
H
Me
Me
3a, 82% (95/5)
3c, 51% (97/3)
3d, 40% (>99/1)
3b, 64% (99/1)
H
H
N
H
H
N
Ph
Ph
N
Ph
MeO
N
Ph
OMe
3e, 62% (99/1)
NO2
3g, 86% (>99/1)
Cl
3f, 48% (91/9)
3h, 76% (>99/1)
H
H
H
N
N
Cl
N
Ph
Cl
Ph
Ph
N
H
n-C7H15
F
3l, 18%, 30%c
3k, 73% (95/5)
3j, 75% (91/9)
3i, 83% (92/8)
H
H
N
Ph
N
Ph
Ph
N
H
Ph
n-C7H15
N
Ph
H
Table 1. Condition Screening for Catalytic N‐Benzylation of
Aniline.
N
+
N
3p, --
3n, --
3o, --
3m, trace
R2
R2
R1CH2Br (10 mol%)
under air, 160 oC, 24 h
- H2O
R1
OH
N
(2)d
Ph
N
H
cat. PhCH2X
Ph
Ph
R3
R1
R3
1
+
Ph
OH
PhNH2
2a
Ph
N
Ph
Ph
N
4a
conditions, 24 h
- H2O
5
H
1a
3a
atm., T (oC)
N2, 120
N2, 150
N2, 150
N2, 150
N2, 150
N2, 160
air, 160
air, 160
air, 160
3a%;a 3a/4ab
trace
N
run
1c
2
1a/2a (mmol)
X (mol%)
Br (5)
N
N
N
N
Ph
5e, trace
Ph
Ph
5c, 50%e
5a, 76%
5d, trace Ph
Ph
5b, 61%
1.5/1
3/2
3/2
2/4
2/3
2/3
2/3
2/3
2/3
Ph
O
Br (5)
76; 91/9
90; 72/28
94; 92/8
50; 98/2
94; 95/5
94 (82); 95/5
(63)
O
cat. PhCH2Br
(3)f
+
Ph
OH
1a
Ph
N
Ph
atm., T, 24 h
Ph
NH2
3
Br (10)
Br (10)
Br (7.5)
Br (7.5)
Br (7.5)
Cl (7.5)
‐‐
H
- H2O
6a
run cat. (mol%) atm., T (oC) 6a%
run cat. (mol%) atm., T (oC) 6a%
4
(1) 10~20
(2) 40
air, 150
air, 150
trace~13 (3) 40
air, 170
N2, 170
63
62
5
37
(4) 40
O
O
O
O
6
N
H
Ph
MeO
N
Ph
N
Ph
Ph
N
H
Ph
Me
7
H
H
Me
6c, 52%
O
6b, 60%
6a, 63%
8
6d, 53%
O
O
O
9
‐‐
N
Ph
Ph
Ph
N
Ph
Ph
N
H
H
H
a
S
HN
6h, 62%
O
GC yields (isolated yields in parenthesis) of 3a based on limiting
O2N
F
Me
6g, 61%
substrate. b Selectivities determined by GC‐MS analysis. c In normal
6e, 61%
6f, 45%
O
O
O
solvents such as dioxane, toluene, DMF, DMSO, etc.
S
N
Ph
N
H
Ph
Me
N
Ph
Ph
N
H
n-C6H13
O
H
We then turned our attention to poor nucleophilic
amines/amides such as the anilines and amides. As shown in
Table 1, solvent effect was initially evaluated in the reaction of
benzyl alcohol (1a) and aniline (2a) with 5 mol% PhCH2Br at 120
oC under N2. Only trace product could be detected (run 1). In
great contrast, when a similar reaction was performed without
any solvent, a good yield of the product with a high selectivity of
the mono‐alkylated 3a (91%) could be obtained at 150 oC (run 2).
Further condition screening showed that higher catalyst loading
(10 mol%) led to lower selectivity (run 3) and higher 2a/1a ratio
to higher 3a selectivity (run 4). Thus, the highest selectivity of
98% was obtained by using 7.5 mol% PhCH2Br with a 2a/1a ratio
of 3/2 (run 5), with the product yield further improved to 94%
Ph
6k, --
Cl
6j, tracec
6l, 50%g
6i, 45%
a Isolated yields based on limiting substrates. 1 (2 mmol), 2 (3
b
mmol). Selectivities shown in parenthesis determined by GC‐MS
c
d
analysis. RI used as the catalyst. 1 (1.5 mmol), secondary amine
e
f
(1 mmol). 20 mol% catalyst. 1 (2.4 mmol), amide (2 mmol). g 40
mol% TBAI added.
Above optimized conditions were then applied to other
amines, amides, and alcohols to extend the scope of the
catalytic N‐alkylation method. With substituted anilines (Table 2,
eq. 1), both electron‐rich and ‐deficient ones, including those
with sterically more bulky ortho‐substituents, afforded the
target mono‐alkylated anilines in high selectivities, with the
yields of the electron‐deficient ones (3g‐k) generally higher than
those of the electron‐rich ones (3b‐f). In contrast, aliphatic
alcohols were less reactive, giving only low yields of the product
even using corresponding alkyl iodide as the catalyst (3l). Pyridyl
and aliphatic amines were not reactive under present conditions.
o
by running the reaction at 160 C (run 6). We also tested the
same reaction in air. It also afforded 3a with the same high yield
and high selectivity (run 7), showing that inert atmosphere
protection is not necessary and operation of the reactions could
be greatly simplified. In comparison, PhCH2Cl is much less active,
2 | J. Name., 2012, 00, 1‐3
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No reaction occurred or only trace products were detected (3m‐ Table 4. Catalytic N‐Alkylation of Amines and Amides with
View Article Online
DOI: 10.1039/C6GC00938G
p).
Secondary and Tertiary Alcohols.a
This method could also be applied to base‐free N‐alkylation of
Ph
Ph
N
Ph
secondary amines (Table 2, eq. 2). Thus, the reactions of
carbazole and indoline with 1a afforded good yields of the
products with 10 mol% catalyst (5a‐b). The reaction of
tetrahydroquinoline was less efficient, but could give a
moderate yield of the product with more catalyst (5c). Other
secondary amines such as tetrahydroisoquinoline and
diphenylamine were not reactive at present (5d‐e).
Ph
cat. Ph2CHBr
atm., 120 oC, 24 h
- H2O
Ph
(4)
Ph
OH + PhNH2
Ph
Ph NH
7a
2a
9a
8a
run 7a/2a cat. (mol%) atm. 8a% 8a/9ab run 7a/2a cat. (mol%) atm. 8a% 8a/9ab
(1) 2/2
(2) 2/3
5
5
air (81) 74/36 (3) 2/3
N2 (76) >99/1 (4) 2/3
10
--
N2 85 (94) >99/1
N2 --
H
H
H
N
H
N
Ph
N
Ph
Me
Ph
N
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
8d, 96% (150 oC)
Inspired by above successful results, the more demanding N‐
alkylation of amides was then investigated (Table 2, eq. 3).
Initially, only low yields of 6a were obtained from the reaction
of 1a and benzamide (eq. 3, run 1). Different to anilines, no di‐
alkylation byproduct was detected in this reaction, possibly due
to the much lower nucleophilicity of the benzamide. By
increasing the catalyst loading and enhancing the reaction
temperature (runs 2‐3), a much higher yield of 6a could be
8c, 93%
8a, 85%
8b, 86%
H
Cl
H
N
H
H
N
Ph
MeO
N
Ph
N
Ph
Ph
Ph
Ph
Ph
EtO
OMe
8e, 78%
8g, 82% (150 oC)
8f, 83%
8h, 52% (150 oC)
H
N
H
H
H
Ph
N
Ph
N
Me
Cl
N
Ph
Cl
Ph
Ph
Ph
Ph
O2N
8j, 90%
8l, 89% (150 oC)
8k, 47% (150 oC)
8i, 68%
H
Ph
H
N
o
N
Me
obtained with 40 mol% PhCH2Br at 170 C (run 3). The same
N
H
Ph
result could also be obtained under N2 (run 4), revealing again
that inert atmosphere protection is not necessary. The reactions
of electron‐rich and ‐deficient amides and alcohols, including
those more bulky ones and a heteroaromatic one, proceeded
smoothly to afford the target alkylated amides in moderate
yields (6b‐i). An aliphatic alcohol and a secondary amide were
also tested, but they were not reactive (6j‐k). The sulfonamide is
even less reactive under the same conditions, giving only trace
amount of 6l, with a 50% yield obtained when 40 mol% TBAI
was added.
n-C5H11
8m, trace
N
8p, --
8n, tracec
8o, --
Ph
Ph
Ph
O
Ph
O
cat. Ph2CHBr
+
(5)
Ph
N
Ph
under air, T, 24 h
NH2
Ph
OH Ph
H
- H2O
7a
run cat. (mol%) T (oC)
10a
10a%
run cat. (mol%) T (oC)
10a%
(1) 10~20
(2) 10
90~170
95~97
(3) 10
(4) --
80
90
61
--
90
97
O
Ph
Me
O
Ph
O
Ph
O
Ph
Me
N
Ph
10c, 77%
99% (130 oC)
Ph
N
Ph
Ph
N
Ph
N
Ph
H
H
H
H
10b, 71%
97% (130 oC)
10d, 67%
94% (130 oC)
Cl Ph
Table 3. Catalytic N,N‐Dibenzylation of Anilines.a
Me
10a, 97%
O
Ph
O
O
OEt
O
Ph
Ph
cat. PhCH2Br
under air, 150 oC, 24 h
- H2O
Ph
N
H
3a
Ph
Ph
OH + PhNH2
Ph
N
N
Ph
N
Ph
N
Ph
10h, 73%
91% (120 oC)
Ph
N
Ph
F
H
1a
2a
Ph
H
H
H
4a
MeO
10e, 69%
90% (130 oC)
Ph
10f, 72%
10g, 93%
run 1a/2a cat. (mol%) 4a% 4a/3a
run 1a/2a cat. (mol%) 4a%
4a/3a
96% (130 oC)
Ph
(1) 3/1
(2) 3/1
(3) 4/1
5
10
5
(88)
(95)
(>99) 87/13
23/77 (4) 4/1
77/23 (5) 4/1
10
15
(>99) 94/6
86 (>99) 98/2
O
O
O
O
Ph
N
Ph
S
HN
10k, 78%
96% (110 oC)
Me
Ph
N
Ph
n-C3H7
N
Ph
H
H
H
Ph
Ph
N
Ph
10l, 63% (170 oC)e
H
O2N
Ph
Ph
10i, 61% (130 oC)
91% (150 oC)d
10j, 81% (170 oC)d
N
Ph
N
Ph
Ph
N
N
Ph
O
Me
O
NO2
O
O
Me
Cl
N
Ph
Cl
N
3g, 83% (sel. 99/1)
H
4a, 86% (sel. 98/2)
4c, (sel. 81/18)
4b, 89% (sel. 99/1)
H
Ph
N
Ph
N
Ph
H
MeO
10n, 62% (150 oC)d
H
F
10p, 16% (170 oC)e
10o, 61% (150 oC)d
10m, 57% (130 oC)
a
Isolated yields (GC yields in parenthesis) of 4 based on 2.
Selectivities determined by GC‐MS analysis.
O
S
Ph
O
S
Ph
O
S
Ph
O
S
Ph
N
Ph
N
Ph
N
Ph
Cl
O
O
O
Cl
H
H
H
Ph
N
Ph
Since more aniline and controlled catalyst loadings led to
selective mono‐alkylation (Table 1), reverse conditions
promisingly providing a selective N,N‐di‐alkylation reaction were
then tested (Table 3). With 5 mol% catalyst and 3 equiv. 1a, the
reaction still gave mainly mono‐alkylated 3a (run 1). More
catalyst and 1a gave di‐alkylated 4a in much higher selectivities
(runs 2‐4). The highest 98% selectivity and a high isolated yield
of 4a were then obtained by using 4 equiv. 1a and 15 mol%
catalyst (run 5). Electron‐deficient anilines reacted efficiently to
give di‐alkylated products in a high selectivity (4b). An ortho‐
substituted one gave the product in a lower selectivity due to
steric effect of the ortho‐group (4c). mono‐Alkylated 3g was still
the major product in the reaction of o‐nitroaniline, most
possibly due to the weak nucleophilicity of the amino moiety
attributed to the ortho‐nitro group.
S
O
H
11d, 99% (130 oC)
Cl
11a, 98% (130 oC)
11c, 96% (130 oC)
11b, 97% (130 oC)
O
Ph
O
S
Me
Ph
O
S
Ph
O
S
Ph
S
N
Ph
N
N
Ph
Me
N
Ph
Me
O
O
H
O
O
H
H
H
MeO
Me
11f, 99% (130 oC) 11g, 99% (130 oC)
11h, 16% (150 oC)d
11e, 98% (130 oC)
O
Me
O
S
S
N
n-C5H11
Ph
N
O
H
O
H
11j, --c
Me
11i, trace (150 oC)d
a
Isolated yields (GC yields in parenthesis) based on limiting
substrates. b Selectivities determined by GC‐MS analysis. c RI used as
the catalyst. d 20 mol% catalyst. e 40 mol% catalyst.
Above catalytic N‐alkylation method could also be applied to
secondary alcohols. Initially, the reaction of 2a and benzohydrol
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(7a) under air gave a mixture of the target product 8a and an suggested that, even if free HBr may be generated in the
View Article Online
DOI: 10.1039/C6GC00938G
imine byproduct 9a (eq. 4, run 1), which is most possibly formed reaction (Scheme 1, path b), it is most possibly trapped
by aerobic oxidation of 7a to the corresponding ketone and instantly by the amines to form the corresponding ammonium
subsequent condensation reaction with the aniline. No di‐ salts, which can then react with alcohols to give alkyl halides
alkylation product was detected most possibly due to the steric and catalyze the reaction to give alkylated products (eq. 7). On
effects of the secondary alcohol. Then, by performing the the other hand, since path b with liberation and loss of HBr can
reaction under N2 and increasing the catalyst loading (runs 2‐3), inevitably result in reduced reaction efficiency, although the
a high yield of the product was obtained in the highest possibility to undergo path b cannot be excluded completely at
selectivity of >99%. No reaction was observed either without present, the reactions are more likely to proceed via path a
the catalyst (run 4). This method was then extended to other (Scheme 1b) based on the experimental findings discussed
anilines and alcohols. The reactions of electron‐rich and – above.
deficient anilines and 1‐phenylehtanol gave good to high yields
of the products with some at higher temperatures (8b‐l).
cat. (7.5 mol%)
under air, 160 oC, 24 h
+
Ph
OH
PhNH2
2a
Ph
N
H
3a
Ph
(6)
Although we tried many times, the reactions of aliphatic
secondary and tertiary alcohols, aliphatic and secondary amines
were not successful under similar conditions (8m‐p).
1a
run cat.
3a%
(1) PhNH2·HBr
(2) PhNH2·HCl
(3) HBr (33 wt% in HOAc) 48
39
22
The reaction of amides with secondary alcohols was then
tested, which was found to be more efficient than the reactions
with primary alcohols (Table 2, eq. 3), giving almost quantitative
yields of the product at above 90oC (Table 4, eq. 5, runs 1‐2).
The reaction was less efficient below 90oC (run 3) and no
reaction occurred at all without the catalyst (run 4). Electron‐
rich and –deficient and heteroaryl amides also gave quantitative
yields of the products with some requiring higher temperatures
and more catalysts (10b‐k). This method was also applicable to
aliphatic amides and other secondary alcohols, giving moderate
yields of the products (10l‐o). Tertiary alcohol like t‐BuOH also
reacted with benzamide, albeit the yield was not high at present
(10p). Different to the preceding unsuccessful reactions with
primary alcohols, the reactions of sulfonamides with
benzohydrol were very efficient, giving almost quantitative
yields of the products at 130 oC (11a‐g). In contrast, no reaction
occurred at all without the catalyst. Moreover, the reactions
with other secondary and tertiary alcohols were not efficient.
Only a low yield of the product could be obtained or trace
products detected at present (11h‐j).
Ph
+
Ph
under air
100 oC, 24 h
- H2O
PhNH2·HBr
Ph
+
Ph
OH
1a
N
H
3a
Ph Ph
+
N
(7)
Ph
Br
9%GC
4a
combined 3a+4a yield:GC 64%; 3a/4a:GC 59/41
Conclusions
In summary, by using only catalytic amounts of alkyl halides, a
selective catalytic Hoffmann N‐alkylation reaction of amines and
amides with alcohols avoiding the use of transition metal
catalysts, solvents, and large amounts of bases and alkyl halides
can be achieved for efficient and green synthesis of mono‐ or di‐
alkylated amine/amide derivatives in high selectivities,
generating no other wastes than the water as the only
byproduct. Although the method is mainly suitable for poor
nucleophilic amines/amides and more active benzylic alcohols at
present, the current results revealed high potential of the
method in synthesis for it provided new synthetic possibilities,
and, there is still much space for improvement of the method by
developing more active catalysts. Although the mechanism of
the reaction is still remained to be elucidated in more depth in
each cases, preliminary results clearly suggested that alkyl
halides are key intermediates/catalysts that can be regenerated
and recovered in the reaction cycle. Extension of the method
such as developing new catalysts, to a wider scope of substrates,
and deeper mechanistic understanding of the reactions are
underway.
Control reactions were then investigated to help
understanding the above successful catalytic Hoffmann N‐
alkylation reactions. As shown in eq. 6, hydrobromide10 even
hydrochloride salt of aniline (PhNH2·HX) was found capable of
catalyzing the reaction to give considerable yields of 3a (runs 1‐
2), revealing that these salts are active intermediates in the
reactions (Scheme 1b). The reaction with catalytic amounts of
HBr was also tested,10 giving 48% 3a (run 3). This yield, much
lower than that of the standard reaction (Table 1), clearly
showed that alkyl halides are far more effective than the
corresponding haloid acids in the N‐alkylation reactions.
Moreover, a considerable amount of benzyl bromide (9%) was
also detected in the reaction of PhNH2·HBr and benzyl alcohol
(eq. 7), implying that alkyl halides can be readily regenerated
from the interaction of alcohols and ammonium salts (Scheme
1b, path a). Regeneration and recovery of the alkyl halides
ultimately led to the catalytic N‐alkylation process (Scheme 1b,
path a). In addition, precipitate of PhNH2·HBr salt was found
instantly formed at the addition of HBr to aniline,10 suggesting
that the reaction with catalytic amounts of HBr (eq. 6, run 3)
most likely proceeded with formation of PhNH2·HBr and via a
PhNH2·HBr‐initiated process (eq. 6, run 1). This results also
Acknowledgment
We thank ZJNSF for Distinguished Young Scholars
(LR14B020002), NNSFC (21502143), and Zhejiang Xinmiao
Talents Program (2015R426062) for financial support.
Notes and references
1
(a) A. W. Hoffmann, Philos. Trans., 1850, CXL, 93; (b) R. N.
Salvatore, C. H. Yoon and K. W. Jung, Tetrahedron, 2001, 57
7785; (c) J. McMurry, Organic Chemistry, Thomson,
Brooks/Cole, 7th ed., 2008.
(a) S. Gabriel, Ber. Dtsch. Chem. Ges., 1887, 20, 2224; (b) U.
Ragnarsson and L. Grehn, Acc. Chem. Res., 1991, 24, 285.
,
2
4 | J. Name., 2012, 00, 1‐3
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Page 5 of 6
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COMMUNICATION
3
(a) R. N. Salvatore, A. S. Nagle, S. E. Schmidt and K. W. Jung,
Org. Lett., 1999, , 1893; (b) R. N. Salvatore, A. S. Nagle and K.
W. Jung, J. Org. Chem., 2002, 67, 674.
View Article Online
DOI: 10.1039/C6GC00938G
1
4
5
6
7
G. Dijkstra, W. H. Kruizinga and R. M. Kellogg, J. Org. Chem.,
1987, 52, 4230.
S. Kobayashi, H. Kiyohara and M. Yamaguchi, J. Am. Chem.
Soc., 2011, 133, 708.
J. A. Buonomo and C. C. Aldrich, Angew. Chem. Int. Ed., 2015,
54, 13041.
(a) A. J. A. Watson and J. M. J. Williams, Science, 2010, 329
635; (b) T. D. Nixon, M. K. Whittlesey and J. M. J. Williams,
Dalton Trans., 2009, 753; (c) G. E. Dobereiner and R. H.
Crabtree, Chem. Rev., 2010, 110, 681; (d) G. Guillena, D. J.
Ramón and M. Yus, Chem. Rev., 2010, 110, 1611; (e) K.‐I.
Fujita and R. Yamaguchi, Synlett, 2005, 560; (f) T. Suzuki,
,
Chem. Rev., 2011, 111, 1825; (g) S. Bähn, S. Imm, L. Neubert,
M. Zhang, H. Neumann and M. Beller, ChemCatChem, 2011,
3
, 1853; (h) Q. Yang, Q. Wang and Z. Yu, Chem. Soc. Rev.,
2015, 44, 2305.
8
9
(a) J. Muzart, Tetrahedron, 2005, 61, 4179; (b) R. J. Detz, H.
Hiemstra and J. H. van Maarseveen, Eur. J. Org. Chem., 2009,
6263; (c) E. Emer, R. Sinisi, M. G. Capdevila, D. Petruzziello, F.
De Vincentiis and P. G. Cozzi, Eur. J. Org. Chem., 2011, 647;
(d) M. Bandini, G. Cera and M. Chiarucci, Synthesis, 2012, 44
504;((e) L. Chen, X.‐P. Yin, C.‐H. Wang and J. Zhou, Org.
Biomol. Chem., 2014, 12, 6033.
(a) Q. Xu, Q. Li, Chin. J. Org. Chem., 2013, 33, 18; (b) S. L.
Feng, C. Z. Liu, Q. Li, X. C. Yu, Q. Xu, Chin. Chem. Lett.,
2011, 22, 1021; (c) C. Liu, S. Liao, Q. Li, S. Feng, Q. Sun, X. Yu
and Q. Xu, J. Org. Chem., 2011, 76, 5759; (d) X. Yu, C. Liu, L.
,
Jiang and Q. Xu, Org. Lett., 2011, 13, 6184; (e) Q. Li, S. Fan, Q.
Sun, H. Tian, X. Yu and Q. Xu, Org. Biomol. Chem., 2012, 10
,
2966; (f) S. Liao, K. Yu, Q. Li, H. Tian, Z. Zhang, X. Yu and Q. Xu,
Org. Biomol. Chem., 2012, 10, 2973;(g) X. Yu, L. Jiang, Q. Li, Y.
Xie, Q. Xu, Chin. J. Chem., 2012, 30, 2322.
10 (a) Q. Xu, J. Chen, H. Tian, X. Yuan, S. Li, C. Zhou and J. Liu,
Angew. Chem. Int. Ed., 2014, 53, 225; (b) Q. Xu, Q. Li, X. Zhu
and J. Chen, Adv. Synth. Catal., 2013, 355, 73; (c) Q. Xu, J.
Chen and Q. Liu, Adv. Synth. Catal., 2013, 355, 697; (d) S. Li,
X. Li, Q. Li, Q. Yuan, X. Shi and Q. Xu, Green Chem., 2015, 17,
3260; (e) Q. Xu, H. Xie, P. Chen, L. Yu, J. Chen and X. Hu,
Green Chem., 2015, 17, 2774; (f) X. Li, S. Li, Q. Li, X. Dong, Y.
Li, X. Yu and Q. Xu, Tetrahedron, 2016, 72, 264.
11 The corresponding solid salt precipitated instantly once HBr
was added to aniline. See ESI for details.
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Table of Contents
Selective Catalytic Hoffmann N-Alkylation of Poor Nucleophilic Amines and Amides with Catalytic Amounts of
Alkyl Halides
Qing Xu,* Huamei Xie, Er-Lei Zhang, Xiantao Ma, Jianhui Chen, Xiao-Chun Yu, and Huan Li
RR1NH or RR1R2N
yields & sel. up to 99%
R OH
Selective Catalytic Hoffmann N-
Alkylation Reaction:
catalytic in RX, high selectivities,
no base/solvent, sole byproduct H2O,
simple conditions (under air) and
operation, easy purification
HX (?)
path b
path a
H2O
cat.
R1NH2
R1R2NH
RR1NH—HX
RR1R2N—HX
R X
R X
A selective Hoffmann N-alkylation reaction of amines/amides catalytic in alkyl halides is achieved, affording mono- or
di-alkylated amines/amides in high selectivities by using alcohols as the alkylating reagents.