The synthesis of 1,5-benzodiazepines in a fluorous aqueous emulsion

Article abstract of DOI:10.1016/j.jfluchem.2009.08.005

The synthesis of 1,5-benzodiazepine derivatives was smoothly carried out in a fluorous aqueous emulsion system composed of perfluorooctane (C₈F₁₈) and potassium perfluorooctanesulfonate (C₈F₁₇SO₃K, KF

Full text of DOI:10.1016/j.jfluchem.2009.08.005

Journal of Fluorine Chemistry 130 (2009) 1054–1058
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Short communication
The synthesis of 1,5-benzodiazepines in a fluorous aqueous emulsion
Wen-Bin Yi *, Chun Cai
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing 210094, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of 1,5-benzodiazepine derivatives was smoothly carried out in a fluorous aqueous
Received 16 July 2009
emulsion system composed of perfluorooctane (C
17SO
used again without a significant loss of efficiency.
8
F
18
)
and potassium perfluorooctanesulfonate
Received in revised form 20 August 2009
Accepted 20 August 2009
Available online 26 August 2009
(C
8
F
3
K, KFOS) at room temperature. The aqueous perfluorinated emulsion can be recovered and
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Aqueous perfluorinated emulsion
Perfluorooctane
Potassium perfluorooctanesulfonate
1
,5-Benzodiazepine
1
. Introduction
solvents (perfluorocarbon, PFC), and organic solvents, has been
reported for the synthesis of 1,5-benzodiazepines from our group
[20]. In this catalytic system, the fluorous catalyst with
perfluoroalkylated ‘‘pony tails’’ can dissolve into the fluorous
phase containing the product after the reaction. However, the
requirement of heavy fluorous Lewis acid and use of fluorous
solvent at high temperature brought about various issues
concerning the cost for catalyst, and solvent leaching by
evaporation. Therefore, the development of the strategy to
eliminate the above requirement for fluorous catalysis is a topic
of enormous importance.
It was known to us that fluorocarbon solvents have poor
miscibility and lower solvation power than ordinary organic
solvents and that these fluorinated solvents have solvophobic
properties that are similar to those observed in water [21–24]. It
was expected that the exclusive property shown by fluorous
solvents and water might cause the organic substrates to remain
in the interfacial area between a fluorous phase and aqueous
media, resulting in the acceleration of their intermolecular
reactions due to repulsion from the both sides (fluorous and
aqueous phase) [21–24]. In 2006, Chiba group reported a
successful example of the Diels–Alder reaction in an aqueous
Benzodiazepines are very important compounds, widely used
in the last decades as anticonvulsant, antianxiety, antitumor,
psychosis, hypnotic and antipyretic agents [1]. Some benzodia-
zepine derivatives are also used in industry, such as light-
sensitive material [2], and also as anti-inflammatory agents [3].
1
,5-Benzodiazepines are also used for preparation of some
fused ring benzodiazepine derivatives, such as triazol [4], and
oxadiazol [5].
Due to their wide range of pharmacological activity, industrial
and synthetic applications, many methods for their preparation are
reported in the literature. These include condensation reactions of
o-phenylenediamine with
2,6], -haloketones [7],
presence of BF –etherate [9], NaBH
11], SiO [11], MgO and POCl [12], cerium (III) chloride/sodium
iodide [13], zirconia [14], acetic acid [15], 12-tungstophosphoric
acid [(NH )H 40] [16], low-valent titanium [17], ytterbium
trichloride (YbCl ) [18] and ytterbium triflate [Yb(OTf) ] [19].
a
b
,
b
-unsaturated carbonyl compounds
-aminoketones [8], or ketones in the
[10], polyphosphoric acid
[
b
3
4
[
2
3
4
2
PW12O
3
3
Unfortunately, many of these processes suffer from major or minor
limitations, such as drastic reaction conditions, tedious work-up
procedures for reusing catalyst and co-occurrence of several side
reactions.
micellar system composed of perfluorohexane (C
6 14
F ) and
lithium perfluorooctanesulfonate (C Li, LiFOS) [25]. In
8 3
F17SO
Recently, fluorous biphasic system composed of fluorous Lewis
continuation of our interest in fluorous technique [26], we have
developed a practical protocol for the synthesis of 1,5-benzo-
diazepine derivatives in a fluorous aqueous emulsion system
3
acid ytterbium perfluorooctanesulfonate [Yb(OPf) ], fluorous
composed of perfluorooctane (C
8
F
18) and potassium perfluor-
ooctanesulfonate (C
room temperature.
8 3
F17SO K, KFOS) under aerobic conditions at
*
Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: yiwenbin@mail.njust.edu.cn (W.-B. Yi).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.08.005

W.-B. Yi, C. Cai / Journal of Fluorine Chemistry 130 (2009) 1054–1058
1055
2
. Experimental
2,3,4-Trimethyl-2-ethyl-2,3-dihydro-1H-1,5-benzodiazepine 4:
yellow solid; m.p. 136–137 8C (Lit. [12] 137–138 8C); IR (KBr):
n
À1
1
2.1. General remarks
3340 (NH), 1643 (C 55 N), 1593 (Ar) cm ; H NMR (300 MHz, TMS,
CDCl 0.98 (t, 3H, CH , J = 7.0 Hz), 1.25 (t, 3H, CH , J = 7.1 Hz), 1.71
(q, 2H, CH , J = 7.0 Hz), 2.16 (m, 2H, –CH ), 2.35 (s, 3H, –CH ), 2.69 (q,
2H, –CH , J = 7.1 Hz), 3.29 (br, 1H, –NH), 6.80–7.31 (m, 4H, Ar);
NMR (50 MHz, TMS, CDCl 175.6, 140.6, 138.1, 127.0, 126.2, 125.3,
3
)
d
3
3
1
13
19
H NMR, C NMR and F NMR spectra were taken with a
2
2
3
13
Bruker Advance RX300 spectrometer. GC–MS analyse was
performed on a Saturn 2000GC/MS instrument. Particle size
distribution was measured on a Mastersize2000 laser granularity
testing apparatus. IR spectra were recorded on a Bomen MB154S
infrared analyzer. Perfluorooctane and potassium perfluoroocta-
nesulfonate were commercially obtained from DeiFu Chemical Co.
of Wuhan. Other fluorous solvents were commercially obtained
from ARCOS Co. Commercially available reagents were used
without further purification.
2
C
3
) d
121.6, 70.8, 42.1, 35.6, 35.6, 26.8, 10.6, 8.4; MS(EI) m/z: 216 (7), 214
(32), 207 (93), 199 (100), 133 (20), 132 (75), 96 (27), 65 (8).
2,4-Dimethyl-3-ethyl-2-(n-propyl)-2,3-dihydro-1H-1,5-benzo-
diazepine 5: yellow solid; m.p. 138–141 8C (Lit. [20] 139–140 8C); IR
À1
1
(KBr):
TMS, CDCl
J = 7.0 Hz), 3.70 (br, 1H, –NH), 6.67–7.44 (m, 4H, Ar); C NMR
50 MHz, TMS, CDCl 173.8, 142.2, 139.6, 132.7, 126.8, 118.1,
117.3, 68.2, 45.9, 30.4, 28.3, 28.0, 12.2, 11.6, 7.8, 7.3; MS(EI) m/z: 244
n
3342 (NH), 1640 (C 55 N), 1589 (Ar) cm ; H NMR (300 MHz,
3
)
d
0.76–1.48 (m, 13H), 2.39 (s, 3H, CH ), 2.89 (q, 1H, CH,
3
13
(
3
) d
2.2. Preparation of fluorous aqueous emulsion
(
11), 202 (13), 201 (100), 161 (13), 133 (16), 132 (25), 87 (3).
10-Spirocyclopentan-1,2,3,9,10,10a-hexahydrobenzo[b]-cyclo-
Potassium perfluorooctanesulfonate (2.94 g, 5 mmol) was added
to a mixture of perfluorooctane (4.38 g, 10 mmol) and deionized
water (10 ml). The mixture was stirred for 2 h and then surged with
sonication for 2 h at ambient temperature. After the completion of
the emulsion formation, the dispersion was partially applied for the
measurement of the particle size distributions at 25 8C.
penta[e][1,4]diazepine 6: yellow solid; m.p. 134–136 8C (Lit. [8]
À1
1
134 8C); IR (KBr):
NMR (300 MHz, TMS, CDCl
CH ), 3.72 (br, 1H, –NH), 6.58–7.23 (m, 4H, Ar); C NMR (50 MHz,
TMS, CDCl 178.0, 143.2, 139.6, 132.2, 126.8, 119.1, 118.6, 68.0,
4.3, 39.2, 38.4, 33.3, 28.9, 24.2, 24.0, 23.6; MS(EI) m/z: 240 (6), 236
n
3338 (NH), 1658 (C 55 N), 1610 (Ar) cm
; H
3
) d
1.01–2.24 (m, 13H), 3.26 (m, 2H,
1
3
2
3
) d
5
2
.3. Typical procedure for the synthesis of 1,5-benzodiazepine in
(16), 207 (24), 187 (98), 145 (63), 132 (100), 92 (12), 55(6).
10-Spirocyclohexan-2,3,4,10,11,11a-hexahydro-1H-dibenzo[-
b,e][1,4]diazepine 7: yellow solid; m.p. 138–139 8C (Lit. [12] 137–
fluorous aqueous emulsion
À1
1
o-Phenylenediamine (0.22 g, 2 mmol) was added to the above
emulsion in a glass flask under vigorous stirring. After ca. 5 min,
acetophenone (0.72 g, 6 mmol) was introduced into the glass flask.
After being stirred at room temperature for 72 h, the mixture was
transferred to an extraction and separation funnel. Ether/hexane
139 8C); IR (KBr):
NMR (300 MHz, TMS, CDCl
CH ), 3.70 (br, 1H, –NH), 6.57–7.18 (m, 4H, Ar); C NMR (50 MHz,
TMS, CDCl 178.4, 142.7, 138.0, 129.4, 126.5, 121.4, 121.2, 63.0,
n
3310 (NH), 1645 (C 55 N), 1600 (Ar) cm
; H
3
) d
0.96–2.35 (m, 17H), 3.25 (m, 2H,
1
3
2
3
) d
52.8, 40.6, 39.2, 34.3, 33.3, 25.4, 24.3, 23.2, 21.7, 21.7; MS(EI) m/z:
(
1:1, 10 ml  3 ml) was added to the funnel to extract organic
268 (3), 188 (24), 145 (100), 132 (43), 92 (8), 65 (8).
substrates. The recovered emulsion was ready for further runs. The
organic extraction was washed with water (10 ml), 10% NaHCO
3
3. Results and discussion
solution (10 ml) and water (10 ml  2 ml), and dried over MgSO
4
.
The solvent was removed under reduced pressure and the residue
was purified by column chromatography on silica gel (eluent:
Initially, effect of the media on the condensation of o-
phenylenediamine with acetophenone was investigated
(Table 1). Potassium perfluorooctanesulfonate was selected as
an emulsifier because it was cheap and easily obtained from
industrial production. The control experiment showed that only
trace amount of condensation product could be obtained in water,
fluorous solvent and ordinary organic solvents. Even in the
presence of aliphatic-chain surfactants such as potassium octyl
sulfate (POS) and sodium dodecyl sulfate (SDS) at higher
temperature, no remarkable acceleration was observed. The
reaction did not improve by addition of potassium perfluoroocta-
nesulfonate, indicating that potassium perfluorooctanesulfonate
itself has almost no catalytic activity for the condensation.
CH
diphenyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine 1 (0.44 g,
1%). All the condensation products are known compounds and
2 2
Cl /MeOH = 90/10) to give the condensation product 2,4-
7
1
13
adequately characterized by IR, H NMR, C NMR and GC–MS.
Diphenyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine
yellow solid; m.p. 150–152 8C (Lit. [12] 151–152 8C); IR (KBr):
1:
n
À1
1
3
342 (NH), 1635 (C 55 N), 1588 (Ar) cm ; H NMR (300 MHz, TMS,
CDCl 1.76 (s, 3H, CH ), 2.93 (d, 2H, –CH , J = 0.17 Hz), 3.10 (d,
, J = 0.17 Hz), 3.36 (br, 1H, –NH), 6.80–7.71 (m, 14H, Ar);
C NMR (50 MHz, TMS, CDCl 167.4, 146.6, 140.2, 139.5, 138.2,
3
)
d
3
2
2
H, –CH
2
1
3
3
) d
129.9, 128.6, 128.4, 128.1, 127.2, 127.2, 126.4, 125.7, 121.7, 121.6,
74.1, 43.0, 29.9; MS(EI) m/z: 312 (10), 310 (14), 295 (100), 132 (65),
92 (12), 65 (8).
Table 1
2
,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine 2: white
solid; m.p. 125–126 8C (Lit. [8] 126 8C); IR (KBr): 3295 (NH), 1640
C 55 N), 1592 (Ar) cm ; H NMR (300 MHz, TMS, CDCl 1.34 (s,
), 3.45 (br, 1H, –NH),
.62–7.21 (m, 4H, Ar); C NMR (50 MHz, TMS, CDCl 171.6,
40.4, 138.0, 126.9, 125.3, 121.8, 121.6, 68.1, 45.4, 30.6, 29.5, 29.5;
a
Media effect for the condensation of o-phenylenediamine with acetophenone .
n
b
b
À1
1
Condition
Yield (%)
Condition
Yield (%)
(
3
) d
c
c,d
6
6
1
H, 2-CH
3
), 2.20 (s, 2H, –CH
2
), 2.36 (s, 3H, –CH
3
H
2
O
2
<1
<1
<1
<1
6
SDS/H
2
O
11–17
37
e
f
13
C H OH
C F /H O/KFOS
2
5
8
8
6
7
7
18
2
2
2
2
3
) d
c
C
8
F
18
C
C
C
C
C
F
F
F
F
18/H
O/KFOS
O/KFOS
71, 68, 69
c
f
n-Octane
14/H
14/H
75
54
49
58
MS(EI) m/z: 188 (40), 173 (100), 132 (64), 131 (22), 92 (10).
,2,4-Triethyl-3-methyl-2,3-dihydro-1H-1,5-benzodiazepine
: yellow solid; m.p. 143 8C (Lit. [12] 144–145 8C); IR (KBr): 3328
NH), 1645 (C 55 N), 1588 (Ar) cm ; H NMR (300 MHz, TMS, CDCl
c
f
Toluene
O/KFOS
c
f
2
C
8
F
18/H
2
O (1:1)
c,d
8
/H
2
O/KFOS
f
POS/H
2
O
8–15
10
F18/H
2
O/KFOS
3
(
n
À1
1
a
3
)
The reaction condition: phenylenediamine, 2 mmol; acetophenone, 6 mmol;
reaction over 72 h at RT.
d
3
CDCl
0.80–1.52 (m, 14H), 2.32 (m, 2H, CH
.69 (br, 1H, –NH), 6.66–7.38 (m, 4H, Ar); C NMR (50 MHz, TMS,
173.8, 142.0, 139.6, 132.7, 126.8, 118.0, 117.4, 68.3, 46.2,
2
), 2.91 (q, 1H, CH, J = 7.0 Hz),
b
13
Isolated yields based on the phenylenediamine.
c
1
0 ml of each reaction medium.
Surfactants, 10 mmol, 25–60 8C.
PFC (10 mmol), H O (10 ml) and KFOS (2 mmol).
PFC (10 mmol), H O (10 ml) and KFOS (5 mmol).
3
)
d
d
e
f
3
5.4, 28.3, 28.0, 12.2, 11.6, 7.8, 7.3; MS(EI) m/z: 244 (12), 201 (100),
2
1
61 (13), 132 (25), 131 (6), 87 (3).
2

1
056
W.-B. Yi, C. Cai / Journal of Fluorine Chemistry 130 (2009) 1054–1058
8 2
Fig. 1. Particle size distributions of C F18/H O/KFOS emulsion.
Fig. 2. The proposed organic synthesis of 1,5-benzodiazepine in the fluorous aqueous emulsion.
However, in the presence of potassium perfluorooctanesulfonate
and fluorous solvents, the aqueous condensation was obviously
accelerated. It was suggested that micelles in fluorous aqueous
emulsion should be effective for the reaction. Stirring and then
yield is lower than that in FBS case (99% yield at 60 8C for 2 h) and
rather longer reaction time is needed in the present protocol, the
fluorous aqueous emulsion strategy eliminates heating and the use
of Lewis acids.
sonication of the mixture of PFC (10 mmol), H
2
O (10 ml) and KFOS
When the reaction was finished, ether/hexane was added to
the reaction mixture to extract the organic compounds. Based on
the F NMR and UV–vis spectroscopic data and GC–MS, no loss
of fluorous surfactant or fluorous solvent to the organic
extraction could be detected. The use of the fluorous aqueous
emulsion recycled without purification was equally effective.
(5 mmol) resulted in the formation of a white, stable emulsion
1
9
having an average diameter of 3.02
m
m (Fig. 1). The organic
substrates showed low miscibility with PFC and water; the
exclusive property of the fluorous/aqueous interface accelerated
the reaction (Fig. 2). The condensation of o-phenylenediamine with
acetophenone gave the product 2,4-diphenyl-2-methyl-2,3-dihy-
dro-1H-1,5-benzodiazepine (1) in 71% yield after 72 h in the
8 2
For example, the yields of condensation in C F18/H O/KFOS
emulsion from the first run to the third run were 71, 68, and
69%, respectively.
8 2
fluorous aqueous emulsion system C F18/H O/KFOS. Although the
Fig. 3. The possible mechanism for the formation of 1,5-benzodiazepins.

W.-B. Yi, C. Cai / Journal of Fluorine Chemistry 130 (2009) 1054–1058
1057
Table 2
a
The synthesis of 2,3-dihydro-1H-1,5-benzodiazepines in the fluorous/aqueous emulsion .
.
b
Reactant
Acetone
Product
Time (h)
72
Yield (%)
8
m.p. (8C)
125–126
(Lit. [8] 126)
3
-Pentanone
36
82
143
(Lit. [12] 144–145)
2
-Butanone
48
48
72
87
79
55
136–137
(Lit. [12] 137–138)
2
-Pentanone
138–141
(Lit. [20] 139–140)
Cyclopentanone
134–136
(Lit. [8] 134)
Cyclohexanone
72
58
138–139
(Lit. [12] 137–139)
a
The reaction condition: phenylenediamine, 2 mmol; ketone, 6 mmol; C
Isolated yields based on the phenylenediamine.
8 2
F18 (10 mmol), H O (10 ml) and KFOS (5 mmol); RT.
b

1
058
W.-B. Yi, C. Cai / Journal of Fluorine Chemistry 130 (2009) 1054–1058
A possible mechanism for the formation of 1,5-benzodiazepine
pines. This fluorous aqueous system will receive considerable
attention in the future because it is possible to carry out the
reactions without heating or the use of Lewis acids.
is shown Fig. 3. Amino groups of o-phenylenediamine attack
carbonyl group of ketone, giving the intermediate diimine A. Then,
a 1,3-shift of the hydrogen attached methyl group occurs to afford
an isomeric enamine B, which cyclizes to produce seven-
membered ring C [11].
Acknowledgements
Fluorous solvents such as, perfluorohexane (C
omethylcyclohexane (C 14), perfluorotoluene (C
fluorodecalin (C10 18, cis and trans-mixture) were also examined
for the condensation. Perfluorohexane (C 14) and perfluoroto-
luene (C ) are in fact miscible with aromatic compounds such as
6
F
14), perfluor-
We thank the Nature and Science Foundation of Jiangsu
Province (BK2007592) and the Ph.D. Programs Foundation of
Ministry of Education of China (No. 200802881024) for financial
support.
7
F
7 8
F ), and per-
F
6
F
7 8
F
acetophenone at room temperature. Thus, it is impossible to
separate the organic compounds from fluorous and aqueous
phases by extraction. The loss of fluorous solvent was very obvious
during repeated reactions when using perfluoromethylcyclohex-
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209–239.
In conclusion,
a fluorous aqueous system composed of
perfluorooctane and potassium perfluorooctanesulfonate was
shown to effectively accelerate the synthesis of 1,5-benzodiaze-