Proton-promoted hydroamination of 3-dialkylthiomethylene-1,4-pentadiynes with o-phenylenediamines: A facile route to benzo[b][1,4]diazepines

Article abstract of DOI:10.1002/adsc.200700547

The first proton-promoted intermolecular hydroamination reaction of the enynes, α,α-dialkynylketene S,S-acetals 2, is described. A series of benzo[b][1,4]diazepines, with the structures of 3 and 5, were prepared chemo- and regioselectively in good to high yields by reacting the readily available 1,4-diynes 2 with both terminal and internal alkyne functions with o-phenylenediamines under very mild conditions.

Full text of DOI:10.1002/adsc.200700547

FULL PAPERS
DOI: 10.1002/adsc.200700547
Proton-Promoted Hydroamination of 3-Dialkylthiomethylene-1,4-
pentadiynes with o-Phenylenediamines: A Facile Route to
Benzo[b][1,4]diazepines
N
Yu-Long Zhao,a,* Da-Zhi Li,a Xiao-Dan Han,a Li Chen,a and Qun Liua,*
a
Department of Chemistry, Northeast Normal University, Changchun 130024, Peopleꢀs Republic of China
Fax : (+86)-431-8509-9759; e-mail: zhaoyl351@nenu.edu.cn
Received: November 17, 2007; Revised: April 2, 2008; Published online: May 21, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The first proton-promoted intermolecular 1,4-diynes 2 with both terminal and internal alkyne
hydroamination reaction of the enynes, a,a-dialk- functions with o-phenylenediamines under very mild
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[1,4]diazepines;
Introduction
aminations. Herein, we report the first proton-pro-
moted intermolecular hydroamination reaction of al-
The generation of C N bonds is of tremendous cur- kylthio-activated enynes under mild conditions.
rent interest. From the atom economic point of view, Over the past decades, the potential of a-oxoketene
À
catalytic hydroamination is one of the most efficient S,S-acetals as versatile intermediates in organic syn-
approaches for the synthesis of nitrogen-containing thesis has been recognized.[6] During the course of
products, which are important bulk and fine chemicals our studies on the chemistry of functionalized ketene
or building blocks in organic chemistry.[1] The cata- dithioacetals,[7] a series of a,a-dialkynylketene S,S-
lyzed hydroamination of alkynes has been attracting acetals 2 (Scheme 1) and analogues were prepared in
increasing interest in recent years with the aim to de- high yields via a consecutive Vilsmeier–Haack and
velop economic and efficient catalysts and to control dehydrochlorination reaction starting from easily
the regioselectivity.[1,2] However, most of the catalysts available a-oxoketene dithioacetals under mild condi-
have some disadvantages with respect to their ex- tions.[8] As synthetic applications of these electron-
treme air- and water-sensitivity, high costs and/or tox- rich enynes, we have described the self-coupling reac-
icity. Therefore, the development of new protocols for tions of the a-ethynylketene cyclic dithioacetals to the
the hydroamination reactions of alkynes remains an corresponding heteroatom-substituted expanded 1,3-
important goal in organicchemistry.
dithiolan[5]radialene[9a] and alkyne-spaced TTFs[9b]
Acid-promoted hydroamination is generally unsuc- and the aza-Diels–Alder reaction of a-ethynylketene
cessful mainly due to the buffering effect of the dithioacetals with N-arylimines to afford 4-functional-
amine substrate. However, some proton-catalyzed hy- ized quinolines.[10] Recently, the addition reaction of
droamination reactions of alkenes were recently car-
ried out in the presence of Brønsted acids.[3] In con-
trast to many examples of proton-catalyzed hydroami-
nation of alkenes, the proton-catalyzed hydroamina-
tion of alkynes is scarcely reported, although selected
metal-catalyzed hydroaminations of alkynes did use
acids as co-catalysts.[4] To the best of our knowledge,
only two examples of proton-catalyzed hydroamina-
tion of alkynes have been reported by Fensterbank
and co-workers[5a] and Cossy and co-workers,[5b] but
these reactions were limited to intramolecular hydro- Scheme 1. Synthesis of a,a-dialkynylketene S,S-acetals 2.
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Yu-Long Zhao et al.
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carboxylic acids to a-ethynylketene S,S-acetals at the with acetonitrile as the solvent (Table 1, entry 6).
carbon-carbon triple bond was also performed succes- Other solvents examined, such as dichloromethane
sively in the absence of catalysts.[11] These studies and and diethyl ether, gave lower yields (Table 1, entries 7
our continued interest in the development of new and 8). When the reaction was carried out in benzene
general methods for biologically important heterocy- or toluene, only a trace amount of 3a1 was observed
cles[12] promoted us to explore the feasibility of the (TLC) (Table 1, entries 9 and 10). In addition, it was
hydroamination reaction of a-alkynylketene S,S-ace- found that the proticaicd, CF 3COOH (2.0 equiv.),
tals with amines. In this paper we describe the results was as efficient as BF3·OEt2 for the above hydroami-
of the hydroamination reaction of a,a-dialkynylke- nation reaction and 3a1 was obtained in 73% yield
tene S,S-acetals with amines.
under essentially identical conditions as above
(Table 1, entry 11). Similarly, a catalytic amount of
CF3COOH (1.0 or 0.5 equiv.) led to lower yields of
3a1 (Table 1, entries 12 and 13). The structure of 3a1
was determined based on its spectroscopic and analyt-
Results and Discussion
In the initial experiment, the hydroamination reaction ical data and confirmed by X-ray crystal structure
of the 1,4-diyne 2a (1.0 equiv.) with o-phenylenedi- analysis (Figure 1).[13] The above experimental results
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To our delight, under essentially identical conditions of heterocyclic compounds because of their wide
as above, the hydroamination reaction of 2a with o- range of therapeutic and pharmacological proper-
phenylenediamine can easily proceed in the presence ties.[14] Obviously, the above results provide an effi-
of BF3·OEt2 (2.0 equiv.) at room temperature for 0.5 h cient route to benzo
A
to give benzo[b][1,4]diazepine 3a1 in 75% yield readily available starting materials. Therefore, the
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(Table 1, entry 3). Meanwhile, it was found that cata- scope of this novel and efficient hydroamination reac-
lyticamounts of BF ·OEt2 (1.0 or 0.5 equiv.) led to tion was extended by the use of 2a or 2b and some
3
lower yields of 3a (Table 1, entries 4 and 5). Among typical o-phenylenediamines in the presence of
the solvents tested, ethanol seemed to be the best CF3COOH or BF3·OEt2 (Table 1, entries 3 and 11)
choice although comparable results were obtained and the results are described in Table 2. It was found
that, with either CF3COOH or BF3·OEt2 as a promot-
er, all of the selected o-phenylenediamines with
either electron-withdrawing or electron-donating
groups on the aryl ring could efficiently react with
1,4-diynes 2a or 2b to give the corresponding benzo-
Table 1. Hydroamination of diyne 2a with o-phenylenedi-
amine under various reaction conditions.
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[1,4]diazepines 3a or 3b in good to high yields, respec-
tively (Table 2, entries 1–16). It was obvious that the
o-phenylenediamine bearing an electron-donating
group on the aryl ring, such as 4-methyl-o-phenylene-
diamine led to higher yields of 3 (Table 2, entries 3, 4,
11 and 12). In comparison, o-phenylenediamines with
an electron-withdrawing group on the aryl ring, for
Entry Catalyst (equiv.) Solvent
Time [h] 3a1
Yield [%][a]
1
Cu
A
-
2
3
4
5
6
7
8
9
10
11
12
13
FeCl3 (2.0)
C2H5OH 24
C2H5OH 0.5
C2H5OH 24
C2H5OH 24
-
BF3·OEt2 (2.0)
BF3·OEt2 (1.0)
BF3·OEt2 (0.5)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
BF3·OEt2 (2.0)
75
30
13
70
35
28
trace
trace
73
32
15
CH3CN
CH2Cl2
0.5
2
A
2
benzene 24
toluene 24
CF3COOH (2.0) C2H5OH 0.5
CF3COOH (1.0) C2H5OH 24
CF3COOH (0.5) C2H5OH 24
[a]
Isolated yields.
Figure 1. ORTEP drawing of 3a1.
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Proton-Promoted Hydroamination of 3-Dialkylthiomethylene-1,4-pentadiynes
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Table 2. Hydroamination of diynes 2a and 2b with o-phenyl-
enediamines.
and 40% yields, respectively (Table 2, entries 17 and
18). However, with BF3·OEt2 as the promoter, the re-
action of 2b with 4-nitro-o-phenylenediamine gave
imine 4 in 72% yield and the benzo[b][1,4]diazepine 5
A
was obtained in 55% yield by reacting 2a with 4-
nitro-o-phenylenediamine (Scheme 2). The molecular
structures of both imine 4 and diazepine 5 were con-
firmed by X-ray analysis (Figure 2 and Figure 3).[15]
In addition, the hydroamination of internal 1,4-
diyne 2c was also investigated in the presence of
CF3COOH (2.0 equiv.) under essentially identical
conditions as above. As expected, the hydroamination
reactions of 2c with o-phenylenediamine and 4-
chloro-o-phenylenediamine could also proceed
smoothly at room temperature for 5–6 h to give the
Entry n R1
Catalyst
Time
[h]
Product Yield
[%][a]
1
2 H
CF3COOH 0.5
BF3·OEt2 0.5
CF3COOH 0.5
BF3·OEt2 0.5
CF3COOH 0.5
BF3·OEt2 0.5
3a1
3a1
3a2
3a2
3a3
3a3
3a4
3a4
3b1
3b1
3b2
3b2
3b3
3b3
3b4
3b4
3a5
3b5
77
75
80
82
61
66
66
60
76
71
83
80
60
63
55
58
65
40
2
2 H
3
4
5
2 CH3
2 CH3
2 Cl
6
2 Cl
7
8
2 PhCO CF3COOH 0.5
2 PhCO BF3·OEt2 0.5
9
1 H
CF3COOH 0.5
BF3·OEt2 0.5
CF3COOH 0.5
BF3·OEt2 0.5
CF3COOH 0.5
BF3·OEt2 0.5
10
11
12
13
14
15
16
17
18
1 H
1 CH3
1 CH3
1 Cl
1 Cl
1 PhCO CF3COOH 0.5
1 PhCO BF3·OEt2 0.5
2 NO2
1 NO2
CF3COOH 1
CF3COOH 1
[a]
Isolated yields.
Figure 2. ORTEP drawing of 4.
example, 4-chloro-o-phenylenediamine and 4-benzo-
yl-o-phenylenediamine, gave relatively lower yields of
3 (Table 2, entries 5–8 and 13–16). In the above cases,
the effects of both the dialkylthio moiety of 1,4-
diynes 2a or 2b and promoters (CF3COOH and
BF3·OEt2) on the hydroamination reaction were not
significant.
However, it was noticed that when the o-pheny-
lenediamine bears a very strong electron-withdrawing
group on the aryl ring, for example, 4-nitro-o-phenyl-
enediamine, the orientation of the reaction was found
to be strongly influenced by both the structure of the
dialkylthio moiety in 1,4-diynes 2a or 2b and the pro-
moters. As a result, when CF3COOH was used as a
promoter, the hydroamination reactions of 2a and 2b
with 4-nitro-o-phenylenediamine produced the corre-
sponding benzo[1,4]diazepines 3a5 and 3b5 in 65% Figure 3. ORTEP drawing of 5.
G
Scheme 2. Reaction of 4-nitro-o-phenylenediamine with 1,4-diynes 2a and 2b in the presence of BF3·OEt2.
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Scheme 3. Hydroamination of 2c with o-phenylenediamines.
corresponding benzo
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75% and 65% yields, respectively (Scheme 3).
In the next studies, the hydroamination reaction of nylenediamine (1.0 equiv.) was also examined and the
diyne 2b with some typical anilines with either elec- results indicated that 1b was intact under the identical
tron-withdrawing or electron-donating groups on the conditions (solvent: ethanol; BF3·OEt2 or CF3COOH:
aryl ring was investigated in the presence of 2.0 equiv.).
CF3COOH or BF3·OEt2 and the results are described
in Table 3. Under identical conditions as above for tive to BF3·OEt2 or CF3COOH and both the hydro-
2 h, it was found that both aniline and 4-nitroaniline amination of a diyne 2 with a suitable aniline and the
The above results reveal that: 1) diynes 2 are sensi-
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readily underwent the hydroamination reaction with polymerization of diynes 2 could be initiated in the
2b to give the corresponding imine products 6b1 (the presence of BF3·OEt2 or CF3COOH; 2) the hydroami-
Z/E isomer ratio of 85/15) and 6b2 (the Z/E isomer nation of diynes 2 is amine-dependent due to the for-
ratio of 75/25) in good to high yields, respectively mation of a complex or salt between amine and
(Table 3, entries 1–4). However, in the case of the re- BF3·OEt2 or CF3COOH. Strong basicamines, such as
action of 4-methylaniline with 2b, although diyne 2b aliphaticethylenediamine and aromatic4-methylben-
was exhausted completely, no hydroamination prod- zeneamine could not give the hydroamination prod-
uct 6b3 was observed (Table 3, entries 5 and 6). Simi- ucts due to the preferential formation of the complex
larly, with either CF3COOH or BF3·OEt2 as a promot- or salt between the strongly basicamines and
er, the reaction of diyne 2b with ethylenediamine BF3·OEt2 or CF3COOH. However, in the case of the
(1.0 equiv.) also did not produce the corresponding hydroamination of diynes 2 and o-phenylenediamines,
[1,4]diazepine product under identical conditions as although the basicity of some o-phenylenediamines,
above and only a polymer was formed. Additionally, such as o-phenylenediamine and 4-methyl-o-pheny-
the polymerization of diyne 2b was also observed
when 2b was treated with BF3·OEt2 (2.0 equiv.) in eth-
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anol solvent in the absence of ethylenediamine or o- created preferentially by the interaction of these
amines with boron trifluoride etherate or CF3COOH,
nevertheless, there should be only one of the two
amino groups with relatively strong basicity involved
Table 3. Hydroamination of diyne 2b with anilines.
and a free amino group left as a nucleophilic center.
According to the above analysis and the regioselectiv-
ity of the hydroamination reaction of diynes 2, a pos-
sible mechanism is proposed in Scheme 4 (with
BF3·OEt2 as a promoter).
As depicted in Scheme 4, initially, the reaction of
BF3·OEt2 with trace amounts of water in the system
generates the Brønsted acid catalyst A.[17] On the
other hand, owing to the strong electron-donating
2
À
effect of the alkylthio groups (S C sp -conjugation),
Entry n R2
Catalyst
Time [h] Product Yield [%][a]
the carbon atom adjacent to R group of diyne 2 is be-
lieved to be more electron-rich, which favors the pro-
tonation occurring at the carbon atom adjacent to the
R group of the carbon-carbon triple bond and leads
to the formation of intermediate B (Scheme 4).[11]
Then, the nucleophilic attacking of the free or higher
basicamino group of an o-phenylenediamine could
occur at either carbon cation of intermediate B or the
1
2
3
4
5
6
1
1
1
1
1
1
H
H
CF3COOH 2
6b1
6b1
6b2
6b2
6b3
6b3
70
65
60
62
-
BF3·OEt2
2
NO2 CF3COOH 2
NO2 BF3·OEt2
CH3 CF3COOH 12
CH3 BF3·OEt2 12
2
-
[a]
Isolated yields.
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Proton-Promoted Hydroamination of 3-Dialkylthiomethylene-1,4-pentadiynes
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Scheme 4. Proposed mechanism for proton-catalyzed hydroamination reaction of diynes 2.
carbon cation of intermediate Bꢀ and the attacking at thiolane methylene moiety of intermediate C was not
the carbon cation of intermediate B (Scheme 4, B to activated as in the formation of the complex of
D) would be preferred at this stage for reasons of BF3·OEt2 with the sulfur atoms of 2, as a result,
steric hindrance. Subsequently, intramolecular hydro- benzo[1,4]diazepines 3a5 and 3b5 were finally pro-
A
amination followed by an ene-amine to imine tauto- duced via a consecutive intramolecular hydroamina-
mer will finally lead to the formation of benzo[b]- tion and rearrangement from C to 3 (Scheme 4).
A
ate E, generated by the intermolecular hydroamina-
tion of diyne 2a with 4-nitro-o-phenylenediamine, the Conclusions
nucleophilicity of the amino group would be largely
reduced due to the existence of two strong EWGs In conclusion, we have documented the first proton-
(imine and nitro group at 2- and 4-positions of the catalyzed intermolecular hydroamination reaction of
aryl ring of intermediate E) and the further transfor- electron-rich alkynes, a,a-dialkynylketene S,S-acetals
mation of the imine intermediate E may be directed 2, with various aromaticamines. The hydroamination
by the relative electrophilicity of the carbon cation reaction can proceed in a highly chemo- and regiose-
and the methylene carbon atom of the 1,3-dithiane lective manner under very mild conditions in the
moiety of intermediate E.
open air and no metal-based catalyst is required. The
[1,4]diazepines 3 and 5 provides
In the previous research, we have found that the synthesis of benzo[b]
AHCTREUNG
methylene carbon atom at the 2-position of the 1,3-di- a new and facile route to these biologically important
thiane moiety of an a-oxoketene dithioacetal com- molecules. Further research on the synthetic applica-
pound was more prone to be attacked by a tethered tions of the alkylthio activated enynes 2 is in progress.
nucleophilic group than that of 1,3-dithiolane cata-
lyzed by a Lewis acid.[7e,18] This might be the reason
why benzo[b][1,4]diazepine 5 was formed via a se-
C
Experimental Section
Typical Procedure for the Preparation of 3–5 (3a1 as
Example)
To a solution of 2a (1.0 mmol, 180 mg) and o-phenylenedi-
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G
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Yu-Long Zhao et al.
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was added dropwise by syringe within 3 min. The reaction References
mixture was stirred for 0.5 h at room temperature. After 2a
had been consumed (monitored by TLC), the reaction mix-
ture was poured into water (30 mL). The solid crude prod-
uct 3a1 was filtered off, then purified by silica gel chroma-
tography (diethyl ether/hexane=1/1, v/v) to give 3a1; yield:
216 mg (75%).
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Physical Data of Typical Compounds Isolated
3a1: white crystals; mp 200–2028C; 1H NMR (CDCl3,
500 MHz): d=2.03–2.24 (m, 2H), 2.76 (s, 6H), 2.78–2.82 (m,
2H), 2.94–2.99 (m, 2H), 7.20 (dt, J=6.0, 3.5 Hz, 2H), 7.38
(dt, J=6.0, 3.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz): d=
23.4, 25.4 (2C), 28.5 (2C), 124.8 (2C), 127.6 (2C), 129.9 (2C),
135.2 (2C), 140.1, 160.1; IR (KBr): n=762, 790, 1213, 1272,
1365, 1426, 1460, 1559, 1620, 2916, 2956, 3442 cmÀ1; MS
(EI): m/z=289 [(M+1)]+; anal. calcd. (found) for
C15H16N2S2: C 62.46 (62.59), H 5.59 (5.64), N 9.71 (9.76).
4: red crystals; mp 183–1858C; 1H NMR (CDCl3,
500 MHz): d=2.26 (s, 3H), 3.40–3.44 (m, 4H), 3.72 (s, 1H),
4.65 (s, 2H), 6.68 (d, J=9.0 Hz, 1H), 7.52 (s, 1H), 7.89 (q,
J=9.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d=19.3, 35.7,
40.7, 82.3, 86.5, 107.9, 112.9, 115.9, 122.1, 134.9, 138.9, 145.9,
165.1, 166.0; IR (KBr): n=740, 830, 1212, 1264, 1309, 1460,
1484, 1500, 1592,1613, 3261, 3351, 3462 cmÀ1; MS (EI):
m/z=320 [(M+1)]+; anal. calcd. (found) for C14H13N3O2S2:
C 52.65 (52.70), H 4.10 (4.05), N 13.16 (13.24).
5: white crystals; mp 220–2228C; 1H NMR (CDCl3,
500 MHz): d=1.88 (s, 3H), 2.36 (s, 3H), 2.38–2.41 (m, 2H),
2.58 (d, J=16.0 Hz, 1H), 3.06 (d, J=16.0 Hz, 1H), 3.75–3.81
(m, 1H), 3.93–3.99 (m, 1H), 7.56 (d, J=9.0 Hz, 1H), 8.03
(d, J=9.0 Hz, 1H), 8.28 (s, 1H); 13C NMR (CDCl3,
125 MHz): d=20.9, 26.0, 27.4, 30.2, 36.2, 119.6, 123.3, 125.8,
128.5, 134.7, 139.9, 143.9, 145.0, 161.9, 163.2; IR (KBr): n=
884, 1085, 1168, 1211, 1248, 1343, 1450, 1511, 1623, 2962,
3433 cmÀ1
;
MS (EI): m/z=334 [(M+1)]+; anal. calcd.
(found) for C15H15N3O2S2: C 54.03 (54.13), H 4.53 (4.55), N
12.60 (12.66).
6b1: yellow crystals; mp 112–1148C; 1H NMR (CDCl3,
500 MHz): d=2.04 (s, 6H), 3.31 (s, 4H), 6.86 (d, J=7.5 Hz,
4H), 7.08 (q, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 4H);
13C NMR (CDCl3, 125 MHz): d=20.1 (2C), 37.5 (2C), 119.8,
119.9 (2C), 120.3, 123.8 (2C), 124.5, 128.2, 128.8, 129.0, 129.3
(2C), 150.2 (2C), 153.8, 166.5; IR (KBr): n=3378, 3060,
1618, 1592, 1483, 1364, 1212, 1159, 802, 701 cmÀ1; MS (EI):
m/z=353 [(M+1)]+.
Acknowledgements
Financial support from the National Natural Sciences Foun-
dation ofChina (20602006), Training Fund ofNENUꢀs Sci-
entific Innovation Project (NENU-STC07017), Science Foun-
dation for Young Teachers of Northeast Normal University
(20070301), and Analysis and Testing Foundation ofNorth-
east Normal University are greatly acknowledged.
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1543