Features and applications of reactions of α,β-unsaturated N-acylbenzotriazoles with amino compounds

Article abstract of DOI:10.1016/j.tet.2008.04.054

Promoted by triethylamine, α,β-unsaturated N-acylbenzotriazoles reacted with amino compounds in a variety of ways. Thus, N-cinnamoylbenzotriazoles reacting with aromatic amines afforded novel addition products β-benzotriazolyl amides 3, which might be normally formed from the alternative but unknown 1,4-addition of benzotriazole to N-cinnamoylamides. The type 3 compounds could also result from the reaction between N-crotonoylbenzotriazole and aliphatic amines. However, normal 1,4-addition could occur between α,β-unsaturated aliphatic N-acylbenzotriazoles and aromatic amines, leading to β-amino N-acylbenzotriazoles 4 in good yields. In addition, exclusive 1,2-addition of aliphatic amines to N-cinnamoylbenzotriazoles gave excellent yields of cinnamides 5. Accordingly, three possible routes were proposed to rationalize the formation of compounds 3-5. Finally, with o-phenylenediamine and o-aminothiophenol as the substrates, the 1,4- and 1,2-addition to α,β-unsaturated N-acylbenzotriazoles could take place concurrently and the corresponding heterocycles 1,5-benzodiazepine-2-one and 1,5-benzothiazepine-4-one were constructed, respectively.

Full text of DOI:10.1016/j.tet.2008.04.054

Tetrahedron 64 (2008) 6510–6521
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Features and applications of reactions of
with amino compounds
a,b-unsaturated N-acylbenzotriazoles
,
b
a,
c
,
a
a
a
a
Xiaoxia Wang a , Zhifang Li , Xiangming Zhu
, Hui Mao , Xuefei Zou , Lichun Kong , Xinsheng Li
*
*
a Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang 321004, PR China
b Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Educations, Hangzhou Normal University, Hangzhou 310012, PR China
c UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Promoted by triethylamine,
a,b
-unsaturated N-acylbenzotriazoles reacted with amino compounds in
Received 27 December 2007
Received in revised form 9 April 2008
Accepted 15 April 2008
a variety of ways. Thus, N-cinnamoylbenzotriazoles reacting with aromatic amines afforded novel ad-
dition products -benzotriazolyl amides 3, which might be normally formed from the alternative but
unknown 1,4-addition of benzotriazole to N-cinnamoylamides. The type 3 compounds could also result
from the reaction between N-crotonoylbenzotriazole and aliphatic amines. However, normal 1,4-addition
b
Available online 18 April 2008
could occur between a,b-unsaturated aliphatic N-acylbenzotriazoles and aromatic amines, leading to b-
Keywords:
a,b-Unsaturated N-acylbenzotriazoles
Amino compounds
Addition
amino N-acylbenzotriazoles 4 in good yields. In addition, exclusive 1,2-addition of aliphatic amines to N-
cinnamoylbenzotriazoles gave excellent yields of cinnamides 5. Accordingly, three possible routes were
proposed to rationalize the formation of compounds 3–5. Finally, with o-phenylenediamine and o-
aminothiophenol as the substrates, the 1,4- and 1,2-addition to
a,b-unsaturated N-acylbenzotriazoles
b-Benzotriazolyl amides
could take place concurrently and the corresponding heterocycles 1,5-benzodiazepine-2-one and 1,5-
benzothiazepine-4-one were constructed, respectively.
b
-Amino N-acylbenzotriazoles
Cinnamides
1,5-Benzodiazepine-2-ones
1,5-Benzothiazepine-2-ones
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
smoothly,3l–s the unsaturated conjugated systems3 were generally
limited to methyl vinyl ketone, acrylonitrile, acrylate, and acryl-
Nucleophilic additions to conjugated unsaturated systems have
been the subject of numerous studies.1 The mode of the reaction,
namely, the 1,4- or 1,2-addition, has been of major interest1e and
can be influenced by the nature of nucleophiles and conjugated
unsaturated systems, temperature, additives, etc. Amines are a class
of heteroatom nucleophiles that have been widely used to effect
amide. b-Substituted, especially, b-aryl substituted a,b-ethylenic
compounds were usually not employed due to their low reactivity
as Michael acceptors, although stereoselective aza-Michael addi-
tion of
b-substituted a,b-ethylenic compounds has been in-
vestigated4 but remains to be a great challenge.5
1,2-Addition of amines to unsaturated conjugated systems is
also known. For example, both aliphatic and aromatic amines could
1,4-addition, i.e., aza-Michael addition to a,b-unsaturated carbonyl
compounds (activated double bonds or electron-deficient double
bonds) and this organic transformation provides a facile synthesis
of important natural and unnatural target molecules.2 Among
undergo the exclusive 1,2-addition with
a
,
b
-unsaturated acyl
chlorides leading to the corresponding
a,b-unsaturated amides in
high yields.6
a variety of conjugated unsaturated systems investigated,
a
,
b
-eth-
Herein, we wish to report versatile addition reactions between
amines and a special type of -unsaturated amide, namely,
unsaturated N-acylbenzotriazoles, which contain a C]C–CON
ylenic compounds such as methyl vinyl ketone, acrylonitrile, ac-
rylate, acrylamide, vinyl sulfones, etc. were found to be particularly
successful aza-Michael addition acceptors.3 Even so, in most cases,
only aliphatic amines were effective nucleophiles while aromatic
amines often failed to undergo the 1,4-addition with the above
Michael acceptors.3a–k Also, even under specific conditions where
the aromatic amines underwent the aza-Michael addition
a,
b
a,b-
functionality.
Among the most common unsaturated conjugated systems, a,b-
unsaturated amides have not been studied extensively as aza-Mi-
chael acceptors due to their low reactivity except for the simple
acrylamide, CH2]CHCONH2.3 Two alternative strategies could be
applied to effect a successful aza-Michael addition of
a,b-un-
saturated amides. One is to enhance the reactivity of the nucleo-
philes by converting amines into lithium amides so that the amines
* Corresponding authors. Fax: þ86 579 82282595.
E-mail addresses: wangxiaoxia@zjnu.cn (X. Wang), xiangming.zhu@ucd.ie
(X. Zhu).
could react with
a,b-unsaturated amides giving rise to the 1,4-ad-
dition products in good yields.7 The other strategy generally
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.054

X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
6511
involves the activation of
appropriate protecting-activating groups onto the nitrogen and
thus transformation of the
sponding imides.8
a,b-unsaturated amides by introducing
Ph
NHPh
Ph
Bt
Et3N
Ph
Bt
+
PhNH2
not
THF, reflux
Bt
O
3aa
NHPhO
3'aa
a,b-unsaturated amides into the corre-
O
1a
2a
N-Acylbenzotriazoles are excellent acylating agents due to the
good leaving ability of benzotriazolyl group and have found wide
applications in the acylation of various nucleophiles.9 However, in
this context, a,b-unsaturated N-acylbenzotriazoles received much
less attention and systematic studies have not been conducted on
N
N
Bt =
N
Scheme 1.
the nucleophilic attack of this type of N-acylbenzotriazoles. Un-
derstandingly, like ordinary N-acylbenzotriazoles, a,b-unsaturated
1H NMR spectrum, the chemical shift of the proton in the
was 6.4 ppm, which seemed too much for an ordinary amine-me-
b-position
N-acylbenzotriazoles could also be used as mild acylating agent,
acting as 1,2-addition acceptor. For instance, N-cinnamoyl benzo-
triazoles have been used to prepare cinnamoyl hydrazides by ac-
ylation of hydrazine;10 lithium enolates of ketones have also been
diated Michael addition product, whose b-H chemical shift usually
locates at around 4.5 ppm.3,4a–e,8 In a research carried out by
Gandelman and Jacobsen,4f the products resulting from the con-
jugate addition of benzotriazole to N-Bz protected cinnamide fol-
acylated with
unsaturated
thiolates12 and aliphatic amines13 with N-cinnamoylbenzo-
triazoles, thus a facile synthesis of -unsaturated thioesters and
a
,b
-unsaturated acylbenzotriazoles to prepare
g,d-
b
-diketones.11 Recently, we reported the acylation of
lowed by conversion into the
a doublet–doublet peak at around 6.3–6.5 ppm in the 1H NMR
spectrum for the -hydrogen. The linkage of benzotriazolyl het-
erocyclic nitrogen to the -position arousing a migration of -hy-
drogen absorption to the lower magnetic field gave us a hint that
the product we isolated may have a -benzotriazolyl structure.
b-benzotriazolyl esters showed
a,b
b
cinnamides has been established. Katritzky et al. reported lately
that Grignard reagents could also undergo readily 1,2-addition to
b
b
different
formation of
actions were considered of great interest11 because the acylating
agents used, -unsaturated acylbenzotriazoles, are stable crys-
a
,
b
-unsaturated N-acylbenzotriazoles resulting in the
a,b
b
-unsaturated ketones.14 The above acylation re-
Also, the broad peak at around 8.0 ppm indicates that there may
exist an amide N–H instead of an amine N–H. Single-crystal X-ray
diffraction analysis18 was further made for the product and the
structure was unambiguously ascertained to be 3aa (Fig. 1), sub-
stantiating the above considerations.
a,b
talline compounds, readily available, and easy to handle, thereby
avoiding the usage of the corresponding acyl chlorides, which are
usually unstable and difficult to handle.
Compound 3aa, from the synthetic design point, may be nor-
mally prepared from the aza-Michael addition of benzotriazole to
N-phenylcinnamide. And correspondingly, its formation in this case
could be conveniently explained as through N-acylation of aniline
followed by Michael addition of the released benzotriazolyl to the
in situ-formed N-phenylcinnamide. However, when a mixture of N-
phenylcinnamide and benzotriazole was refluxed in THF under the
same conditions, no reaction occurred at all (Scheme 2). Although
the mechanism remains to be further explored, it was reasonable to
deduce that the addition of benzotriazolyl may occur in-
tramolecularly in a concerted process before it cleaved away.
Other base, stronger than triethylamine, such as DBU, was also
examined as a promoter for the production of 3aa, only to find that
cinnamide as a co-product was formed in considerable amount
(32%, isolated yield) besides the desired 3aa (48%, isolated yield).
Therefore, with compound 3aa as a sole product and isolated in
very good yield (73%) promoted by triethylamine, further in-
vestigations have then been carried out under the conditions and
the results are summarized in Table 1. Again, aniline reacted
smoothly with N-cinnamoylbenzotriazoles 2b and 2c giving rise
to the products 3ab and 3ac in good yields (Table 1, entries 2
and 3). The reactions between other aromatic amines, such
as p,m,o-toluidine, 1-naphthylamine, p-chlorobenzenamine,
In addition,
a,b-unsaturated N-acylbenzotriazoles have been
demonstrated to be very useful Michael addition acceptors as well.
Our recent studies indicate that with samarium(III) iodide as the
catalyst, indole derivatives can undergo regiospecifically 1,4-addi-
tion to
a,b-unsaturated N-acylbenzotriazoles at their 3-position
rather than being acylated.15 In continuation of our previous study
concerning the reactions between amines and N-cinna-
moylbenzotriazoles,13 here we present exhaustively the versatile
addition reactions of
different amino-containing compounds, such as aromatic amines,
aliphatic amines, o-phenylenediamine, and o-aminothiophenol.
a,b-unsaturated N-acylbenzotriazoles with
2. Results and discussion
2.1. The reaction between aromatic amines and N-
cinnamoylbenzotriazoles
As mentioned above, N-acylbenzotriazoles are highly efficient
N-acylating agents. Both aromatic and aliphatic amines have thus
been acylated with these agents under neutral conditions to pro-
duce various amides in very good to excellent yields.16 Also,
Katritzky et al. reported recently that a variety of N-acylbenzo-
triazoles including N-cinnamoylbenzotriazoles could be coupled
with either aromatic or aliphatic amines to form amides efficiently
under microwave conditions.17 However, when a mixture of aniline
and N-cinnamoylbenzotriazole 2a was refluxed in anhydrous THF
in the presence of triethylamine, as shown in Scheme 1, a new
product was obtained, which was previously characterized as b-
amino N-acylbenzotriazole 30aa resulting from a normal aza-Mi-
chael addition (1,4-addition) of aniline to 2a.13 Surprisingly, in our
subsequent studies it was found that no reaction could occur be-
tween the alleged b
-amino N-acylbenzotriazole 30aa and primary
amines under a variety of Lewis acid or base promoted conditions.
Its failure to act as an acylating reagent as common N-acylbenzo-
triazoles9 made us reconsider the structure of the product as 30aa0s
regioisomer 3aa.
Although three doublet–doublet peaks, which were character-
istic of the aza-Michael addition product, were well observed in the
Figure 1. The crystal structure of 3aa.

6512
X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
Table 1
The formation of
cinnamoylbenzotriazoles
Ph
NHPh
Ph
NHPh
Et3N
b
-benzotriazolyl amide
3
from aromatic amines and N-
+
BtH
Bt
O
THF, reflux
O
3aa
Ar'
NHAr
Ar'
Bt
Et3N
N
Scheme 2.
+
Ar NH2
1
Bt
O
N
THF, reflux
Bt =
O
N
2
3
p-anisidine, p-nitroaniline, N-ethylaniline, and N-phenylaniline,
and different N-cinnamoylbenzotriazole derivatives were also in-
vestigated in order to widen the range and nature of the sub-
stituents on the aromatic ring. As expected, most reactions
proceeded smoothly and led to products 3 in good to high yields
(Table 1, entries 4–10, 14, and 15). It bears noting that under the
present conditions both unsubstituted aromatic amines, like 1f, and
substituted aromatic amines with either a weak electron-donating
group like 1b–d or a weak electron-withdrawing group like 1g
could react well with various N-cinnamoylbenzotriazoles.
However, the reaction mode varied when p-anisidine 1e was
used (Table 1, entries 11–13). Reaction of 1e with 2a gave only
a small amount of the expected 3ea and predominantly the acyl-
ation product 4ea in a 1:14 ratio, as shown in Scheme 3. Lower
selectivity in favor of 1,2-addition was also observed in the coupling
of 1e and 2d. However, anisidine 1e reacted with N-cinna-
moylbenzotriazole 2e under the same conditions to give 3ee in very
good yield (72%). In addition, the coupling of p-nitroaniline and N-
cinnamoylbenzotriazole failed to provide any product even after
prolonged reaction times, as shown in entry 16 in Table 1, which
might be caused by the low nucleophilicity of p-nitroaniline. Also,
no coupling took place under the same conditions between either
N-ethylaniline or N-phenylaniline and 2a due presumably to their
weakened nucleophilicity (Table 1, entries 17 and 18).
Entry
Aromatic amines 1
Ar0 of 2
Products 3 Reaction Yielda
time (h) (%)
1
2
1a
1a
2a 3aa
2b 3ab
18
18
73
68
NH2
NH2
Cl
3
4
1a
1b
2c 3ac
2a 3ba
18
18
52
75
NH2
O
H3C
NH2
NH2
NH2
NH2
5
1b
1b
1b
1c
1c
1d
1e
1e
1e
2d 3bd
2b 3bb
2e 3be
2a 3ca
2f 3cf
2f 3df
2a 3ea
2d 3ed
2e 3ee
18
10
24
24
21
18
18
18
18
81
H3C
H3C
O2N
Cl
6
67
H3C
H3C
7
56
8
60
H3C
H3C
NH2
NH2
9
55
Cl
Cl
2.2. The reaction between aliphatic amines and
N-crotonoylbenzotriazole
CH3
10
11
12
13
76
NH2
To obtain more information on the reactions between amines
and
a,b-unsaturated N-acylbenzotriazoles, we then turned to use
4 (56)b
21 (37)b
72 (d)c
H3CO
H3CO
H3CO
NH2
NH2
NH2
a,b
-unsaturated aliphatic N-acylbenzotriazoles as electrophilic
agents. Interestingly, under the same mild conditions, reaction of
aliphatic amines such as piperidine, phenethylamine, n-butyl-
amine, and diethylamine with 2h also afforded the corresponding
H3C
O2N
b
-benzotriazolyl amides 3 in very good yields at room temperature
under solvent-free conditions even within shorter time (Table 2).
The
-H chemical shift in the 1H NMR spectra of 3oh, 3lh, 3nh, and
b
NH2
3qh all appeared at around 5.5 ppm, with migration to the lower
magnetic field observed again. The attribution was also consistent
14
1f
2f 3ff
18
70
Cl
with that of the
of benzotriazole to
b
-benzotriazolyl imides resulting from the addition
a,b
-unsaturated aliphatic imides.4f In addition,
15
16
1g
1h
2a 3ga
24
36
65
Cl
NH2
p-toluidine was used as a nucleophile to react with 3lh. Not sur-
prisingly, the reaction failed to produce any product, which proved
that 3lh, instead of aliphatic amine-mediated aza-Michael addition
product, was the compound formed here. The same 1H NMR
spectral pattern of 3oh, 3nh, and 3qh made the determination of
their structures equally reasonable.
2a d
dd
O2N
NH2
17
18
1i
1j
2a d
2a d
36
36
dd
dd
CH2CH3
N
H
2.3. The Michael addition of aromatic amines to
N
H
a
,b-unsaturated aliphatic N-acylbenzotriazoles
a
Isolated yields based on N-cinnamoylbenzotriazoles.
b
An inseparable mixture of 1,4- and 1,2-adduct was obtained as shown by the 1
H
Exposure of N-crotonoylbenzotriazole 2h to p-toluidine and
NMR. The yields of the 1,2-adducts are shown in parentheses.
Et3N in THF led smoothly to the normal 1,4-adduct within 2.5 h and
5bh was isolated in very good yield (75%). p-Anisidine could also
react readily with 2h in 1,4-attack mode affording 5eh in good yield
(62%). Both of the reactions proceeded at room temperature and
c
The byproduct was not isolated due to its trace amount but detected by TLC.
d
No reaction.
and expectedly, the aza-Michael addition products 5bi, 5gi, and 5ci
were all produced in very good yields (Table 3, entries 3–5). The
characterization as the products 5 instead of the type 3 compounds
completed within a few hours. In addition,
phatic N-acylbenzotriazole 2i derived from
was also treated with aromatic amines 1b, 1g, and 1c, respectively,
a
,b
-unsaturated ali-
a
-methyl acrylic acid
was based upon their b-H chemical shift at around 4.2–4.5 ppm in

X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
6513
H
H
N
N
Ar'
Et3N
Ar'
MeO
NH2
+
2a or 2d
+
THF, reflux
Bt
O
O
OMe
OMe
3
4
1e
Ar' = C6H5
Ar' = p-CH3C6H4
3ea : 4ea = 1 : 14
3ed : 4ed = 1 : 1.8
Scheme 3. Reaction of p-anisidine with N-cinnamoylbenzotriazoles 2a and 2d.
2.4. The acylation of aliphatic amines with N-
Table 2
The formation of
crotonoylbenzotriazole
b-benzotriazolyl amide from aliphatic amines and N-
cinnamoylbenzotriazoles
H3C
NHR
Although most aromatic amines readily reacted with
saturated N-acylbenzotriazole derivatives affording either the
novel addition or the normal aza-Michael addition products as
a
,
b
-un-
Et3N
r.t.
H3C
Bt
+
NH2
R
Bt
O
O
1
2h
3
Entry
Amine
R1
R2 Product Reaction
time (min)
Yieldsa (%)
Table 4
The acylation (1,2-addition) of aliphatic amines with N-cinnamoylbenzotriazoles
R1
N
1
2
1o CH3– 2h
1l CH3– 2h
H
H
3oh
3lh
5
5
80
85
NH
R1
R2
+
Et3N
2
Ar'
N
H
+
BtH
R2
THF, reflux
NH2
O
1
4
Entry
1
Alkyl amines 1
Ar0 of 2
Product Reaction Yielda (%)
3
4
n-C4H9NH2
(C2H5)2NH
1n CH3– 2h
1q CH3– 2h
H
H
3nh
3qh
5
5
82
80
1k
1l
2d 4kd
2f 4lf
6 h
91
86
91
a
NH2
NH2
H3C
Cl
Isolated yields based on a,b-unsaturated aliphatic N-acylbenzotriazoles.
2
2.5 h
1.5 h
Table 3
The Michael addition of aromatic amines to
acylbenzotriazoles
a
,b
-unsaturated aliphatic N-
3
n-C3H7NH2
n-C4H9NH2
n-C4H9NH2
n-C3H7NH2
1m
1n
1n
1m
1o
1p
1q
1q
1q
2g 4mg
2f 4nf
2f 4nf
2e 4me
2a 4oa
2a 4pa
2f 4qf
2f 4qf
2f 4qf
H3CO
Cl
R2
R2
R1
Bt
Et3N
THF, r.t.
4
10 min 95
30 minb 95
10 minb 95
R1
Bt
+
Ar NH2
NH
O
1
Ar
2
O
5
5
Cl
Entry
Amine
R1
R2
Product Reaction Yieldsa (%)
time (h)
6
O2N
1
2
3
4
1b CH3– 2h
1e CH3– 2h
H
H
5bh
5eh
2.5
4
75
62
80
82
7
3 h
88
H3C
H3CO
H3C
Cl
NH2
NH2
NH2
NH
8
3 h
83
O
NH
1b
1g
H
H
2i CH3 5bi
2i CH3 5gi
3.5
4.5
9
(C2H5)2NH
(C2H5)2NH
(C2H5)2NH
3 h
80
Cl
Cl
Cl
10
11
24 h
24 h
82c
85d
NH2
5
1c
H
2i CH3 5ci
5
82
H3C
NH2
a
12
(C2H5)2NH
1q
2c 4qc
1.5 h
87
Isolated yields based on a,b-unsaturated aliphatic N-acylbenzotriazoles.
O
a
the 1H NMR spectra. Besides, product 5ci could, to our anticipation,
acylate p-anisidine smoothly and afforded the corresponding am-
ide 6 (Scheme 4), indicating that the N-acylbenzotriazole structure
was included in compounds 5.
Isolated yields based on N-cinnamoylbenzotriazoles.
Carried out at room temperature.
Prolonging the reaction to comparable time did not afford any detectable
b
c
amount of type 3 compounds.
d
Diethylamine (2.2 equiv) was used.
CH3
Bt
CH3
H
N
H3C
NH
O
ZnCl2
MeO
NH2
+
H3C
NH
O
OMe
THF, r.t.
1e
5ci
6
Scheme 4. The acylation of p-anisidine with aza-Michael product 5ci.

6514
X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
O
R1 = aryl, R2 = alkyl
R1
NHR2
4
O
(a)
(b)
N
R2NH2
R1
N
N
R2
NH
H
R2
O
O
N
H2N
R1
R
1 = aryl, R2 = aryl;
N
R1
N
N
or R1 = alkyl, R2 = aryl;
2
N
N
or R1 = alkyl, R2 = alkyl
A
Et3N
R2
H
R2
H
N
Et3NH
N
R1
O
O
C
C
R1
R2
H
N
N
N
N
O
N
(c)
N
R1
N
N
R1 = alkyl, R2 = aryl
N
N
B
R1 = aryl, R2 = aryl;
or R1 = alkyl, R2 = alkyl
1,3-amino group migration
R2
(d)
R2
O
HN
R1
N
N
N
N
NH
R1
O
N
C
C
O
N
N
N
N
R1
NHR2
Et3NH
3
Et3N
R2
R2
N
O
HN
R2
N
Et3N
N
H
C
R1
N
H
N
Et3NH
R1
O
R1
C O
N
5
N
N
N
N
N
D
Scheme 5. Proposed routes for the formation of compounds 3–5.
described above, to our surprise, when cyclohexylamine, an ali-
phatic amine, was treated with N-cinnamoylbenzotriazole 2d in the
presence of Et3N, the corresponding cinnamide 4kd was isolated in
excellent yield (91%) (Table 4, entry 1). Apparently, this product was
generated through 1,2-attack of cyclohexylamine to the N-cinna-
moylbenzotriazole. In order to further explore the scope of this
reaction, we proceeded to use various aliphatic amines 1l–q as the
nucleophiles, as outlined in Table 4.
Interestingly, all the primary and secondary aliphatic amines in
Table 4 gave solely the acylation products by reaction with different
N-cinnamoylbenzotriazole derivatives in high to excellent yields
(80–95%). For instance, reaction of phenethylamine 1l with N-cin-
namoylbenzotriazole 2f under the above described conditions led
further aza-Michael addition of diethylamine to cinnamide 4qf
could not be observed either.
2.5. Mechanism discussion for the formation
of compounds 3–5
As could be summarized from the above results, the versatile
reactions presented are interesting and can offer useful methods
for the preparation of
pared from routine aza-Michael addition),
4 (by avoidance of using moisture sensitive
chlorides here), and -amino N-acylbenzotriazoles 5 (useful in-
termediates for -amino acid derivatives).
b
-benzotriazolyl amide 3 (could not be pre-
-unsaturated amides
-unsaturated acyl
a,b
a,b
b
to the
a
,b
-unsaturated amide 4lf in 86% yield (Table 4, entry 2).
b
Similarly, acylation of diethylamine 1q with N-cinnamoylbenzo-
triazoles 2f and 2c in THF and in the presence of Et3N also pro-
ceeded smoothly to give the corresponding amides 4qf and 4qc in
80% and 87% yields, respectively (Table 4, entries 9 and 12). It is
worth mentioning that only cinnamides 4 was formed exclusively
even after prolonging the reaction time to 24 h (Table 4, entry 10),
suggesting once again that the released benzotriazoyl did not un-
dergo further aza-Michael addition to the in situ-formed 4 to afford
type 3 compounds. Diethylamine, a stronger nucleophile than
benzotriazole, was used in excessive amount (Table 4, entry 11), but
Although a thorough mechanistic investigation is pending, the
discrimination of aromatic and aliphatic amines by N-cinna-
moylbenzotriazoles and
a,b-unsaturated aliphatic N-acylbenzo-
triazoles may be tentatively rationalized based on the hard–soft
acid–base (HSAB) theory and steric effect. Aliphatic amines tend to
be hard bases with the unshared electron localized intensely on the
nitrogen atom itself. As such, they attacked predominantly the hard
acid position, i.e., the 2-position of N-cinnamoylbenzotriazole (the
carbonyl carbon), thereby giving rise to cinnamides 4 (Scheme 5,
route a). Also, the relatively bulky aryl group at the 4-position of

X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
6515
Table 5
N-cinnamoylbenzotriazoles disfavored the Michael addition, which
Synthesis of 1,3,4,5-tetrahydro-4-substituted-1,5-benzodiazepine-2-ones 7
could also account for the observed 1,2-addition.
R
O
Aromatic amines behave more like soft bases since the un-
shared electron of the nitrogen atom can delocalize to the phenyl
ring. They are thus prone to attack the soft acid center (the 4-
NH2
NH2
R
Bt
Et3N
HN
NH
+
BtH
+
THF, reflux
O
positon of a,b-unsaturated N-acylbenzotriazoles, the olefinic car-
bon). In other words, the aza-Michael addition was favored for
aromatic amines (Scheme 5, route b). However, the observed aza-
Michael addition of aliphatic amines to N-crotonoylbenzotriazole
(R1¼R2¼alkyl) (Scheme 5, route b) may be attributed to the de-
1r
2
7
Entry
R of 2
Product
Reaction Yielda (%)
time (h)
creased steric hindrance of the 4-position of the a,b-unsaturated
systems and the steric effect may thus exert predominant in-
fluence in this case.
O
Benzotriazolyl group is a good leaving group, therefore, it is
possible for the Michael addition intermediate A to transform into
the ketene intermediate B, in which the ketene forms contact ion
pair with the benzotriazole anion. A subsequent intramolecular
amino attack could take place giving a four-membered cyclic in-
termediate D,19 as shown in route d of Scheme 5. In other words,
the above aza-Michael addition products could undergo in situ
rearrangement via the D-like intermediates to form the product 3.
In this respect, the more nucleophilic aliphatic amines could mi-
grate more readily,20 so when R2 is an alkyl, the rearrangement
would be more favorable than the cases where R2 is an aryl group.
However, it should be noted that the aryl substituent of R1 in in-
termediate B could also facilitate the arylamino group (when
R2¼aryl) migration since in those cases cleavage of a benzylic C–N
bond would be involved. In addition, when R1 in intermediate B is
an alkyl group, the aryl assistance does not exist and the migration
of the less nucleophilic aromatic amino group does not occur.
Hence, the reaction could proceed in a different way, as shown in
route c of Scheme 5, in which the benzotriazole anion attacks the
carbonyl carbon resulting in the formation of the normal Michael
addition product 5 through intermediate C.
1
2a
2c
7ra 12
85
76
HN
HN
NH
O
O
2
7rc 12
NH
O
H3C
O
3
2d
7rd 12
76
H3C
HN
NH
Cl
O
4
2f
7rf 10
81
Cl
HN
NH
2.6. Synthesis of heterocycles from o-phenylenediamine and
a
,b-unsaturated N-acylbenzotriazoles
O2N
Encouraged by the above results, our attention then turned to-
ward applying the procedure to the construction of heterocycles. To
test the feasibility of this strategy, we first chose o-phenylenedi-
O
5
2e
7re
7rh
2
83
80
O2N
HN
NH
amine 1r as the nucleophile to react with a series of
a,b-un-
saturated N-acylbenzotriazoles, as listed in Table 4. Reaction of 1r
with N-cinnamoylbenzotriazole 2a in the presence of Et3N in THF
gave, fortunately, the desired product 7ra in high yield (85%). By the
same procedure, heterocycles 7rc–e were also efficiently prepared
from 1r and the corresponding N-cinnamoylbenzotriazoles 2c–e in
76%, 76%, 81%, and 83% yields, respectively (Table 5, entries 2–5).
Similarly, the amino groups in 1r can also be ring-closed by its
transformation with N-crotonoylbenzotriazole 2h to the 1,3,4,5-
tetrahydro-4-methyl-1,5-benzodiazepine-2-one 7rh in 80% yield. It
should be mentioned here that the 1,5-benzodiazepine ring is often
encountered in biologically active natural products as well as drug
candidates,21 thus the compounds synthesized in Table 5 could be
potential bioactive agents. Therefore, these smooth reactions, to-
gether with the following reactions (as seen in Table 6), provided
a convenient access to biologically interesting heterocycles, which
can be used for further chemical manipulation or biological
screening.
O
HN
NH
6
CH3–
2h
2.5
a
Isolated yields based on a,b-unsaturated N-acylbenzotriazoles.
followed by immediate acylation in the same reaction, or vice
versa.
2.7. Synthesis of heterocycles from o-aminothiophenol and
a
,
b
-unsaturated N-acylbenzotriazoles
It could be concluded from our experimental results that with
two nucleophilic sites available in the same nucleophilic agent, the
The ready formation of 1,5-benzodiazepine derivatives sug-
gested that the present strategy could also be practicable for the
synthesis of other different heterocycles. Hence, o-amino-
thiophenol 1s was chosen as another nucleophile to react with
Michael addition and acylation reaction of
a,b-unsaturated N-
acylbenzotriazoles could proceed concurrently to generate in-
teresting cyclized products. In other words, Michael addition of
several
a,b-unsaturated N-acylbenzotriazoles. The results are
a,b-unsaturated N-acylbenzotriazoles could be accompanied or
summarized in Table 6. As expected, all the reactions worked well

6516
X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
Table 6
carried out either under relatively harsh conditions or using Me3Al
as the reagent.24
Synthesis of 2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-ones 8.
R2
R1
O
3. Conclusion
R2
NH2
SH
S
NH
Et3N
+
BtH
R1
Bt
In summary, we have studied systematically the nucleophilic
+
THF, reflux
additions of
amines and aliphatic amines, and observed versatile reactions.
Unsaturated N-acylbenzotriazoles have been demonstrated to be
useful in the preparation of -benzotriazolyl amides, -amino N-
acylbenzotriazoles, and cinnamides depending on the type of
unsaturated N-acylbenzotriazoles and amines used. Furthermore,
the concurrent 1,4- and 1,2-addition of -unsaturated N-acyl-
a,b-unsaturated N-acylbenzotriazoles with aromatic
O
a,b-
1s
2
8
b
b
Entry
R1
R2
Products
Reaction
time (h)
Yielda
(%)
a,b-
O2N
a,b
benzotriazoles with binucleophiles, o-phenylenediamine and o-
aminothiophenol, was also investigated and the corresponding
biologically interesting seven-membered heterocycles were suc-
cessfully constructed.
O
1
2e
H
8se 10
69
O2N
S
NH
4. Experimental section
4.1. General information
Cl
O
THF was distilled from sodium–benzophenone. Flash chroma-
tography was performed with the indicated solvent system using
2
3
2f
H
H
8sf 10
70
Cl
S
NH
30–60 m
m silica gel. The melting points were uncorrected. 1H NMR
spectra were recorded with 400 MHz instrument using tetrame-
thylsilane as an internal standard, while 13C NMR spectra were
recorded at 100 MHz. High-resolution mass spectra were measured
at UCD, Ireland on a Micromass Quattro. IR spectra were recorded in
film or using KBr disks with a NEXUS 670 FTIR spectrometer. Mass
spectra were recorded on an HP 5989B MS spectrometer. Elemental
O
H3C
S
NH
CH3-–
2h
8sh 10
70
78
analyses were performed on a Vario-ELIII instrument.
a,b-Un-
CH3
saturated N-acylbenzotriazoles were prepared by following the
O
literature procedure.10,25
4
H
2i CH3
8si
4
S
NH
4.2. General procedure for the novel addition of aromatic
amines to N-cinnamoylbenzotriazoles (Table 1)
a
Isolated yields based on a,b-unsaturated N-acylbenzotriazoles.
To a stirred solution of the appropriate N-cinnamoylbenzo-
triazole (1 mmol) and the corresponding aromatic amine
(1.1 mmol) in THF (10 mL) was added triethylamine (1 mL). The
resulting mixture was refluxed until the disappearance of the N-
cinnamoylbenzotriazole, as determined by TLC (typically 18–24 h).
At this time, the mixture was concentrated under reduced pressure
to give a residue, which was then purified by flash column chro-
under the same conditions and led to the desired 2,3-dihy-
drobenzo[b][1,4]thiazepin-4(5H)-ones 8se, 8sf, 8sh, and 8si in very
good yields (69–78%), in which the sulfhydryl group of the
nucleophile attacked the 4-position of
a
,
b-unsaturated N-acyl-
matography (cyclohexane–EtOAc) to afford the corresponding b-
benzotriazoles while the amino group attacked the 2-position. The
resulting seven-membered N,S-heterocycle derivatives were char-
acterized on the basis of their exact mass spectrometries and their
benzotriazolyl amide 3.
4.2.1. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-N-3-diphenyl-
NMR spectroscopic data, which exhibited signals between
d
171
propanamide (3aa)
and 173 ppm in the 13C NMR spectra for the amide carbons. The
chemical shift was in agreement with the literature values for this
type of heterocycles,22 which have 13C NMR chemical shift at 176–
179 ppm for the amide carbons. On the other hand, alternative
attack of o-aminothiophenol, i.e., the sulfhydryl group attacking
Mp 167–169 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.02 (d, J¼8.2 Hz,
1H, ArH), 7.97 (br s, 1H, CONH), 7.46–7.23 (m, 12H, ArH), 7.06–7.03
(m, 1H, ArH), 6.45 (dd, J¼5.2, 10.0 Hz, 1H, H-3), 4.09 (dd, J¼10.0,
15.2 Hz, 1H, H-2a), 3.46 (dd, J¼5.20, 15.2 Hz, 1H, H-2b); 13C NMR
(100 MHz, CDCl3)
d 167.5, 146.0, 138.7, 137.7, 129.1, 129.0, 128.9,
2-position whereas the amino group attacking 4-position of
a
,
b
-
128.6, 127.7, 126.6, 124.5, 124.4, 120.2, 119.6, 110.1, 56.0, 43.6; IR nmax
(KBr) 3299 (NH), 3257, 3138, 3085, 1682 (C]O), 1602 cmꢁ1; EIMS
m/z (%) 342 (0.8, Mþ), 341 (2.1, Mþꢁ1), 266 (3.2, MþꢁPhþ1), 237
(6.1), 223 (5.5), 118 (100, Bt); ESI-HRMS calcd for C21H19N4O
[MþH]þ 343.1559, found 343.1555.
unsaturated N-acylbenzotriazoles, would have led to thioester
functionality, which has 13C NMR chemical shift at much lower field
(w190 ppm). Apparently, our data indicated clearly the formation
of benzothiazepin derivatives 8.
It is worth mentioning here that aromatic ring-fused 1,4-thia-
zepine derivatives represent an important group of compounds
possessing biologically interesting properties.23 Although 2,3-
dihydrobenzo[b][1,4]thiazepin-4(5H)-one scaffold has been con-
structed previously from o-aminothiophenol and cinnamates, two
separate steps were needed and the cyclization step had to be
4.2.2. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(2-chlorophenyl)-
N-phenylpropan-amide (3ab)
Mp 179–180 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.30 (br s,
1H, CONH), 8.00 (d, J¼8.4 Hz, 1H, ArH), 7.56–7.34 (m, 6H, ArH),
7.22–7.02 (m, 7H), 4.06 (dd, J¼10.0, 15.2 Hz, 1H, H-2a), 3.50 (dd,

X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
6517
J¼4.4, 15.2 Hz, 1H, H-2b); 13C NMR (100 MHz, CDCl3)
d
166.9, 146.0,
129.5, 128.3, 127.8, 124.9, 124.3, 120.2, 119.8, 109.6, 58.9, 43.1, 20.9;
136.2, 133.3, 132.4, 130.0, 129.8, 128.9, 128.0, 127.9, 127.7, 124.5,
124.4, 120.0, 119.7, 110.1, 110.0, 56.1, 42.2; IR nmax (KBr) 3274 (NH),
3065, 1687 (C]O), 1599 cmꢁ1; ESI-HRMS calcd for C21H18N4OCl
[MþH]þ 377.1169, found 377.1185.
IR nmax (KBr) 3122, 1668 (C]O), 1609 cmꢁ1; ESI-HRMS calcd for
C
22H20N5O3 [MþH]þ 402.1566, found 402.1560.
4.2.8. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-phenyl-N-m-tolyl-
propanamide (3ca)
4.2.3. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(furan-2-yl)-N-phenyl-
Mp 158–160 ꢀC; 1H NMR (400 MHz, DMSO)
d 10.13 (br s, 1H,
propanamide (3ac)
CONH), 7.99 (d, J¼8.0 Hz, 1H, ArH), 7.90 (d, J¼8.0 Hz, 1H, ArH), 7.50–
7.44 (m, 3H, ArH), 7.38–7.22 (m, 6H, ArH), 7.12 (t, J¼8.0 Hz,1H, ArH),
6.79 (d, J¼7.2 Hz, 1H, ArH), 6.58 (dd, J¼5.2, 10.0 Hz, 1H, H-3), 3.92
(dd, J¼10.0, 15.6 Hz, 1H, H-2a), 3.49 (dd, J¼5.2, 15.6 Hz, 1H, H-2b),
Mp 193–195 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.50 (br s, 1H,
CONH), 8.02 (t, J¼8.4 Hz, 1H, ArH), 7.69 (d, J¼8.4 Hz, 1H, ArH), 7.51–
7.22 (m, 7H, ArH), 7.08–7.04 (m, 1H, ArH), 6.62–6.61 (m, 1H, H-3),
6.37–6.35 (m, 1H, ArH), 6.29–6.26 (m, 1H, ArH), 4.62–3.95 (m, 1H,
H-2a), 3.74 (dd, J¼5.6, 15.2 Hz, 1H, H-2b); 13C NMR (100 MHz,
2.19 (s, 3H, Me); 13C NMR (100 MHz, DMSO)
d 167.7, 145.7, 139.5,
139.3, 138.4, 133.2, 129.3, 129.0, 128.7, 127.9, 127.3, 124.7, 124.4,
119.9, 119.6, 116.6, 111.3, 58.9, 41.9, 21.6; IR nmax (KBr) 3140,
1681(C]O), 1614 cmꢁ1; ESI-HRMS calcd for C22H21N4O [MþH]þ
357.1715, found 357.1700.
CDCl3)
d 167.2, 151.3, 145.6, 144.0, 139.2, 133.0, 129.2, 127.9, 124.6,
123.8, 119.7, 119.5, 111.3, 111.1, 108.9, 52.9, 39.0; IR nmax (KBr)
3309 (NH), 3271, 2918, 2853, 1685 (C]O), 1602, 1544 cmꢁ1; EIMS
m/z (%) 332 (5.8, Mþ), 331 (19.4, Mþꢁ1), 213 (7.8), 170 (21.8), 118
(100, Bt); ESI-HRMS calcd for C19H17N4O2 [MþH]þ 333.1352, found
333.1344.
4.2.9. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(4-chlorophenyl)-
N-m-tolylpropanamide (3cf)
Mp 173–175 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.90 (br s, 1H,
4.2.4. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-phenyl-N-p-tolyl-
CONH), 8.01 (d, J¼8.4 Hz, 1H, ArH), 7.53 (d, J¼8.4 Hz, 1H, ArH), 7.46–
7.21 (m, 8H, ArH), 7.15–7.13 (m, 1H, ArH), 6.87 (d, J¼7.2 Hz, 1H, ArH),
6.51 (dd, J¼6.4, 8.0 Hz,1H, H-2a), 4.09 (dd, J¼8.4, 16.6 Hz,1H, H-2b),
3.73 (dd, J¼6.4, 15.2 Hz, 1H, CH), 2.26 (s, 3H, Me); 13C NMR
propanamide (3ba)
Mp 207–209 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.42 (br s, 1H,
CONH), 8.00 (d, J¼8.0 Hz, 1H, ArH), 7.51–7.26 (m, 10H, ArH), 7.03 (d,
J¼8.0 Hz, 2H, ArH), 6.48 (dd, J¼5.6, 8.8 Hz, 1H, CH, H-3), 4.10 (dd,
J¼9.2, 15.2 Hz, 1H, CH, H-2a), 3.60 (dd, J¼5.6, 15.2 Hz, 1H, CH, H-2b),
(100 MHz, CDCl3)
d 167.2, 145.9, 138.8, 137.7, 137.1, 134.6, 133.1,
129.3, 128.7, 128.2, 127.9, 125.3, 124.7, 120.8, 119.6, 117.2, 110.0,
2.26 (s, 3H, Me); 13C NMR (100 MHz, CDCl3)
d
167.2, 146.1, 138.7,
59.1, 43.3, 21.4; IR nmax (KBr) 3327 (NH), 1693 (C]O), 1590 cmꢁ1
;
134.9, 134.2, 133.2, 129.4, 129.1, 128.6, 127.6, 126.5, 124.3, 120.2,
119.8, 110.0, 60.0, 43.9, 20.8; IR nmax (KBr) 3303 (NH), 3267, 3197,
3127, 3066, 1683 (C]O), 1603, 1542 cmꢁ1; ESI-HRMS calcd for
ESI-HRMS calcd for
391.1311.
C
22H20ClN4O [MþH]þ 391.1326, found
C
22H21N4O [MþH]þ 357.1715, found 357.1702.
4.2.10. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(4-chlorophenyl)-N-
o-tolylpropanamide (3df)
4.2.5. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-N-3-di-p-tolyl-
Mp 211–213 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.01 (d, J¼8.4 Hz,
propanamide (3bd)
1H, ArH), 7.76 (br s, 1H, CONH), 7.49–7.42 (m, 3H, ArH), 7.36–7.26
(m, 5H, ArH), 7.12–7.10 (m, 2H, ArH), 7.06–7.04 (m, 1H, ArH), 6.42
(dd, J¼5.2, 9.6 Hz, 1H, H-3), 4.05 (dd, J¼5.6, 14.4 Hz, 1H, H-2a), 3.49
(dd, J¼5.2, 14.4 Hz, 1H, H-2b), 2.05 (s, 3H, Me); 13C NMR (100 MHz,
Mp 174–176 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.37 (br s, 1H,
CONH), 8.00 (d, J¼4.0 Hz, 1H, ArH), 7.50–7.48 (m, 1H, ArH), 7.43–
7.39 (m, 1H, ArH), 7.34–7.24 (m, 5H, ArH), 7.09–7.02 (m, 4H, ArH),
6.43 (dd, J¼4.0, 8.0 Hz, 1H, H-3), 4.06 (dd, J¼4.0, 8.0 Hz, 1H, H-2a),
3.54 (dd, J¼4.0, 7.6 Hz, 1H, Hꢁ2b), 2.27 (s, 3H, Me), 2.26 (s, 3H, Me);
CDCl3)
d 167.2, 146.1, 137.1, 135.0, 134.7, 133.0, 130.6, 130.4, 129.4,
128.0, 127.9, 126.6, 125.8, 124.5, 123.8, 119.9, 109.8, 59.4, 43.6, 17.6;
13C NMR (100 MHz, CDCl3)
d
167.5, 145.9, 138.4, 135.7, 135.4, 133.9,
IR nmax (KBr) 3257 (NH), 3185, 3097, 1680 (C]O), 1600, 1521 cmꢁ1
;
133.2, 129.7, 129.3, 127.6, 126.6, 124.4, 120.2, 119.5, 110.2, 59.8, 43.4,
21.1, 20.8; IR nmax (KBr) 3309 (NH), 3271, 3131, 3072, 1686
(C]O), 1608 cmꢁ1; EIMS m/z (%) 369 (9.4, Mþꢁ1), 212 (4.3), 118
(100, Bt); ESI-HRMS calcd for C23H23N4O [MþH]þ 371.1872, found
371.1868.
ESI-HRMS calcd for C22H20ClN4O [MþH]þ 391.1326, found 391.1323.
4.2.11. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-N-(4-methoxyphenyl)-
3-(4-nitrophenyl)propanamide (3ee)
Mp 200–202 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.16 (d, J¼8.8 Hz,
2H, ArH), 8.08 (br s, 1H, CONH), 8.05 (d, J¼8.4 Hz, 1H, ArH), 7.54–
7.34 (m, 5H, ArH), 7.30–7.26 (m, 2H, ArH), 6.79 (d, J¼8.8 Hz, 2H,
ArH), 6.59 (dd, J¼5.6, 8.4 Hz, 1H, H-3), 4.04 (dd, J¼8.8, 15.2 Hz, 1H,
H-2a), 3.75 (s, 3H, Me), 3.58 (dd, J¼6.0, 15.2 Hz, 1H, H-2b); 13C NMR
4.2.6. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(2-chlorophenyl)-N-p-
tolylpropanamide (3bb)
Mp 205–207 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.01 (d, J¼8.4 Hz,
1H, ArH), 7.95 (br s, 1H, CONH), 7.55 (d, J¼8.0 Hz, 1H, ArH), 7.43–
7.42 (m, 2H, ArH), 7.34 (t, J¼8.0 Hz, 1H, ArH), 7.27–7.12 (m, 5H, ArH),
7.03–6.98 (m, 3H), 4.00 (dd, J¼10.8, 14.8 Hz, 1H, H-2a), 3.44 (dd,
J¼13.2, 25.6 Hz, 1H, H-2b), 2.25 (s, 3H, Me); 13C NMR (100 MHz,
(100 MHz, CDCl3) d 166.3, 156.8, 145.5, 130.2, 128.2, 127.7, 124.8,
124.4, 122.1, 120.0, 114.2, 109.5, 59.0, 55.5, 43.3; IR nmax (KBr)
3245(NH), 3133, 2835, 1674 (C]O), 1607 cmꢁ1; ESI-HRMS calcd for
C
22H20N5O4 [MþH]þ 418.1515, found 418.1533.
CDCl3)
d 166.8, 145.9, 136.2, 135.1, 134.0, 133.3, 132.5, 130.0, 129.8,
129.3, 128.0, 127.9, 127.7, 124.5, 120.1, 119.6, 110.2, 56.0, 42.1, 20.8; IR
nmax (KBr) 3368 (NH), 3120, 1685(C]O), 1600, 1536 cmꢁ1; ESI-
HRMS calcd for C22H20ClN4O [MþH]þ 391.1326, found 391.1320.
4.2.12. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(4-chlorophenyl)-
N-(naphthalen-1-yl)propanamide (3ff)
Mp 230–232 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.23 (br s, 1H,
CONH), 8.00 (d, J¼8.0 Hz, 1H, ArH), 7.80 (d, J¼8.0 Hz, 1H, ArH), 7.68
(d, J¼8.0 Hz, 1H, ArH), 7.60 (d, J¼8.0 Hz, 1H, ArH), 7.50 (d, J¼8.0 Hz,
1H, ArH), 7.46–7.29 (m, 10H, ArH), 6.46 (dd, J¼8.0, 16.0 Hz, 1H, H-3),
4.16 (dd, J¼8.0, 16.0 Hz, 1H, H-2a), 3.67 (dd, J¼8.0, 16.0 Hz, 1H, H-
4.2.7. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(4-nitrophenyl)-
N-p-tolylpropanamide (3be)
Mp 184–186 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.75 (br s, 1H,
CONH), 8.11 (d, J¼8.0 Hz, 2H, ArH), 8.01 (d, J¼8.0 Hz, 1H, ArH), 7.56–
7.46 (m, 4H, ArH), 7.41–7.31 (m, 3H, ArH), 7.05 (d, J¼8.0 Hz, 2H,
ArH), 6.63 (dd, J¼4.0, 4.0 Hz, 1H, H-3), 4.10 (dd, J¼8.0, 16.0 Hz, 1H,
H-2a), 3.77 (dd, J¼4.0, 16.0 Hz, 1H, H-2b), 2.27 (s, 3H, Me); 13C NMR
2b); 13C NMR (100 MHz, CDCl3)
d 168.0, 146.0, 137.1, 135.9, 135.2,
133.4, 131.7, 129.4, 128.5, 128.1, 127.9, 126.6, 126.5, 126.1, 125.5,
124.5, 121.4, 122.0, 121.1, 119.9, 109.8, 59.6, 43.7; IR nmax (KBr) 3220
(NH), 3061, 2963, 1680 (C]O), 1596, 1509 cmꢁ1; ESI-HRMS calcd
for C25H20ClN4O [MþH]þ 427.1326, found 427.1327.
(100 MHz, CDCl3)
d 166.5, 147.9, 145.9, 145.4, 134.9, 134.5, 133.1,

6518
X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
4.2.13. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-N-(4-chlorophenyl)-3-
J¼8.0 Hz, 1H, ArH), 5.56–5.51 (m, 1H, H-3), 3.40–3.14 (m, 5H,
2ꢂCH2, H-2a), 2.95 (dd, J¼5.6, 15.6 Hz, 1H, H-2b), 1.77 (d, J¼6.8 Hz,
3H, Me), 1.12 (t, J¼7.2 Hz, 3H, Me), 0.88 (t, J¼7.2 Hz, 3H, Me); 13C
phenylpropanamide (3ga)
Mp decomposed beyond 219 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.29
(br s,1H, CONH), 8.01 (d, J¼8.0 Hz,1H, ArH), 7.55–7.26 (m,11H, ArH),
7.19 (d, J¼8.8 Hz, 1H, ArH), 6.43 (dd, J¼5.2, 9.6 Hz, 1H, H-3), 4.11 (dd,
J¼9.6,14.8 Hz,1H, H-2a), 3.49 (dd, J¼4.4,14.8 Hz,1H, H-2b); 13C NMR
NMR (100 MHz, CDCl3) d 168.5, 145.6, 132.9, 127.1, 123.9, 119.6,
110.0, 52.1, 42.0, 40.3, 39.6, 21.3, 14.3, 12.7; IR nmax (KBr) 2988, 2970,
2931, 1633 (C]O) cmꢁ1; EIMS m/z (%) 260 (5.7, Mþ), 160 (89.8), 132
(100), 118 (96.1, Bt), 72 (100, Et2N). Anal. Calcd for C14H20N4O: C,
64.59; H, 7.74; N, 21.52. Found: C, 64.30; H, 7.85; N, 21.63.
(100 MHz, DMSO)
d 168.0, 145.7, 139.4, 138.2, 133.2, 129.3, 129.1,
128.8, 127.9, 127.3, 127.2, 124.7, 121.0, 120.0, 111.3, 58.8, 42.0. IR nmax
(KBr) 3262 (NH), 3193, 3123, 3063, 1684 (C]O), 1609, 1547 cmꢁ1
;
ESI-HRMS calcd for C21H18ClN4O [MþH]þ 377.1169, found 377.1151.
4.4. General procedure for the aza-Michael addition of
aromatic amines to
a,b-unsaturated aliphatic N-acyl-
4.3. General procedure for the novel addition of aliphatic
benzotriazoles (Table 3)
amines to N-crotonoyl benzotriazoles (Table 2)
To a stirred solution of the appropriate a,b-unsaturated aliphatic
N-Crotonoylbenzotriazole (1 mmol) and the corresponding ali-
phatic amine (1.1 mmol) were mixed and stirred at room temper-
ature. After completion of the reaction in 5 min as determined by
TLC, the reaction mixture was directly purified by flash column
chromatography (cyclohexane–EtOAc) to afford the corresponding
N-acylbenzotriazole (1 mmol) and the corresponding aliphatic
amine (1.1 mmol) in THF (10 mL) was added triethylamine (1 mL).
The resulting mixture was stirred at room temperature for the in-
dicated time (monitored by TLC) and then concentrated under re-
duced pressure to give a residue, which was then purified by flash
column chromatography (cyclohexane–EtOAc) to afford the corre-
b-benzotriazolyl amide 3.
sponding b-amino-N-acylbenzotriazole 5.
4.3.1. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-(piperidin-1-yl)butan-
1-one (3oh)
4.4.1. 3-(p-Toluidino)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-butan-1-
one (5bh)
Oil; 1H NMR (400 MHz, CDCl3)
d
8.03 (d, J¼8.4 Hz, 1H, ArH), 7.66
(d, J¼8.4 Hz, 1H, ArH), 7.48 (t, J¼7.6 Hz, 1H, ArH), 7.35 (t, J¼7.6 Hz,
1H, ArH), 5.52–5.47 (m, 1H, H-3), 3.43–3.29 (m, 5H), 2.96 (dd, J¼6.0,
16.0 Hz, H-2b), 1.76 (d, J¼6.8 Hz, 3H, Me), 1.57–1.47 (m, 4H), 1.33–
Mp 131–133 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.24 (d, J¼8.4 Hz,
1H, ArH), 8.09 (d, J¼8.4 Hz, 1H, ArH), 7.61 (t, J¼8.0 Hz, 1H, ArH), 7.47
(d, J¼8.0 Hz, 1H, ArH), 6.94 (d, J¼7.2 Hz, 2H, ArH), 6.59 (d, J¼8.0 Hz,
2H, ArH), 4.32–4.27 (m, 1H, CH, H-3), 3.78 (dd, J¼6.0,15.2 Hz,1H, H-
2a), 3.42 (dd, J¼6.4, 15.2 Hz, 1H, H-2b), 2.18 (s, 3H, Me), 1.39 (d,
1.26 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 167.6, 145.7, 132.8, 127.2,
123.9,119.6, 110.0, 52.1, 46.6, 42.8, 39.5, 26.3, 25.4, 24.3, 21.5; IR nmax
(neat) 2938, 2858, 1642 (C]O), 1550 cmꢁ1; EIMS m/z (%) 272 (12.8,
Mþ), 160 (47.8), 146 (39.2), 132 (100), 118 (72.9, Bt), 84 (100,
piperidyl). Anal. Calcd for C15H20N4O: C, 66.15; H, 7.40; N, 20.57.
Found: C, 65.85; H, 7.49; N, 20.35.
J¼6.4 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3)
d 168.0, 145.4, 135.4,
134.0, 132.9, 129.4, 127.5, 124.4, 120.3, 119.4, 110.0, 52.2, 43.8, 20.9,
20.1; IR nmax (KBr) 3303 (NH), 3266, 3193, 3121, 3064, 2937, 2919,
1688 (C]O), 1606 cmꢁ1; EIMS m/z (%) 294 (70.2, Mþ), 188 (100,
Mþꢁp-CH3C6H4NH), 160 (100), 132 (100), 118 (78.2, Bt), 106 (100),
91 (100); ESI-HRMS calcd for C17H19N4O [MþH]þ 295.1559, found
295.1557.
4.3.2. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-N-phenethylbutanamide
(3lh)
Oil; 1H NMR (400 MHz, CDCl3)
d
7.98 (d, J¼8.4 Hz, 1H, ArH), 7.64
(d, J¼8.4 Hz, 1H, ArH), 7.48 (t, J¼8.0 Hz, 1H, ArH), 7.35 (t, J¼7.6 Hz,
1H, ArH), 7.22–7.14 (m, 3H, ArH), 6.97 (d, J¼6.8 Hz, 2H, ArH), 6.31
(br s, 1H, CONH), 5.46–5.41 (m, 1H, H-3), 3.37–3.30 (m, 2H, CH2),
3.08 (dd, J¼8.4, 14.8 Hz, 1H, H-2a), 2.92 (dd, J¼6.0, 14.8 Hz, 1H, H-
2b), 2.56–2.47 (m, 2H, CH2), 1.71 (d, J¼6.8 Hz, 3H, Me); 13C NMR
4.4.2. 1-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(4-methoxyphenyl-
amino)butan-1-one (5eh)
Oil; 1H NMR (400 MHz, CDCl3)
d
8.27 (d, J¼8.4 Hz, 1H, ArH), 8.11
(d, J¼8.4 Hz, 1H, ArH), 7.65 (t, J¼7.2 Hz, 1H, ArH), 7.51 (t, J¼8.0 Hz,
1H, ArH), 6.75–6.71 (m, 2H, ArH), 6.67–6.64 (m, 2H, ArH), 4.26–4.24
(m, 1H, H-3), 3.80 (dd, J¼6.4, 15.2 Hz, 1H, H-2a), 3.70 (s, 3H, Me),
3.42 (dd, J¼6.8, 15.2 Hz, 1H, H-2b), 1.40 (d, J¼6.4 Hz, 3H, Me); 13C
(100 MHz, CDCl3)
d 169.4, 145.6, 138.6, 132.9, 128.6, 128.5, 127.4,
126.4, 124.2, 119.6, 110.0, 52.2, 43.4, 40.7, 35.4, 21.1; IR nmax (neat)
3304 (NH), 3066, 3029, 2978, 2931, 1669 (C]O), 1549 cmꢁ1; EIMS
m/z (%) 308 (65.8, Mþ), 188 (100, MþꢁPhCH2CH2NH), 118 (100, Bt).
Anal. Calcd for C18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C,
69.06; H, 6.65; N, 18.20.
NMR (100 MHz, CDCl3)
d 171.0, 146.2, 140.5, 131.0, 130.5, 126.3,
125.8, 120.1, 115.8, 115.0, 114.5, 55.7, 47.9, 42,3, 21.1; IR nmax (KBr)
3236 (NH), 3178, 3065, 2830, 1691 (C]O), 1603 cmꢁ1; ESI-HRMS
calcd for C17H19N4O [MþH]þ 311.1508, found 311.1562.
4.3.3. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-N-butylbutanamide (3nh)
4.4.3. 3-(p-Toluidino)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-2-methyl-
propan-1-one (5bi)
Oil; 1H NMR (400 MHz, CDCl3)
d
7.99 (d, J¼8.4 Hz, 1H, ArH), 7.66
(d, J¼8.4 Hz, 1H, ArH), 7.48 (t, J¼7.2 Hz, 1H, ArH), 7.36 (t, J¼7.6 Hz,
1H, ArH), 6.61 (br s, 1H, CONH), 5.49–5.45 (m, 1H, H-3), 3.20–2.98
(m, 4H, CH2, H-2a, H-2b), 1.75 (d, J¼6.8 Hz, 3H, Me), 1.21–1.16 (m,
2H, CH2), 1.12–1.04 (m, 2H, CH2), 0.74 (t, J¼7.2 Hz, 3H, Me); 13C NMR
Mp 100–102 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.28 (d, J¼8.0 Hz,
1H, ArH), 8.11 (d, J¼8.0 Hz, 1H, ArH), 7.65 (t, J¼8.0 Hz, 1H, ArH), 7.50
(t, J¼8.0 Hz, 1H, ArH), 6.94 (d, J¼8.0 Hz, 2H, ArH), 6.55 (d, J¼8.4 Hz,
2H, ArH), 4.48–4.43 (m, 1H, CH, H-3), 3.88 (br s, 1H, NH), 3.77 (dd,
J¼8.0, 16.0 Hz, 1H, CH, H-2a), 3.44 (dd, J¼8.0, 16.0 Hz, 1H, CH, H-2b),
2.19 (s, 3H, Me), 1.49 (d, J¼8.0, 3H, Me); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d 169.4, 145.5, 132.9, 127.3, 124.2, 119.4, 110.0,
52.4, 43.5, 39.2, 31.2, 21.1, 19.8, 13.6; IR nmax (neat) 3307 (NH), 3073,
2960, 2932, 2873, 1666 (C]O), 1551 cmꢁ1; EIMS m/z (%) 261 (1.0,
Mþþ1), 160 (26.2), 146 (11.3), 132 (80.0), 118 (100, Bt), 57 (65.3, n-
Bu). Anal. Calcd for C14H20N4O: C, 64.59; H, 7.74; N, 21.52. Found: C,
63.90; H, 7.86; N, 21.26.
d
175.0, 146.2, 145.1, 131.2, 130.4, 129.8, 127.2, 126.2, 120.2, 114.6,
113.2, 47.5, 39.6, 20.3, 15.4; IR nmax (KBr) 3398 (NH), 3134, 1729
(C]O), 1619 cmꢁ1
295.1559, found 295.1545.
;
ESI-HRMS calcd for C17H19N4O [MþH]þ
4.3.4. 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-N,N-diethylbutanamide
4.4.4. 1-(1H-Benzo[d][1,2,3]triazol-1-yl)-3-(4-chlorophenylamino)-
(3qh)
2-methylpropan-1-one (5gi)
Mp 78–80 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.02 (d, J¼8.4 Hz, 1H,
Mp 105–107 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.27 (d, J¼8.4 Hz,
ArH), 7.67 (d, J¼8.4 Hz, 1H, ArH), 7.48 (t, J¼7.6 Hz, 1H, ArH), 7.35 (t,
1H, ArH), 8.12 (d, J¼8.4 Hz, 1H, ArH), 7.67 (t, J¼7.6 Hz, 1H, ArH), 7.52

X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
6519
(t, J¼8.0 Hz, 1H, ArH), 7.07 (d, J¼8.8 Hz, 2H, ArH), 6.55 (d, J¼8.4 Hz,
2H, ArH), 4.48–4.42 (m, 1H, H-3), 4.05 (br s, 1H, NH), 3.80–3.73 (m,
1H, H-2a), 3.47–3.41 (m, 1H, H-2b), 1.49 (d, J¼7.2 Hz, 3H, Me); 13C
1.72 (m, 2H, Cy), 1.43–1.36 (m, 2H, Cy), 1.25–1.14 (m, 4H, Cy); 13C
NMR (100 MHz, CDCl3) 165.1, 140.6, 139.8, 132.2, 129.5, 127.7,
120.1, 48.3, 33.3, 25.6, 24.9, 21.4; IR nmax (KBr) 3288 (NH), 3072,
3025, 2927, 2853, 1660 (C]O), 1618, 1553 cmꢁ1; EIMS m/z (%) 244
(26.2, Mþþ1), 243 (75.5, Mþ), 160 (100, MþꢁCy); ESI-HRMS calcd
for C16H22NO [MþH]þ 244.1701, found 244.1690.
d
NMR (100 MHz, CDCl3) d 174.8,146.2,145.9,131.1,130.6,129.1,126.4,
122.5, 120.2, 114.5, 114.0, 47.1, 39.5, 15.4; IR nmax (KBr) 3393 (NH),
3128, 1728 (C]O), 1601 cmꢁ1; ESI-HRMS calcd for C16H16ClN4O
[MþH]þ 315.1013, found 315.1007.
4.6.2. (E)-3-(4-Chlorophenyl)-N-phenethylacrylamide (4lf)
4.4.5. 3-(m-Toluidino)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-2-
methylpropan-1-one (5ci)
Mp 174–176 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.57 (d, J¼15.6 Hz,
1H, C]CH), 7.40 (m, 3H, ArH), 7.35–7.22 (m, 6H, ArH), 6.28 (d,
J¼15.6 Hz, 1H, C]CH), 5.60 (br s, 1H, CONH), 3.67 (q, J¼6.8 Hz, 2H),
Mp 78–80 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.28 (d, J¼8.4 Hz, 1H,
ArH), 8.11 (d, J¼8.0 Hz, 1H, ArH), 7.64 (t, J¼8.0 Hz, 1H, ArH), 7.50 (t,
J¼8.0 Hz, 1H, ArH), 7.05–7.01 (m, 1H, ArH), 6.50–6.44 (m, 3H, ArH),
4.48–4.43 (m, 1H, H-3), 3.99 (br s, 1H, NH), 3.78 (dd, J¼8.0, 16.0 Hz,
1H, H-2a), 3.46 (dd, J¼4.0, 12.0 Hz, 1H, H-2b), 2.23 (s, 3H, Me), 1.50
2.89 (t, J¼6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 165.6, 139.7,
138.8, 135.5, 133.3, 129.1, 128.9, 128.7, 128.6, 126.6, 121.2, 40.8, 35.6;
IR nmax (KBr) 3309 (NH), 3085, 3032, 2925, 2853, 1655 (C]O), 1623,
1550 cmꢁ1; ESI-HRMS calcd for C17H17ClNO [MþH]þ 286.0999,
found 286.0989.
(d, J¼4.0 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3)
d 175.0, 147.4,
146.2, 139.1, 131.2, 130.5, 129.2, 126.3, 120.2, 118.8, 114.6, 113.7, 110.1,
47.1, 39.6, 21.6, 15.4; IR nmax (KBr) 3388 (NH), 3116, 3036, 2979, 1732
4.6.3. (E)-3-(4-Methoxyphenyl)-N-propylacrylamide (4mg)
(C]O), 1605 cmꢁ1
;
ESI-HRMS calcd for C17H19N4O [MþH]þ
Mp 104–106 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.57 (d, J¼15.6 Hz,
295.1559, found 295.1563.
1H, C]CH), 7.42 (d, J¼8.0 Hz, 2H, ArH), 6.87–6.84 (m, 2H, ArH),
6.34–6.29 (m, 1H, C]CH), 6.02 (br s, 1H, CONH), 3.80 (s, 3H, Me),
4.5. Typical procedure for the acylation of p-anisidine with
amino-N-acylbenzotriazole 5ci
b
-
3.34 (q, J¼6.8 Hz, 2H), 1.62–1.56 (m, 2H), 0.95 (t, J¼7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3)
d 166.4, 160.8, 140.2, 129.3, 127.7, 118.6,
114.2, 55.3, 41.5, 23.0, 11.4; IR nmax (KBr) 3268 (NH), 3072, 2966,
To 10 mL of dry THF were added ZnCl2 (0.014 g, 0.1 mmol), p-
anisidine (0.068 g, 0.55 mmol), and -amino-N-acylbenzotriazole
2934, 2871, 1657 (C]O), 1605, 1554 cmꢁ1; ESI-HRMS calcd for
C
b
13H18NO2 [MþH]þ 220.1338, found 220.1327.
5ci (0.147 g, 0.5 mmol). The mixture was stirred at room tempera-
ture for 1 h and dilute hydrochloric acid (0.3 N, 5 mL) was added.
The resulting mixture was extracted with ethyl acetate (10 mLꢂ3),
and the combined organic layer was washed by saturated Na2CO3
and then by brine. Removal of the solvent and purification by flash
column chromatography (cyclohexane–EtOAc 4:1) afforded 0.122 g
of compound 6 (82% yield).
4.6.4. (E)-N-Butyl-3-(4-chlorophenyl)acrylamide (4nf)
Mp 115–117 ꢀC (lit.26 115–116 ꢀC); 1H NMR (400 MHz, CDCl3)
d
7.56 (d, J¼15.6 Hz, 1H, C]CH), 7.41 (d, J¼8.0 Hz, 2H, ArH), 7.32 (d,
J¼8.0 Hz, 2H, ArH), 6.37 (d, J¼15.6 Hz, 1H, C]CH), 5.99 (br s, 1H,
CONH), 3.39 (q, J¼6.8 Hz, 2H), 1.59–1.52 (m, 2H), 1.44–1.36 (m, 2H),
0.94 (t, J¼7.2 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3)
d 165.7,
139.4, 135.4, 133.4, 129.0, 128.9, 121.5, 39.6, 31.7, 20.1, 13.8; IR nmax
(KBr) 3297 (NH), 3068, 2960, 2933, 2871, 1653 (C]O), 1618,
4.5.1. 3-(m-Toluidino)-N-(4-methoxyphenyl)-2-methyl-
propanamide (6)
1547 cmꢁ1
.
Mp 117–119 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.56 (br s, 1H,
CONH), 7.35 (d, J¼8.8 Hz, 2H, ArH), 7.08 (t, J¼8.0 Hz, 1H, ArH), 6.82
(d, J¼8.8 Hz, 2H, ArH), 6.57 (d, J¼7.6 Hz, 1H, ArH), 6.45–6.46 (m, 2H,
ArH), 3.77 (s, 3H, Me), 3.41 (dd, J¼9.2, 10.2 Hz, 1H, H-3a), 3.46 (dd,
J¼4.4, 9.9 Hz, 1H, H-3b), 2.74–2.69 (m, 1H, H-2), 2.28 (s, 3H, Me),
4.6.5. (E)-3-(4-Nitrophenyl)-N-propylacrylamide (4me)
Mp 124–126 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.22 (d, J¼8.8 Hz,
2H, ArH), 7.69–7.63 (m, 3H), 6.54 (d, J¼15.6 Hz, 1H, C]CH), 5.85 (br
s, 1H, CONH), 3.38 (q, J¼6.8 Hz, 2H), 1.64–1.59 (m, 2H), 0.98 (t,
1.28 (d, J¼6.8 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3)
d
173.2, 156.4,
J¼7.6 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3)
d 164.8, 148.2, 141.2,
147.5, 139.3, 130.9, 129.3, 121.8, 119.1, 114.2, 114.1, 110.5, 55.5, 47.7,
41.1, 21.6, 15.5; IR nmax (KBr) 3375 (NH), 3128 (NH), 1644 (C]O),
1607, 1607, 1400 cmꢁ1. Anal. Calcd for C18H22N2O2: C, 72.46; H, 7.43;
N, 9.39. Found: C, 72.56; H, 7.48; N, 9.36.
138.2, 128.2, 125.0, 124.0, 41.6, 22.7, 11.4; IR nmax (KBr) 3255 (NH),
3075, 2963, 2923, 2880, 1658 (C]O), 1623, 1555 cmꢁ1; ESI-HRMS
calcd for C12H15N2O3 [MþH]þ 235.1083, found 235.1071.
4.6.6. (E)-3-Phenyl-1-(piperidin-1-yl)prop-2-en-1-one (4oa)
4.6. General procedure for the acylation of aliphatic amines
Mp 116–118 ꢀC (lit.27 114–117 ꢀC); 1H NMR (400 MHz, CDCl3)
with N-cinnamoylbenzotriazoles (Table 4)
d
7.64 (d, J¼15.6 Hz, 1H, C]CH), 7.52 (d, J¼7.6 Hz, 2H, ArH), 7.38–
7.27 (m, 3H, ArH), 6.90 (d, J¼15.6 Hz, 1H, C]CH), 3.66–3.59 (m, 4H),
1.69–1.61 (m, 6H); 13C NMR (100 MHz, CDCl3)
165.4, 142.1, 135.5,
To a stirred solution of the appropriate N-cinnamoylbenzo-
triazole (1 mmol) and the corresponding aliphatic amine
(1.1 mmol) in THF (10 mL) was added triethylamine (1 mL). The
resulting mixture was refluxed for the indicated time (monitored
by TLC), then diluted with Et2O (60 mL), and washed with saturated
aqueous NaHCO3. The organic layer was dried over MgSO4 and
concentrated in vacuo to give a residue, which was either recrys-
tallized from EtOH or purified by flash column chromatography
d
129.4, 128.8, 127.7, 117.8, 47.0, 43.4, 26.8, 25.6, 24.7; IR nmax (KBr)
3027, 2935, 2856, 1645 (C]O), 1589 cmꢁ1; ESI-HRMS calcd for
C
14H18NO [MþH]þ 216.1388, found 216.1381.
4.6.7. (E)-1-Morpholino-3-phenylprop-2-en-1-one (4pa)
Mp 64–66 ꢀC (lit.28 65 ꢀC); 1H NMR (400 MHz, CDCl3)
d 7.71 (d,
J¼15.6 Hz, 1H, C]CH), 7.55–7.52 (m, 2H, ArH), 7.40–7.37 (m, 3H,
(cyclohexane–EtOAc) to afford the corresponding a,b-unsaturated
amide 4.
ArH), 6.86 (d, J¼15.6 Hz, 1H, C]CH), 3.74–3.70 (m, 8H); 13C NMR
(100 MHz, CDCl3) d 165.6, 143.2, 135.1, 129.8, 128.8, 127.8, 116.6,
66.9; IR nmax (KBr) 2965, 2923, 2857, 1650 (C]O), 1599 cmꢁ1
.
4.6.1. (E)-N-Cyclohexyl-3-p-tolylacrylamide (4kd)
Mp 165–167 ꢀC; 1H NMR (400 MHz, CDCl3)
1H, C]CH), 7.39 (d, J¼8.0 Hz, 2H, ArH), 7.16 (d, J¼8.0 Hz, 2H, ArH),
6.31 (d, J¼15.6 Hz, 1H, C]CH), 5.44 (br, d, J¼6.4 Hz, 1H, CONH),
3.92–3.90 (m, 1H, CH), 2.36 (s, 3H, Me), 2.00–1.97 (m, 2H, Cy), 1.75–
d
7.57 (d, J¼15.6 Hz,
4.6.8. (E)-3-(4-Chlorophenyl)-N,N-diethylacrylamide (4qf)
Oil;29 1H NMR (400 MHz, CDCl3)
d
7.65 (d, J¼15.6 Hz,1H, C]CH),
7.46 (d, J¼8.4 Hz, 2H, ArH), 7.33 (d, J¼8.4 Hz, 2H, ArH), 6.80 (d,
J¼15.6 Hz, 1H, C]CH), 3.50–3.44 (m, 4H), 1.27–1.17 (m, 6H); 13C

6520
X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
NMR (100 MHz, CDCl3)
d
165.4, 140.8, 135.2, 134.0, 129.0, 128.9,
J¼7.6 Hz, 1H, ArH), 5.05 (t, J¼6.4 Hz, 1H, H-4), 3.79 (br s, 1H, NH),
118.4, 42.3, 41.1, 15.1, 13.2; IR nmax (KBr) 3075, 2990, 1660 (C]O),
1615, 1580 cmꢁ1
2.82 (d, J¼6.8 Hz, 2H, H-3); 13C NMR (100 MHz, CDCl3)
d 171.9,
.
142.5, 138.2, 133.9, 129.1, 128.0, 127.4, 126.3, 122.5, 121.9, 121.3, 62.9,
41.5; IR nmax (KBr) 3291 (NH), 3220, 3045, 2959, 1670 (C]O),
1596 cmꢁ1; ESI-HRMS calcd for C15H14ClN2O [MþH]þ 273.0795,
found 273.0798.
4.6.9. (E)-N,N-Diethyl-3-(furan-2-yl)acrylamide (4qc)30
1H NMR (400 MHz, CDCl3)
7.49–7.44 (m, 2H), 6.74 (d,
J¼15.2 Hz, 1H, C]CH), 6.52–6.44 (m, 2H, ArH), 3.47–3.45 (m, 4H),
1.25–1.16 (m, 6H); 13C NMR (100 MHz, CDCl3)
165.5, 151.7, 143.7,
129.1, 115.2, 113.5, 112.1, 42.2, 41.0, 15.0, 13.1; IR nmax (neat): 3117
(NH), 2975, 2931, 1651, 1605 cmꢁ1
d
d
4.7.5. 4-(4-Nitrophenyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-
2(3H)-one (7re)
.
Mp decomposed beyond 185 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.18 (d, J¼8.8 Hz, 2H, ArH), 8.14 (br s, 1H, CONH), 7.62 (d, J¼8.0 Hz,
4.7. General procedure for the synthesis of heterocycles 7 and
8 (Tables 5 and 6)
2H, ArH), 7.13–7.09 (m, 1H, ArH), 7.00–6.89 (m, 3H, ArH), 5.20 (m,
1H, H-4), 3.88 (s, 1H, NH), 2.91 (dd, J¼4.0, 12.0 Hz, 1H, H-3a), 2.75
(dd, J¼8.0, 12.0 Hz, 1H, H-3b); 13C NMR (100 MHz, CDCl3)
d 171.1,
To a stirred solution of the appropriate
a
,b
-unsaturated N-
150.8, 147.7, 138.0, 128.4, 127.1, 126.4, 124.2, 122.6, 122.4, 121.4, 63.0
41.0; IR nmax (KBr) 3304 (NH), 3227, 3075, 2980, 1671 (C]O),
1601 cmꢁ1; ESI-HRMS calcd for C15H14N3O3 [MþH]þ 284.1035,
found 284.1037.
acylbenzotriazole (1 mmol) and o-phenylenediamine or o-amino-
thiophenol (1.1 mmol) in THF (10 mL) was added triethylamine
(1 mL). The resulting mixture was refluxed until the disappearance
of the a,b-unsaturated N-acylbenzotriazole, as determined by TLC,
and then concentrated under reduced pressure to give a residue,
which was then purified by flash column chromatography (cyclo-
hexane–EtOAc) to afford the corresponding 1,5-benzodiazepine-2-
one 7 or 2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one 8.
4.7.6. 4-Methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one
(7rh)
Mp 182–184 ꢀC (lit.29 184 ꢀC); 1H NMR (400 MHz, CDCl3)
d 7.60
(br s, 1H, CONH), 7.03–6.98 (m, 1H, ArH), 6.91–6.87 (m, 2H, ArH),
6.79–6.77 (m, 1H, ArH), 4.06–4.00 (m, 1H, H-4), 3.53 (br s, 1H, NH),
2.93 (dd, J¼4.0, 13.6 Hz, 1H, H-3a), 2.47–2.41 (m, 1H, H-3b), 1.33 (d,
4.7.1. 4-Phenyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one
(7ra)
J¼6.4 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3)
d 173.3, 138.3, 128.0,
125.6, 122.2, 121.3, 120.9, 54.1, 41.5, 23.7; IR nmax (KBr) 3300 (NH),
Mp decomposed beyond 83 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.92
(s, 1H, CONH), 7.45–7.30 (m, 5H, ArH), 7.09–7.07 (m, 1H, ArH), 6.96–
6.94 (m, 2H, ArH), 6.85 (d, J¼8.0 Hz, 1H, ArH), 5.04 (dd, J¼4.0,
12.0 Hz, 1H, H-4), 3.85 (br s, 1H, NH), 2.91 (dd, J¼8.0, 12.0 Hz, 1H, H-
3a), 2.78 (dd, J¼4.0, 12.0 Hz, 1H, H-3b); 13C NMR (100 MHz, CDCl3)
3181, 3034, 2966, 1658 (C]O), 1595 cmꢁ1
.
4.7.7. 2-(4-Nitrophenyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-
one (8se)
d
172.8, 144.2, 138.5, 129.0, 128.2, 127.7, 126.3, 126.1, 122.6, 121.6,
Mp187–189 ꢀC;1HNMR (400 MHz, CDCl3)
d8.30 (brs,1H,CONH),
121.2, 63.5, 41.8; IR nmax (KBr) 3335 (NH), 3178, 3060, 2958, 2904,
1666 (C]O), 1596 cmꢁ1; EIMS m/z (%) 239 (22.1, Mþþ1), 238 (100,
Mþ); ESI-HRMS calcd for C15H15N2O [MþH]þ 239.1184, found
239.1184.
8.16 (d, J¼8.8 Hz, 2H, ArH), 7.37 (d, J¼8.8 Hz, 2H, ArH), 7.31–7.19 (m,
2H, ArH), 7.08–7.04 (m, 1H, ArH), 6.87–6.85 (m, 1H, ArH), 3.68 (dd,
J¼5.6, 9.6 Hz, 1H, H-2), 3.41 (dd, J¼5.6, 14.0 Hz, 1H, H-3a), 2.98 (dd,
J¼9.2, 14.0 Hz, 1H, H-3b); 13C NMR (400 MHz, CDCl3)
d 166.9, 147.1,
144.6,135.8,130.3,128.4,127.6,124.4, 123.7,118.1,117.1, 43.6, 35.3; IR
nmax (KBr) 3122, 3115, 2894, 1663 (C]O), 1605 cmꢁ1; EIMS m/z (%)
300 (45.0, Mþ), 164 (100),134 (75.0). Anal. Calcd for C15H12N2O3S: C,
59.99; H, 4.03; N, 9.33. Found: C, 58.96; H, 4.11; N, 9.26.
4.7.2. 4-(Furan-2-yl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-
2(3H)-one (7rc)
Mp 180–182 ꢀC (lit.31 185 ꢀC); 1H NMR (400 MHz, CDCl3)
d 7.91
(br s, 1H, CONH), 7.51–7.30 (m, 2H, ArH), 7.06–6.95 (m, 2H, ArH),
6.81 (d, J¼7.6 Hz, 1H, ArH), 6.59–6.47 (m, 1H, ArH), 6.32–6.23 (m,
1H, ArH), 5.08 (dd, J¼4.4, 9.6 Hz, 1H, H-4), 3.88 (br s, 1H, NH), 2.93
4.7.8. 2-(4-Chlorophenyl)-2,3-dihydrobenzo[b][1,4]thiazepin-
4(5H)-one (8sf)
(dd, J¼9.6, 13.6 Hz, 1H, H-3a), 2.80 (dd, J¼4.4, 9.2 Hz, 1H, H-3b); 13
C
Mp 205–207 ꢀC (lit.32 207–208 ꢀC); 1H NMR (400 MHz, CDCl3)
NMR (100 MHz, CDCl3)
d
172.0, 155.5, 142.2, 137.6, 129.2, 126.1,
d
7.96 (br s, 1H, CONH), 7.65 (d, J¼8.8 Hz, 1H, ArH), 7.46–7.42 (m, 1H,
122.5, 122.2, 122.1, 110.3, 105.6, 57.0, 38.1; IR nmax (KBr) 3323 (NH),
3188, 3057, 2946, 1660 (C]O) cmꢁ1
ArH), 7.30–7.24 (m, 5H, ArH), 7.17 (d, J¼8.0 Hz, 1H, ArH), 4.85 (dd,
.
J¼6.0,10.4 Hz,1H, H-2), 2.88–2.77 (m, 2H, H-3); 13C NMR (400 MHz,
CDCl3)
d 172.0, 141.7, 141.3, 135.8, 133.6, 130.4, 129.0, 127.9, 126.8,
4.7.3. 4-p-Tolyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one
(7rd)
126.3, 123.3, 52.5, 41.3; IR nmax (KBr) 3184, 3106, 2894, 1661
(C]O) cmꢁ1; EIMS m/z (%) 291 (18.0, Mþ, 37Cl), 289 (49.0, Mþ, 35Cl),
165 (100), 125 (100).
Mp decomposed beyond 151 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.69 (br s, 1H, CONH), 7.44 (s, 1H, ArH), 7.29–7.24 (m, 1H, ArH), 7.16
(d, J¼8.0 Hz, 2H, ArH), 7.08–7.04 (m, 1H, ArH), 6.94–6.93 (m, 2H,
ArH), 6.82 (d, J¼8.0 Hz, 1H, ArH), 4.99(dd, J¼4.0, 10.0 Hz, 1H, H-4),
3.80 (br s, 1H, NH), 2.87 (dd, J¼9.6, 13.6 Hz, 1H, H-3a), 2.73 (dd,
J¼4.0, 13.2 Hz, 1H, H-3b), 2.34 (s, 3H, Me); 13C NMR (100 MHz,
4.7.9. 2-Methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one
(8sh)33
Mp 201–203 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.99 (br s, 1H,
CONH), 7.60 (d, J¼7.6 Hz, 1H, ArH), 7.36 (t, J¼7.6 Hz, 1H, ArH), 7.17 (t,
J¼7.6 Hz, 1H, ArH), 7.10 (d, J¼7.6 Hz, 1H, ArH), 3.94–3.86 (m, 1H, H-
2), 2.65 (dd, J¼5.6, 12.4 Hz, 1H, H-3a), 2.34 (dd, J¼8.8, 12.4 Hz, 1H,
H-3b), 1.43 (d, J¼6.4 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3)
CDCl3)
d 172.2, 141.4, 138.4, 137.9, 129.6, 127.7, 126.1, 125.9, 122.5,
121.5, 121.1, 63.0, 41.9, 21.1; IR nmax (KBr) 3345 (NH), 3178, 3061,
2958, 1667 (C]O), 1602 cmꢁ1; ESI-HRMS calcd for C16H17N2O
[MþH]þ 253.1341, found 253.1331.
d
172.8,141.4,135.9,129.9,126.7,126.3,123.1, 44.9, 41.3, 23.6; IR nmax
(KBr) 3178, 3111, 2954, 1682 (C]O) cmꢁ1
.
4.7.4. 4-(4-Chlorophenyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-
2(3H)-one (7rf)
4.7.10. 3-Methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one
(8si)
Mp decomposed beyond 145 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.90 (br s, 1H, CONH), 7.47–7.44 (m, 2H, ArH), 7.35–7.30 (m, 3H,
Mp 176–178 ꢀC (lit.34 177.5–178.5 ꢀC); 1H NMR (400 MHz, CDCl3)
ArH), 7.09–7.07 (m, 1H, ArH), 6.98–6.96 (m, 1H, ArH), 6.85 (d,
d
8.51 (br s, 1H, CONH), 7.58 (d, J¼7.6 Hz, 1H, ArH), 7.35 (t, J¼7.6 Hz,

X. Wang et al. / Tetrahedron 64 (2008) 6510–6521
6521
3568; (f) Gandelman, M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 2393–
2397.
5. For recent reviews, see: (a) Xu, L. W.; Xia, C. G. Eur. J. Org. Chem. 2005, 633–639;
(b) See Ref. 2b.
6. (a) Papa, D.; Schwenk, E.; Villani, F.; Klingsberg, E. J. Am. Chem. Soc. 1950, 72,
3885–3886; (b) Delaney, A. D.; Currie, D. J.; Holmes, H. L. Can. J. Chem. 1969, 47,
3273–3277; (c) Alberghina, G.; Arcoria, A.; Fisichella, S. J. Org. Chem. 1978, 43,
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1H, ArH), 7.17–7.13 (m, 2H, ArH), 3.48 (dd, J¼5.6, 10.8 Hz, 1H, H-2),
3.00 (t, J¼12.0 Hz, 1H, H-3a), 2.81–2.75 (m, 1H, H-3b), 1.18 (d,
J¼6.8 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3)
d 176.1, 141.3, 135.1,
129.7, 127.6, 126.3, 123.5, 41.6, 36.6, 15.5; IR nmax (KBr) 3187, 3113,
3066, 2964, 2895, 1677 (C]O) cmꢁ1
C
; ESI-HRMS calcd for
10H12NOS [MþH]þ 194.0640, found 194.0643.
Acknowledgements
8. For some examples of aza-Michael addition of activated
a,b-unsaturated
amides, see: (a) Molteni, M.; Volonterio, A.; Fossati, G.; Lazzari, P.; Zanda, M.
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We thank the Department of Science and Technology, Zhejiang
Province (Project No. 2006C11262) and University College Dublin
for financial support.
Supplementary data
Copies of 1H and 13C NMR spectra for new compounds 2, com-
pounds 3, 4, 5, 7 and 8. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.04.054.
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