Ytterbium perfluorooctanesulfonate-catalyzed synthesis of 1,5-benzodiazepine derivatives in fluorous solvents

Article abstract of DOI:10.1080/00397910701572464

Ytterbium perfluorooctanesulfonate [Yb(OPf)3] catalyses the highly efficient synthesis of 2,3-dihydro-1H-1,5-benzodiazepines in fluorous solvents. By simple separation of the fluorous phase containing only the catalyst, the reaction can be repeated severa

Full text of DOI:10.1080/00397910701572464

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Ytterbium
Perfluorooctanesulfonate–Catalyzed Synthesis
of 1,5‐Benzodiazepine Derivatives in
Fluorous Solvents
Wen‐Bin Yi a & Chun Cai a
a Chemical Engineering College, Nanjing University of Science and
Technology , Nanjing, China
Published online: 19 Oct 2007.
To cite this article: Wen‐Bin Yi & Chun Cai (2007) Ytterbium Perfluorooctanesulfonate–Catalyzed Synthesis of
1,5‐Benzodiazepine Derivatives in Fluorous Solvents, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:21, 3827-3833, DOI: 10.1080/00397910701572464
To link to this article: http://dx.doi.org/10.1080/00397910701572464
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Synthetic Communicationsw, 37: 3827–3833, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701572464
Ytterbium Perfluorooctanesulfonate–
Catalyzed Synthesis of 1,5-Benzodiazepine
Derivatives in Fluorous Solvents
Wen-Bin Yi and Chun Cai
Chemical Engineering College, Nanjing University of Science
and Technology, Nanjing, China
Abstract: Ytterbium perfluorooctanesulfonate [Yb(OPf)3] catalyses the highly
efficient synthesis of 2,3-dihydro-1H-1,5-benzodiazepines in fluorous solvents. By
simple separation of the fluorous phase containing only the catalyst, the reaction can
be repeated several times.
Keywords: 2,3-dihydro-1H-1,5-benzodiazepines, fluorous biphasic catalysis,
ytterbium perfluorooctanesulfonate
INTRODUCTION
Benzodiazepines are very important compounds, widely used in past decades
as anticonvulsant, antianxiety, antitumor, psychosis, hypnotic, and antipyretic
agents.[1] Some benzodiazepine derivatives are also used in industry, such as
light-sensitive material,[2] and also as anti-inflammatory agents.[3] 1,5-Benzo-
diazepines are also used for preparation of some fused-ring benzodiazepine
derivatives, such as triazol[4] and oxadiazol.[5]
Because of their wide range of pharmacological activity and industrial and
synthetic applications, many methods for their preparation are reported in the
literature. These include condensation reactions of o-phenylenediamine with
a,b-unsaturated carbonyl compounds,[2,6] b-haloketones,[7] b-aminoketones,[8]
Received in Japan February 27, 2007
Address correspondence to Wen-Bin Yi, Chemical Engineering College, Nanjing
University of Science and Technology, Nanjing 210094, China. E-mail: yiwenbin@
mail.njust.edu.cn
3827

3828
W.-B. Yi and C. Cai
or ketones in the presence of BF3-etherate,[9] NaBH4,[10] polyphosphoric
acid,[11] SiO2,[11] MgO and POCl3,[12] cerium (III) chloride/sodium iodide,[13]
zirconia,[14] acetic acid,[15] and low-valent titanium.[16] However, all of these
methods have problems, including drastic reaction conditions, low yields, and
severe side reactions. Giri et al. reported a reusable and efficient heterogeneous
catalyst,
monoammonium
salt
of
12-tungstophosphoric
acid
[(NH4)H2PW12O40], for the synthesis of 1,5-benzodiazepines.[17] Wu et al.[18]
and Curini et al.[19] reported that ytterbium trichloride (YbCl3) and ytterbium
triflate [Yb(OTf)3] respectively can catalyze the formation of 1,5-benzo-
diazepines from o-phenylenediamine and ketones in good to excellent yields.
However, reusing these catalysts required tedious workup procedures such as fil-
tration, purification, and drying.
Recently, a new kind of Lewis acid of rare earth (III) perfluorooctanesul-
fonates (RE(OSO2C8F17)3, RE(OPf)3, RE ¼ Sc,Y, LaꢀLu) has been of
special interest because they have characteristic features such as low hygro-
scopicity, ease of handling, robustness for recycling, and high solubility in
fluorous solvent.[20] On the other hand, perfluorocarbon solvents, especially
perfluoroalkanes, have some unique properties that make them attractive
alternatives for conventional organic solvents.[21] The compounds functiona-
lized with perfluorinated groups often dissolve preferentially in fluorous
solvents, and this property can be used to extract fluorous components from
reaction mixtures.[22] As a part of our studies to explore the utility of lantha-
nide perfluorooctanesulfonate–catalyzed reactions in fluorous solvents,[23] we
decided to investigate Yb(OPf)3-catalyzed synthesis of 2,3-dihydro-1H-1,5-
benzodiazepines by condensation of o-phenylenediamine with ketones
(Scheme 1).
RESULTS AND DISCUSSION
Yb(OPf)3 was capable of producing quantitive yields of 2,2,4-trimethyl-2,3-
dihydro-1H-1,5-benzodiazepine by condensation of o-phenylenediamine
with acetone in perfluorodecalin (C10F18, cis and trans-mixture). When
using perfluorotoluene (C7F8) and perfluoromethylcyclohexane (C7F14) as
fluorous solvents, the condensation also proceeded smoothly to give the
desired product. However, perfluorotoluene is in fact miscible with reaction
substrates such as acetone at room temperature. Thus, it is impossible to
Scheme 1.

Synthesis of 1,5-Benzodiazepine Derivatives
3829
recover the fluorous phase by phase separation. In addition, during repeated
condensation reactions, the loss of fluorous solvent is very serious when
using perfluoromethylcyclohexane (C7F14) as a fluorous solvent because it
is very volatile (bp 768C).
Thus, the use of the catalytic systems Yb(OPf)3/C10F18 was extended to the
synthesis of other 1,5-benzodiazepine derivatives as summarized in Table 1. As
shown in Table 1, both acyclic and cyclic ketones react to give the corresponding
2,3-dihydro-1H-1,5-benzodiazepines in nearly quantitative yield. The reaction
products were isolated and identified as 1,5-benzodiazepines, and no side
reactions were observed. It is interesting to note that when using unsymmetrical
ketones such as 2-butanone or 2-pentanone as substrates, the ring closure occurs
selectively from only one side of the carbon skeleton, giving a single product.
In addition, we found that a catalyst loading of only 0.4% was required when
using fluorous phase technology, which is more effective than the 5% of
Yb(OTf)3 required to catalyze the condensation. When the reaction was
finished, the reaction mixture was cooled to room temperature. The fluorous
phase with Yb(OPf)3 catalysts can separate from the organic layer and return
to the bottom layer. Based on gas chromatography-mass spectrography (GC-
MS) data, no loss of fluorous solvent to the organic phase can be detected. By
simple phase separation, the separated fluorous phase containing only catalyst
could be reused for the next reaction without any treatment and without any
loss of activity. The condensations of o-phenylenediamine with acetone under
the conditions mentioned previously were run for five consecutive cycles,
furnishing the corresponding 1 with 99, 98, 99, 97, and 97% isolated yields.
In conclusion, the use of Yb(OPf)3 as catalyst in properly chosen fluorous
solvents for preparation of 1,5-benzodiazepines can be considered an interest-
ing new alternative to existing heterogeneous catalysts. The simple procedures
as well as easy recovery and reuse of this novel catalytic system are expected
to contribute to the development of more benign synthesis of benzodiazepines.
EXPERIMENTAL
Typical Procedure for Condensation of o-Phenylenediamine
with Acetone
A mixture of Yb(OPf)3 (67 mg, 0.04 mmol), o-phenylenediamine (1.08 g,
10 mmol), acetone (3.5 mL, 30 mmol), and perfluorodecalin (C10F18, cis
and trans-mixture, 1.5 mL) was stirred at 608C for 2 h. When the reaction
was finished, the reaction mixture was cooled to room temperature. The
fluorous layer on the bottom was separated for the next condensation. The
upper organic phase was washed with water (10 mL), 10% NaHCO3
solution (10 mL), and water (10 mL ꢀ 2) and dried over MgSO4. The
solvent was removed under reduced pressure, and the residue was purified
by column chromatography on a silica-gel column (eluent: CH2Cl2/

3830
W.-B. Yi and C. Cai
Table 1. Yb(OPf)3-catalyzed synthesis of 2,3-dihydro-1H-1,5-benzodiazepines in
C10F18
Reactant
Acetone
Product
Yield (%)a
Mp (8C)
99 (99b, 98c)
124–125 (lit.[8]
126)
Acetophenone
2-Butanone
99
96
150–151 (lit.[12]
151–152)
137–138 (lit.[12]
137–138)
2-Pentanone
94
95
99
139–140
3-Pentanone
142–143 (lit.[12]
144–145)
Cyclopentanone
134–135 (lit.[8]
134)
Cyclohexanone
92
137–138 (lit.[12]
137–139)
aYieldsofpureisolatedproducts,characterizedbyIR,GC-MS,1HNMR, and13CNMR.
b,cPerfluorotoluene and perfluoromethylcyclohexane as fluorous solvents
respectively.

Synthesis of 1,5-Benzodiazepine Derivatives
3831
MeOH ¼ 90/10) to give the condensation product. All the condensation
1
products were adequately characterized by IR, H NMR, 13C NMR, and
GC-MS. The products 1, 2, 3, 5, 6, and 7 have been reported earlier.
Data
2,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine 1: white solid; mp
1
124–1258C; IR (KBr): n 3290 (NH), 1642 (C55N), 1592 (Ar) cm21; H
NMR (300 MHz, TMS, CDCl3) d 1.34 (s, 6H, 2-CH3), 2.20 (s, 2H, -CH2),
2.36 (s, 3H, -CH3), 3.45 (br, 1H, -NH), 6.62–7.21 (m, 4H, Ar); 13C NMR
(300 MHz, TMS, CDCl3) d 171.6, 140.4, 138.0, 126.9, 125.3, 121.8, 121.6,
68.1, 45.4, 30.6, 29.5, 29.5; GC/MS: Mþ ¼ 188.
2,4-Diphenyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine 2: yellow solid;
1
mp 150–1518C; IR (KBr): n 3342 (NH), 1635 (C55N), 1588 (Ar) cm21; H
NMR (300 MHz, TMS, CDCl3) d 1.76 (s, 3H, CH3), 2.93 (d, 2H, -CH2,
J ¼ 0.17 Hz), 3.10 (d, 2H, -CH2, J ¼ 0.17 Hz), 3.36 (br, 1H, -NH), 6.80–7.71
(m, 14H, Ar); 13C NMR (50 MHz, TMS, CDCl3) d 167.4, 146.6, 140.2,
139.5, 138.2, 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; GC/MS: Mþ ¼ 312.
2,3,4-Trimethyl-2-ethyl-2,3-dihydro-1H-1,5-benzodiazepine 3: yellow solid;
1
mp 137–1388C; IR (KBr): n 3338 (NH), 1637 (C55N), 1590 (Ar) cm21; H
NMR (300 MHz, TMS, CDCl3) d 0.98 (t, 3H, CH3, J ¼ 7.0 Hz), 1.24 (t, 3H,
CH3, J ¼ 7.1 Hz), 1.69 (q, 2H, CH2, J ¼ 7.0 Hz), 2.16 (m, 2H, -CH2), 2.34
(s, 3H, -CH3), 2.69 (q, 2H, -CH2, J ¼ 7.1 Hz), 3.29 (br, 1H, -NH), 6.80–7.31
(m, 4H, Ar); 13C NMR (50 MHz, TMS, CDCl3) d 175.6, 140.6, 138.1, 127.0,
126.2, 125.3, 121.6, 70.8, 42.1, 35.6, 35.6, 26.8, 10.6, 8.4; GC/MS: Mþ ¼ 216.
2,4-Dimethyl-3-ethyl-2-(n-propyl)-2,3-dihydro-1H-1,5-benzodiazepine 4:
yellow solid; mp 139–1408C; IR (KBr): n 3336 (NH), 1640 (C55N), 1589
1
(Ar) cm21; H NMR (300 MHz, TMS, CDCl3) d 0.76–1.48 (m, 13H), 2.38
(s, 3H, CH3), 2.89 (q, 1H, CH, J ¼ 7.0 Hz), 3.70 (br, 1H, -NH), 6.68–7.43
(m, 4H, Ar); 13C NMR (50 MHz, TMS, CDCl3) d 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;
GC/MS: Mþ ¼ 244.
2,2,4-Triethyl-3-methyl-2,3-dihydro-1H-1,5-benzodiazepine 5: yellow solid;
1
mp 142–1438C; IR (KBr): n 3330 (NH), 1639 (C55N), 1586 (Ar) cm21; H
NMR (300 MHz, TMS, CDCl3) d 0.80–1.52 (m, 14H), 2.33 (m, 2H, CH2),
2.91 (q, 1H, CH, J ¼ 7.0 Hz), 3.69 (br, 1H, -NH), 6.66–7.40 (m, 4H, Ar); 13
C
NMR (50 MHz, TMS, CDCl3) d 173.8, 142.0, 139.6, 132.7, 126.8, 118.0,
117.4, 68.3, 46.2, 35.4, 28.3, 28.0, 12.2, 11.6, 7.8, 7.3; GC/MS: Mþ ¼ 244.
10-Spirocyclopentan-1,2,3,9,10,10a-hexahydrobenzo[b]-cyclopenta[e][1,4]
diazepine 6: yellow solid; mp 134–1358C; IR (KBr): n 3334 (NH), 1658

3832
W.-B. Yi and C. Cai
1
(C55N), 1600 (Ar) cm21; H NMR (300 MHz, TMS, CDCl3) d 1.01–2.24
(m, 13H), 3.26 (m, 2H, CH2), 3.72 (br, 1H, -NH), 6.58–7.23 (m, 4H, Ar);
13C NMR (50 MHz, TMS, CDCl3) d 178.0, 143.2, 139.6, 132.2, 126.8,
119.1, 118.6, 68.0, 54.3, 39.2, 38.4, 33.3, 28.9, 24.2, 24.0, 23.6; GC/MS:
Mþ ¼ 240.
10-Spirocyclohexan-2,3,4,10,11,11a-hexahydro-1H-dibenzo[b,e][1,4]diaze-
pine 7: yellow solid; mp 137–1388C; IR (KBr): n 3300 (NH), 1642 (C55N),
1
1600 (Ar) cm21; H NMR (300 MHz, TMS, CDCl3) d 0.96–2.36 (m, 17H),
3.24 (m, 2H, CH2), 3.70 (br, 1H, -NH), 6.56–7.18 (m, 4H, Ar); 13C NMR
(50 MHz, TMS, CDCl3) d 178.4, 142.7, 138.0, 129.4, 126.5, 121.4, 121.2,
63.0, 52.8, 40.6, 39.2, 34.3, 33.3, 25.4, 24.3, 23.2, 21.7, 21.7; GC/MS:
Mþ ¼ 268.
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