Structure-dependent tautomerization induced catalyst-free autocatalyzed N-alkylation of heteroaryl amines with alcohols

Article abstract of DOI:10.1039/c4gc02542c

Catalyst-free autocatalyzed dehydrative N-alkylation reactions of 2-aminobenzothiazoles, 2-aminopyrimidines, and 2-aminopyrazine with primary and secondary alcohols have been achieved for efficient, practical, and green synthesis of the versatile heteroaryl amine derivatives. These reactions were interestingly induced by structure-dependent tautomeric equilibria of the heteroaryl amines via MPV-O transfer hydrogenation of the imino tautomers by alcohols to give aldehydes as the key initiating step.

Full text of DOI:10.1039/c4gc02542c

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DOI: 10.1039/C4GC02542C
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Structure-dependent tautomerization induced
catalyst-free autocatalyzed N-alkylation of heteroaryl
amines with alcohols†
Cite this: DOI: 10.1039/x0xx00000x
Shuangyan Li, Xiaohui Li, Qiang Li, Qiaochao Yuan, Xinkang Shi, and Qing Xu*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Catalyst-free
autocatalyzed
dehydrative N-alkylation methods for selective synthesis of the ketone or alcohol
reactions of 2-aminobenzothiazoles, 2-aminopyrimidines, and products (Scheme 1A-1B).10a
2-aminopyrazine with primary and secondary alcohols have
A. Structrural Dependence and General Process for Alcohol-Based Catalyst-Free
been achieved for efficient, practical, and green synthesis of
the versatile heteroaryl amine derivatives. These reactions
were interestingly induced by structure-dependent
tautomeric equilibriums of the heteroaryl amines via MPV-O
transfer hydrogenation of the imino tautomers by alcohols to
give aldehydes as the key initiating step.
Autocatalyzed Alkylation Reactions (MA: main group metals Li, Na, K, Cs etc.)9
XH
Dehydrative
R1
Alkylation
R
R
Nu R1
H
O
MA
H
R1
OH
MA
O
+
XH
initiation
step
X
R1
OH
+
or
X
R1
R
X
H
H2Nu
- H2O
R
NuH2
R
NuH2
MPV-O processes
Nu R1
H
B. Previous Work:10a X = O, Nu = CH
Developing efficient, practical, and green methods1 for C-N
bond formation is a major topic in synthetic chemistry, because
the organonitrogen compounds like amine and amide
derivatives are key structures in pharmaceuticals, bioactive
molecules, and natural products.2-4 Due to the green features of
readily available alcohols and their advantages as synthetic
catalyst-free
OH
O
O
autocatalyzed
R1
+
OH
or
R2
R1
R2
R1
R2
- H2O
C. Screening Potential Substrates Containing the RC(=X)NuH2 Structural Unit (X = O, N):
Results of Reactions with Alcohols under Catalyst-Free Conditions (NR: no reaction)12
O
S
O
S
O
R
N
R
N
NH2
NR
NH2
R
NH2
R
R
NH2
R
NH2
N
H
O
NR
S
NH2
NR~47%isol.
NR~98%GC (95%isol.
)
NR
R
reagents,
transition
metal
(TM)-catalyzed
anaerobic
N
N
N
N
R
N
dehydrogenative
N
-alkylation reactions of amines and amides
R
NR
NH2
R
N
NH2
N
NH2
NH2
with alcohols, namely the borrowing hydrogen or hydrogen
autotransfer methodology,4,5 have recently become a useful way
to achieve the versatile amine and amide derivatives. To
develop greener and more practical alcohol-based alkylation
methods, we have previously reported air-promoted TM-
catalyzed aerobic N- and C-alkylation reactions6 and related
aerobic imination reactions of alcohols and amines.7 During our
continuous studies and based on an extensive survey of the
literature, we gradually realized that, in addition to the known
anaerobic dehydrogenation strategy,4,5 there should be more
greener, more practical, but still efficient protocols for alcohol
activation.8 Later, we accidentally found that lone aldehyde
could also catalyze the N- and C-alkylation reactions of amides,
amines, and secondary alcohols with primary alcohols.9 More
interestingly, we also observed that substrate ketones could
even act as the catalyst in C-alkylation of methyl ketones with
alcohols, which led to catalyst-free autocatalyzed C-alkylation
72%GC (60%isol.
)
NR~44%GC
)
NR
80%GC (70%isol.
D. This Work: X = N, Nu = N
N
R2
OH
or
R
NH2
R1
OH
(1)
R1
R1
N
X
S
N
R1
R2
2
NH
NH
X
N
N
catalyst-free conditions
autocatalyzed version
N
R
- H2O
X = S, N, CH
N
NH2
NH2
4
3
Scheme 1. Alcohol-based catalyst-free autocatalyzed alkylation
reactions: general process, structural dependence, and substrate
design/discovery.
Further analysis of this catalyst-free autocatalyzed alkylation
reaction suggested that it is most likely a RC(=X)NuH2
structural unit-dependent process (Scheme 1A), which involves
a crucial initial aldehyde generation step accomplished by
transfer hydrogenation of RC(=X)NuH2 by alcohols via the key
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TM-free
Meerwein-Pondorf-Verley-Oppenauer
(MPV-O) attempts to reduce the loading of NaOH and the reaction
process.9-11 Since we have also observed that C=N double temperature gave no better result.13
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DOI: 10.1039/C4GC02542C
bonds of imine intermediates could also be reduced by alcohols Table 1. Condition optimization for catalyst-free autocatalyzed
via MPV-O process,9a we hypothesized that certain amines or exo-selective N-alkylation of 2-aminobenzothiazole.a
S
Ph
S
S
amides bearing the typical RC(=X)NH2 structural unit (X = O
or N, Nu = N) should also meet the requirements for the
catalyst-free reactions and thus can undergo the alkylation
reactions without any external catalysts12 (Scheme 1C).
However, such reactions have not been described in the
literature yet.4-6,9 Herein we report an advance in the field by
describing
catalyst-free autocatalyzed dehydrative N-alkylation reactions
of 2-aminobenzothiazoles ( ), 2-aminopyrimidines ( ), and 2-
aminopyrazine ( ) with primary and secondary alcohols ( ),
which provides an efficient, practical, and green method for
synthesis of the useful heteroaryl amine derivatives without
using any external catalysts such as TM catalysts4-6 or
aldehydes9 (Scheme 1D).
To test the supposed theory of structural dependence,
anilines without RC(=X)NH2 structure were firstly investigated
under catalyst-free conditions (Scheme 1C).13 To avoid
aldehyde contamination in the alcohols and the presence of air
in the reactions that can lead to misguiding results,6,9 redistilled
NaOH
NH
Ph
Ph
OH
+
NH2
NH
N
atm., T, t
N
N
1a
5a'
2a
5a
not detected
b
entry
additive (mol%)
atm., T, t
5a%
1c
2c
3c
4c
5d
6d
7c
8c
9c
-
N2, 120 oC, 6 h
N2, 100 oC, 6 h
N2, 100 oC, 12 h
air, 100 oC, 6 h
N2, 100 oC, 6 h
air, 100 oC, 6 h
N2, 100 oC, 6 h
N2, 100 oC, 6 h
N2, 100 oC, 6 h
98 (95)
82 (78)
96 (84)
98 (92)
97 (90)
99 (93)
(80)
structure-dependent
tautomerization-induced
-
-
2
3
-
4
1
-
-
Ph2C=CH2 (20 mol%)
TEMPO (20 mol%)
in dark
(93)
(73)
a
The mixture of 1a (1.5 mmol, 1.5 equiv.), 2a (1 mmol), and NaOH
(20 mol%)9 sealed in a 10 mL Schlenk tube was heated and monitored
b
by GC-MS and/or TLC.
based on 2a
GC yields (isolated yields in parenthesis)
c
d
.
1a of 100% purity was used. Commercial 1a (>99%
purity) was directly used.
pure alcohols
1 (100% purity) were used and the reactions were
To prove or exclude the reaction’s possibility of undergoing
the radical mechanism in the presence of bases, control
reactions 1a and 2a with radical scavengers or in dark were
examined. As shown in Table 1, the reaction of pure 1a and 2a
with 1,1-diphenylethylene as radical scavenger gave a close
yield of 3a (entry 7) with that of the blank reaction (entry 2).
Another reaction with TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxyl) gave a higher yield of 3a under the same
conditions (entry 8). This is mostly because TEMPO is not only
a radical scavenger, but also a co-catalyst in aerobic alcohol
oxidation reactions7 that can initiate the N-alkylation of amines
by direct conversion of alcohols to aldehydes.9a Moreover, the
reaction in dark also gave a good yield of 3a (entry 9). All these
results clearly revealed that these control reactions preceded
equally well under the radical-free conditions (entries 7-9) with
the blank reaction (entry 2). Therefore, the possibility of a
radical participated process in present catalyst-free N-alkylation
reaction can be excluded.
strictly degassed and then heated under nitrogen. In agreement
with the hypothesis, no reaction occurred or only trace product
was detected in the reactions of anilines. Then, various
sulfonamides, sulfinamides, carboxylic amides, and heteroaryl
amines bearing the typical RC(=X)NH2 structural unit were
investigated to figure out which can undergo the catalyst-free
autocatalyzed alkylation reactions.13 For some substrates, no
target reaction occurred at all, or only low yields of the target
products were detected. To our delight, 2-aminobenzothiazole
(2a), 2-aminopyrimidine (3a), and 2-aminopyrazine (4)
behaved differently under the catalyst-free conditions and their
reactions efficiently afforded good to high yields of the target
products in the presence of a suitable base.12 These results
revealed that substrates that can conform to the requirements of
catalyst-free autocatalyzed alkylation process indeed exist in a
broad scope.
The above optimized condition (Table 1, entry 6) was then
applied to other alcohols and 2-aminobenzothiazoles to extend
the scope of the exo-selective dehydraitve N-alkylation reaction.
As shown in Table 2, for the reactions of unsubstituted 2a, it
reacted with various benzylic (entries 1-10) and heterobenzylic
alcohols (entries 11-12), including those bearing the more
bulky substituents (entries 2, 5, 10) and those with more
reactive halide groups (entries 5-9), to give good to high yields
of the exo-N-alkylation products under similar conditions. For
some substituted alcohols, they required longer reaction times
The reaction conditions of 2-aminobenzothiazole 2a were
firstly optimized. As shown in Table 1, the neat mixture of pure
o
benzyl alcohol 1a and 2a was initially heated at 120 C under
nitrogen with 20 mol% NaOH,9a,12 giving a high isolated yield
of a new product in only 6 h (entry 1). Spectra analysis of the
product showed that, different to the known N-alkylation of 2-
aminobenzothiazoles
2 with alkyl halides that occurred at the
more basic endo-nitrogen and gave endo-N-alkylated 5a’,3 the
present reaction gave specifically the exo-N-alkylated 5a as the
sole product. The reaction was so fast (entry 1) that it was still
o
(12-24 h) or a higher temperature of 120 C. This is similar
o
with the reactions of substituted 2-aminobenzothiazoles and 1a
very efficient at a lower temperature of 100 C (entries 2-3).
(entries 13-19), which generally required higher temperatures
Then, running the reaction under air or directly using the
commercial 1a can both shorten the reaction time (entries 4-5).
Therefore, the best result was obtained by running the reaction
o
of 120-135 C. This is most possibly due to the higher melting
points of the substituted substrates and the adopted solvent-free
condition of the present method, because, for some substrates,
once the reactions reached a higher temperature, they could
o
at 100 C under air directly using commercial 1a, giving 5a in
93% isolated yield (entry 6). Base screening and further
2 | J. Name., 2012, 00, 1‐3
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become very fast (entries 13-19, 3-6 h). As shown in the table, Table 3. Catalyst-free autocatalyzed N-alkylation of 2-
substrates bearing the reactive halide groups were tolerated aminopyrimidines and 2-aminopyrazine with primary alcohols.a
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H
H
R1
N
NH2
or
under basic conditions to give the target amines (entries 5-9,
18-19), which are useful building blocks in synthetic chemistry.
As to reactions using aliphatic alcohols as the alkylating
reagents, although we tried many times, they were found not
reactive in present reactions even under harsher conditions like
higher temperatures and more amounts of bases, giving only
trace yields of the products.
N
NH2
N
N
R1
N
N
DOI: 10.1039/C4GC02542C
NaOH (50 mol%)
air, 150 oC, 24 h
R2
R1
OH
R2
or
+
N
N
1
N
N
6
3
4
7
H
N
(1)b NaOH (40 mol%), under N2: 60% (72%)c
(2)b NaOH (50 mol%), under air: 73% (87%)c
(3) NaOH (50 mol%), under air: 82% (95%)c
N
Ph
N
6a
Me
(4)
(5)
N
OMe
(7)
(6)
H
H
N
H
N
H
N
N
N
N
N
Cl
Table 2. Catalyst-free autocatalyzed exo-N-alkylation of 2-
N
N
N
N
Cl
aminobenzothiazoles with alcohols.a
6c: 90%
6b: 91%
6e: 89%
6d: 85%
R1
S
N
S
Cl
Br
NaOH (20 mol%)
(9)
N
(10)
N
(11)
(8)
R2
H
N
R1
OH +
R2
NH2
H
NH
H
N
H
N
N
air, T, t
N
N
Br
N
1
N
5
2
N
N
N
6f: 90%
6g: 89%
6h: 94%
6i: 92%
Me
(14)d
OMe
(3)
(6)
(12)
N
(13)
N
S
H
(1)
(2)
(15)e
MeO
H
S
N
S
N
S
H
H
N
N
N
N
NH
NH
NH
N
N
OMe
N
MeO
N
N
N
N
Br
5a: 100 oC, 6 h, 93%
5c: 120 oC, 12 h, 74%
5b: 100 oC, 6 h, 95%
6l: 58%
6k: 59%
6m: 61%
6j: 79%
OMe
(5)
(8)
(4)
(7)
H
N
OMe
S
S
S
N
N
Ph
(16)b NaOH (40 mol%), under N2: 70% (80%)c
(17)b NaOH (50 mol%), under air: 80% (95%)c
(18) NaOH (50 mol%), under air: 86% (95%)c
NH
N
NH
NH
N
N
Cl
Cl
5d: 120 oC, 24 h, 96%
7a
5f: 100 oC, 6 h, 94%
5e: 100 oC, 6 h, 94%
(19)
(21)
(20)
Cl
Me
(9)
Br
S
Cl
S
S
H
H
H
N
N
N
NH
N
N
N
N
N
N
NH
N
NH
N
OMe
Br
N
a
5g: 100 oC, 6 h, 94%
5h: 100 oC, 12 h, 90%
5i: 100 oC, 12 h, 76%
7b: 89%
7d: 70%
7c: 90%
(10)
S
N
See Table 1 for similar conditions.13 Unless otherwise indicated,
commercial (>99% purity) was directly used under air.
Isolated yields based on
Yields in parenthesis are GC yields. 80 mol% NaOH. 80
mol% LiOH.
N
S
(12)
(11)
(14)
S
S
NH
1
NH
N
NH
N
c
3
or 4.
b 1a of 100% purity was used.
d e
5k: 100 oC, 12 h, 80%
5j: 100 oC, 24 h, 90%
5l: 100 oC, 12 h, 63%
(15)b
MeO
(13)
S
Me
S
N
S
NH
N
NH
NH
N
Me
The optimized conditions were then applied to other alcohols
and substituted heteroaryl amines to extend the scope of the
5n: 135 oC, 6 h, 93%
5m: 120 oC, 6 h, 90%
5o: 120 oC, 6 h, 95%
(18)c
F
(16)b
EtO
(17)
Me
Me
S
N
S
S
method. Thus, 3a and
4 readily reacted with substituted
NH
NH
N
NH
N
benzylic alcohols (entries 4-12, 19-21) and a heterobenzylic
alcohol (entry 13), including the ortho-substituted and more
bulky ones (entries 6, 11, 12) and those bearing the reactive
halide groups (entries 6-10, 21), to give good to high yields of
the target products under the standard conditions. For electron-
deficient 2-aminopyrimidine bearing a 5-Br moiety, the
reaction was less efficient and required more amounts of NaOH
to ensure an effective reaction (entry 14). In the case of 4,6-
5q: 135 oC, 6 h, 69%
5r: 135 oC, 3 h, 95%
5p: 120 oC, 6 h, 95%
(19)c
Cl
S
N
NH
5s: 135 oC, 3 h, 95%
a
Unless otherwise noted, see entry 6 of Table 1 for similar
conditions. Isolated yields based on 2. 2 equiv. 1a
1a
b
c
. 3 equiv.
.
We then investigated the catalyst-free reactions of alcohols dimethoxyl-2-aminopyrimidine, the product was obtained in
with 2-aminopyrimidines ( ) and 2-aminopyrazine ( ). As only a low yield due to formation of transetherification
3
4
shown in Table 3, the initial reaction of pure 1a with 3a and
4
byproducts in the presence of NaOH. Base screening showed
under N2 at 150 oC readily gave 60% and 70% isolated yields of that LiOH is the best one, giving 61% isolated yield of the
the target product 6a and 7a, respectively (entries 1 and 16), target 6m (entry 15).
suggesting amines 3a and
4
also belong to the family of
The more challenging catalyst-free N-alkylation reaction
catalyst-free autocatalyzed alkylation reactions. Then, running with secondary alcohols was also attempted. Secondary
the reactions with more amounts of NaOH under air gave alcohols have not been successfully used in the catalyst-free C-
higher product yields (entries 2 and 17). Similar to the reaction alkylation reactions.10a In fact, they were also seldom used in
of 2a (Table 1, entry 5), the reactions of 3a and
4
under air alcohol-based dehydrative alkylation reactions.4-6,8-10 As shown
using directly commercial 1a gave even better results, affording in Table 4, the reaction of 2-aminopyrimidine 3a and
the highest yields of both 6a and 7a (Scheme 3, entries 3 and benzohydrol was initially performed under the preceding
18). The reactions were also investigated using various bases or optimized conditions using NaOH as the base. However, no
at lower temperatures, but they gave only lower yields of the reaction occurred either under neat or solvent conditions, either
products.13
under air or under nitrogen (entry 1). Then, other alkali bases
This journal is © The Royal Society of Chemistry 2012
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like LiOH, KOH, CsOH, t-BuONa, t-BuOK, and even TBAOH Besides, the preceding observations neither support the base-
(tetrabutylammonium hydroxide) were carefully screened under mediated radical mechanism in these reactions (Table 1). We
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neat or solvent conditions (entries 2-7).13 The results showed later noticed that tautomeric equilibriuDmOsI: 1a0l.w10a3y9s/Ce4xGiCs0t25w4i2tCh
that CsOH is a much better base, giving a high yield of the many heterocycle compounds,3,14 i.e., the heteroaryl amines
target product 8a with only 30 mol% of CsOH in toluene (entry should exist in both amino and imino tautomers (eq. 1). We
7, method A). The same reaction under nitrogen also gave a realized that this may be the key to the success of heteroaryl
similar high yield of 8a (entry 8), suggesting this is also a amines
2-4 and may also be responsible for the observed
catalyst-free reaction. Further optimization of the reaction moderate reactivities of aminopyridines and sulfinamides
condition at lower temperatures gave a lower yield of 8a (entry (Scheme 1C). Therefore, a possible mechanism supported by
9).
additional experimental findings (vide infra) was proposed for
Table 4. Catalyst-free autocatalyzed N-alkylation of 2- these catalyst-free autocatalyzed N-alkylation reactions
aminopyrimidines and 2-aminopyrazine with secondary (Scheme 2).
alcohols.a
N
X
NH
X
tautomerization
X = S, N, CH
(1)
NH2
2-4
NH
H
H
CsOH·H2O (30 mol%)
toluene, air
method A: 150 oC, 24 h
method B: 110 oC, 18 h
R2
N
N
R1
or
N
N
NH2
N
NH2
or
N
N
N
R1
2'-4'
R
+
R
R1
OH
N
R2
R2
imino form
amino form
N
1
3
8
9
4
(1) NaOH (50 mol%), N2 or air, neat or toluene, 150 oC, 24 h: no reaction
(2) LiOH (100 mol%), air, toluene, 150 oC, 24 h: no reaction
(3) KOH (100 mol%), air, toluene, 150 oC, 24 h: (32%)b
(4) TBAOH (50 mol%), air, toluene, 150 oC, 24 h: no reaction
(5) t-BuONa (50 mol%), air, toluene, 150 oC, 24 h: (23%)b
(6) t-BuOK (50 mol%), air, toluene, 150 oC, 24 h: (28%)b
(7) CsOH·H2O (30 mol%), toluene, air, 150 oC, 24 h: 83% (95%)b (method A)
(8) CsOH·H2O (30 mol%), toluene, N2, 150 oC, 24 h: 80% (96%)b
(9) CsOH·H2O (30 mol%), toluene, air, 130 oC, 24 h: (90%)b
As shown in Scheme 2, due to the presence of the more
reactive terminal C=N double bond, the imino tautomers of
H
N
N
Ph
heteroaryl amines
in the presence of a base to give catalytic amounts of the key
initiating aldehydes 10 and the reduced heterocylic amines 2’’
2-4, 2’-4’, may react efficiently with alcohols
N
8a
Ph
1
-
4’’ via TM-free MPV-O processes (step ii). It is hard to detect
the existence of aldehyde 10 in the reaction mixtures, but its
catalytic activity to promote an originally ineffective reaction
can be observed to prove the formation of aldehdyes in the
reaction mixtures. As shown in eq. 2, the blank reaction of the
less reactive sulfinamide 12 and 1a afforded only 47% yield of
target 13 (entry 1 or Scheme 1C). In contrast, addition of only
10 mol% of 2-aminobenzothiazole (2a) greatly promoted the
reaction to finally give 83% 13 under the same conditions
(entry 2), suggesting that 10 should be generated from the
reaction of 10 mol% 2a and 1a (Scheme 2, step ii) and then
greatly promoted the reaction of 12 and 1a, just as in the
catalyst-free autocatalyzed reactions of 2-4 with the alcohols.
Indeed, when the blank reaction of 1a and 12 was heated at 125
oC to achieve a more efficient autocatalyzed aldehyde
generation process at higher temperatures, 13 could be obtained
in a higher yield of 66% (entry 3). These results further
supported step ii in the proposed mechanism that the rate of
aldehyde generation is dependent on the structure of the amine
substrate and also the reaction temperature, which led to varied
reactivities of the amine substrates under catalyst-free
conditions (Scheme 1C) and higher reactivities at higher
H
N
(10) CsOH·H2O (30 mol%), toluene, air, 150 oC, 24 h: 95% (>99%)b (method A)
(11) CsOH·H2O (30 mol%), toluene, N2, 150 oC, 24 h: 78%
N
N
Ph
Ph
Ph
(12) CsOH·H2O (30 mol%), toluene, air, 110 oC, 18 h: 95% (>99%)b (method B)
9a
(14)
H
Me
(15) 21% (B)
(16) 85% (A)
Me
(13)
Me
N
N
Ph
H
H
N
N
N
N
N
N
Ph
Ph
9b
N
8c: 50% (A)
8b: 58% (A)
a See Table 1 for similar conditions.12 Isolated yields based on
or
. b Yields in parenthesis are GC yields.
3
4
The same condition was then applied to 2-aminopyrazine
As shown in Table 4, the reactions of and benzohydrol under
air and under nitrogen both gave good to high yields of the
target product 9a (entries 10-11), indicating that this is also a
catalyst-free reaction. Temperature screening showed that the
reaction is still efficient at 110 C, giving a high yield of 9a in
18 h (entry 12, method B). The optimized conditions A and B
were then applied to substituted substrates. With 2-
aminopyrimidines
moderate yields of products 8b
aminopyrazine , the reaction with a substituted benzohydrol
was not efficient at 110 C (entry 15). Thus, the reaction was
heated at 150 oC to give a good yield of product 9b (entry 16).
The above results that different amines and amides bearing
the similar RC(=X)NH2 structural unit behaved great
differently from non-reactive to lowly reactive to even highly
reactive under catalyst-free conditions aroused our attention in
the mechanism of these interesting N-alkylation reactions. We
originally speculated that alcohols should able to reduce the
C=X bond of RC(=X)NH2 unit in the presence of a suitable
main group base to give the initiating aldehydes (Scheme 1A).
However, this is clearly not the fact because no reaction
occurred with some potential substrates like carboxylic amides
(Scheme 1C), which is close to methyl ketones in structure.10a
4.
4
o
3
, the reactions were less efficient and gave
-c
(entries 13-14). With 2-
4
o
temperatures.
N
N
H
5-9
R1
X
R1
OH
N
N
X
NH
X
air
1
NH2
2-4
NH2
base
(v)
2''-4''
(iv)
N
A
(i)
NH
R1
10
R1
B
O
base
(ii)
X
11
NH
X
N
R1
OH
(iii)
2'-4'
1
NH2
2-4
H2O
X
Scheme 2. Possible mechanism for catalyst-free autocatalyzed
N-alkylation of heteroaryl amines with alcohols induced by
structure-dependent tautomerization.
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 6
Journal Name
Green Chemistry
COMMUNICATION
O
S
O
S
†
Electronic Supplementary Information (ESI) available: detailed
condition screening tables, experimental details, and 1H and 13C NMR
spectra of the products. See DOI: 10.1039/c000000x/
(2)
+
OH
Ph
t-Bu
N
Ph
t-Bu
NH2
N2, NaOH (1.0 equiv.)
H
1a
13
12
1
(a) P. T. Anastas and J. C. Warner, Green Chemistry:
ViewTAhrteicoleryOnalinnde
(100% purity)
1) no additive, 100 oC, 12 h: 47%isol.
2) 2a (10 mol%), 100 oC, 12 h: 83%isol.
3) no additive, 125 oC, 12 h: 66%isol.
DOI: 10.1039/C4GC02542C
Practice, Oxford University Press, Oxford, England; New York,
1998; ( ) K. Sanderson, Nature, 2011, 469, 18.
) G. T. Brooks and T. R. Roberts, Pesticide Chemistry and
Bioscience, Royal Society of Chemistry, Cambridge, U.K., 1999; (
J. L. McGuire, Pharmaceuticals: Classes, Therapeutic Agents, Areas
of Application, Wiley-VCH, Weinheim, Germany, 2000, Vols. 1-4; (
R. Hili and A. K. Yudin, Nat. Chem. Bio. 2006, , 284; ( ) E. D. Cox
and J. M. Cook, Chem. Rev. 1995, 95, 1797; ( ) J. M. Humphrey and
A. R. Chamberlin, Chem. Rev. 1997, 97, 2243; ( ) C. Hansch, P. G.
Sammes and J. B. Taylor, Comprehensive Medicinal Chemistry
Pergamon Press, Oxford, 1990, Vol. 2, Chapter 7.1; ( ) E. E. Connor,
Sulfonamide Antibiotics Prim. Care Update Ob. Gyn. 1998, , 32; (
A. Kleemann, J. Engel, B. Kutscher and D. Reichert, Pharmaceutical
Substances, Synthesis, Patents, Applications, Thieme, Stuggart, 1999
) S.-Y. Park, P. Fung, N. Nishimura, D. R. Jensen, H. Fujii, Y. Zhao,
b
2
(
a
Consequently, upon generation, aldehyde 10 should quickly
condense with to give imine intermediates 11 (step iii),
which was further transfer hydrogenated by alcohols via TM-
free MPV-O process9-11 to give alkylated products
and
b
)
2-4
1
c
)
2
d
5-9
e
regenerate 10 (step iv) to finish the aldehyde-catalyzed
dehydrative N-alkylation cycle (cycle B).9a
f
,
As to cycle A, the reduced heterocylic amines 2’’
not be detected due to their instable nature. We suppose they
were oxidized by air to regenerate (step v) during the
workup. Because, we found heterocycle 14, an analogue of 2’’
4’’, could be easily oxidized to give aromatized 16 when it was
prepared in situ from 10a and 2-aminothiophenol 15 either
under air or under nitrogen (eq. 3, by in situ oxidation in the
reaction under air, or by oxidation during workup in the
reaction under nitrogen). Therefore, once generated, 2’’
may be oxidized by air to regenerate in reactions under air
(step v), which will further undergo alkylation to give products.
This well explains the higher yields of the products obtained
from reactions under air than under nitrogen, further supporting
cycle A in the proposed mechanism.
-4’’ could
g
5
h)
2-4
-
;
(
i
S. Lumba, J. Santiago, A. Rodrigues, T. F. Chow, S. E. Alfred, D.
Bonetta, R. Finkelstein, N. J. Provart, D. Desveaux, P. L. Rodriguez,
P. McCourt, J.-K. Zhu, J. I. Schroeder, B. F. Volkman and S. R.
Cutler, Science, 2009, 324, 1068.
-4’’
3
4
(
a
)
J. V. Metzger, Thiazoles and their Benzo Derivatives.
Comprehensive Heterocyclic Chemistry, Pergamon Press Ltd, New
York, 1984, vol. 6, pp. 235–331; ( ) X. Zhu, Q.-S. Yu, R. G. Cutler,
C. W. Culmsee, H. W. Holloway, D. K. Lahiri, M. P. Mattson and N.
H. Greig, J. Med. Chem., 2002, 45, 5090; ( ) S. D. Barchéchath, R. I.
2-4
b
c
Tawatao, M. Corr, D. A. Carson and H. B. Cottam, J. Med. Chem.
2005, 48, 6409.
,
SH
S
S
toluene
100 oC, 24 h
(3)
PhCHO +
Ph
Ph
(
a
) A. J. A. Watson and J. M. J. Williams, Science, 2010, 329, 635; (
T. D. Nixon, M. K. Whittlesey and J. M. J. Williams, Dalton Trans.
2009, 753; ( ) G. E. Dobereiner and R. H. Crabtree, Chem. Rev.
2010, 110, 681; ( ) G. Guillena, D. J. Ramón and M. Yus, Chem.
Rev., 2010, 110, 1611; ( ) K.-I. Fujita and R. Yamaguchi, Synlett,
2005, 560; ( ) T. Suzuki, Chem. Rev., 2011, 111, 1825; ( ) S. Bähn, S.
Imm, L. Neubert, M. Zhang, H. Neumann and M. Beller,
ChemCatChem, 2011, , 1853.
) M. H. S. A. Hamid, C. L. Allen, A. C. Maxwell, H. C. Maytum, A.
J. A. Watson and J. M. J. Williams, J. Am. Chem. Soc., 2009, 131
1766; ( ) Y. Zhang, X. Qi, X. Cui, F. Shi, and Y. Deng, Tetrahedron
Lett., 2011, 52, 1334; ( ) F. Li, H. Shan, Q. Kang and L. Chen, Chem.
Commun., 2011, 47, 5058; ( ) F. Li, H. Shan, L. Chen, Q. Kang and
P. Zou, Chem. Commun., 2012, 48, 603; ( ) F. Li, L. Chen, Q. Kang,
J. Cai and G. Zhu, New J. Chem., 2013, 37, 624.
) S. L. Feng, C. Z. Liu, Q. Li, X. C. Yu and Q. Xu, Chin. Chem.
Lett., 2011, 22, 1021; ( ) C. Liu, S. Liao, Q. Li, S. Feng, Q. Sun, X.
Yu and Q. Xu, J. Org. Chem., 2011, 76, 5759; ( ) X. Yu, C. Liu, L.
Jiang and Q. Xu, Org. Lett., 2011, 13, 6184; ( ) Q. Li, S. Fan, Q. Sun,
H. Tian, X. Yu and Q. Xu, Org. Biomol. Chem., 2012, 10, 2966; ( ) S.
Liao, K. Yu, Q. Li, H. Tian, Z. Zhang, X. Yu and Q. Xu, Org. Biomol.
Chem., 2012, 10, 2973; ( ) X. Yu, L. Jiang, Q. Li, Y. Xie and Q. Xu,
Chin. J. Chem., 2012, 30, 2322.
) L. Jiang, L. Jin, H. Tian, X. Yuan, X. Yu and Q. Xu, Chem.
Commun., 2011, 47, 10833; ( ) H. Tian, X. Yu, Q. Li, J. Wang and Q.
Xu, Adv. Synth. Catal., 2012, 354, 2671; ( ) B. Huang, H. Tian, S.
Lin, M. Xie, X. Yu and Q. Xu, Tetrahedron Lett., 2013, 54, 2861; (
b)
N
H
N
NH2
,
16
air: 93%; N2: 91%
15
14: analogue of 2''-4''
c
,
d
e
In conclusion, we have developed catalyst-free autocatalyzed
N-alkylation reactions of 2-aminobenzothiazoles, 2-
aminopyrimidines, and 2-aminopyrazine with primary and
secondary alcohols, providing an efficient, practical, and green
method for synthesis of the versatile heteroaryl amine
derivatives without using any external catalysts. Mechanistic
studies revealed that these interesting catalyst-free N-alkylation
reactions were induced by structure-dependent tautomeric
equilibriums of the heteroaryl amines through MPV-O transfer
hydrogenation of the imino tautomers by alcohols to give the
key initiating aldehydes, which then catalyzed the reactions to
complete to the give products. Further application and
extension of the catalyst-free alkylation reactions and deeper
mechanistic insights are underway.
f
g
3
5
6
(a
,
b
c
d
e
(
a
b
c
d
e
f
7
(a
Acknowledgments
b
c
We thank ZJNSF for Distinguished Young Scholars
(LR14B020002), NNSFC (20902070), and 580 Oversea Talents
Program of Wenzhou City for financial support.
d
)
E. Zhang, H. Tian, S. Xu, X. Yu and Q. Xu, Org. Lett., 2013, 15
2704.
,
8
9
Q. Xu and Q. Li, Chin. J. Org. Chem., 2013, 33, 18.
(
a
) Q. Xu, Q. Li and X. Zhu, J. Chen, Adv. Synth. Catal., 2013, 355
73; ( ) Q. Xu, J. Chen and Q. Liu, Adv. Synth. Catal., 2013
10 ( ) Q. Xu, J. Chen, H. Tian, X. Yuan, S. Li, C. Zhou and J. Liu,
Angew. Chem. Int. Ed., 2014, 53, 225; ( ) For a closely related
,
Notes and references
b
, 355, 697.
College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou, Zhejiang, 325035, China. E-mail: qing-xu@wzu.edu.cn; Fax:
(+)-86-577-86689302; Tel: (+)-86-138-57745327
a
b
ketone-initiated dehydrative alkylation of indole and pyrrole: X. Han
and J. Wu, Angew. Chem. Int. Ed., 2013, 52, 4637.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1‐3 | 5

Green Chemistry
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Journal Name
COMMUNICATION
11 For reviews on MPV-O reactions: (a) J. S. Cha, Org. Pro. Res. Dev.,
2006, 10, 1032; (
b) S. Gladiali and E. Alberico, Chem. Soc. Rev.,
2006, 35, 226; ( ) Ref 4c.
c
View Article Online
12 Although bases were essential additives in TM-catalyzed dehydrative
alkylation reactions, they were not considered as the catalyst of the
reactions (ref. 4-5). We observe this point in our previous study (ref.
10a) and the present work.
DOI: 10.1039/C4GC02542C
13 See ESI† for details.
14 (
Kovačková and A. Holý, Eur. J. Org. Chem., 2011, 777; (
Milletti and A. Vulpetti, J. Chem. Inf. Model., 2010, 50, 1062; (
Kosenkov, Y. Kholod, L. Gorb, O. Shishkin, D. M. Hovorun, M.
Mons and J. Leszczynski, J. Phys. Chem. B, 2009, 113, 6140; ( ) F.
Oellien, J. Cramer, C. Beyer, W.-D. Ihlenfeldt, and P. M. Selzer, J.
Chem. Inf. Model., 2006, 46, 2342; ( ) L. Blancafort, J. Bertran and
a
)
M. Dračínský, P. Jansa, J. Chocholoušová, J. Vacek, S.
) F.
) D.
b
c
d
e
M. Sodupe, J. Am. Chem. Soc., 2004, 126, 12770; (
J. L. Wong, J. Org. Chem., 1976, 41, 2491.
f) M. F. Zady and
6 | J. Name., 2012, 00, 1‐3
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