A metal-catalyzed tandem 1,4-benzodiazepine synthesis based on two hydrogen-transfer reactions

Article abstract of DOI:10.1002/ejoc.201403261

Starting from 2-aminobenzyl alcohols and 1,2-amino alcohols, 2,3,4,5-tetrahydro-1H-1,4-benzodiazepines (THBDZ) can be prepared through a one-pot ruthenium-catalyzed reaction encompassing two consecutive borrowing hydrogen cycles. First, benzyl alcohol oxidation, condensation with the amino alcohol, and imine reduction occurs. This is followed by oxidation of the other alcohol functionality and reductive cyclocondensation to give the TH-BDZ derivatives. A single catalyst does the entire job, with two molecules of water being the only waste product. Many new substituted 2,3,4,5-tetrahydro-1H-1,4-benzodiazepines have been prepared to demonstrate the versatility of this method, which can be used for the preparation of privileged scaffolds for drug discovery.

Full text of DOI:10.1002/ejoc.201403261

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FULL PAPER
DOI: 10.1002/ejoc.201403261
A Metal-Catalyzed Tandem 1,4-Benzodiazepine Synthesis Based on Two
Hydrogen-Transfer Reactions
Varsha R. Jumde,[a] Elena Cini,[a] Andrea Porcheddu,[b] and Maurizio Taddei*[a]
Keywords: Hydrogen transfer / Homogeneous catalysis / Ruthenium / Cyclization / Domino reactions
Starting from 2-aminobenzyl alcohols and 1,2-amino
alcohols, 2,3,4,5-tetrahydro-1H-1,4-benzodiazepines (TH-
reductive cyclocondensation to give the TH-BDZ derivatives.
A single catalyst does the entire job, with two molecules of
BDZ) can be prepared through a one-pot ruthenium-cata- water being the only waste product. Many new substituted
lyzed reaction encompassing two consecutive borrowing 2,3,4,5-tetrahydro-1H-1,4-benzodiazepines have been pre-
hydrogen cycles. First, benzyl alcohol oxidation, condensa- pared to demonstrate the versatility of this method, which
tion with the amino alcohol, and imine reduction occurs. This
is followed by oxidation of the other alcohol functionality and
can be used for the preparation of privileged scaffolds for
drug discovery.
reported.[8] However, the direct synthesis of saturated sim-
ple 2,3,4,5-tetrahydro-1H-1,4-benzodiazepines (TH-BDZ)
is less well explored. The reduction of the corresponding
benzodiazepin(edi)ones with LiAlH4 or other strong metal
hydrides is often the method of choice for TH-BDZ synthe-
sis.[9] In view of the numerous applications of the BDZ scaf-
fold in medicinal chemistry, a simple and direct access to
TH-BDZs is highly desirable.
Following our interest in hydrogen-autotransfer strateg-
ies,[4d,4k–4m] we decided to explore a tandem process[10] en-
compassing two consecutive series of oxidation, condensa-
tion, cyclocondensation, and reduction to provide TH-
BDZs starting from 2-aminobenzyl alcohols and β-amino
alcohols (Scheme 1).
Introduction
The development of more efficient processes is one of the
major goals of contemporary synthetic organic chemistry.[1]
Multicomponent and cascade reactions play a key role in
reducing the number of steps, with savings in time and in
the materials required for purification of intermediates. Ca-
talysis, meanwhile, helps to increase atom economy and to
use milder and more sustainable reaction conditions.[2]
Among the metal-catalyzed reactions regularly used in
organic synthesis, the redox process called “borrowing
hydrogen” (or hydrogen autotransfer)[3] has found several
interesting applications, especially in the field of hetero-
cyclic chemistry. Under the influence of a catalyst, often
containing iridium or ruthenium, an alcohol is oxidized to
an aldehyde, which may undergo a nucleophilic addition.
The condensation product can be further manipulated to
prepare diverse heterocyclic scaffolds such as pyrroles, pyr-
idines, quinolines, quinoxalines, benzimidazoles, benzox-
azoles, and indoles.[4] Among the various heterocyclic com-
pounds, benzodiazepines (BDZ) are important molecules
with several applications[5] in medicinal chemistry (treat-
ment of central nervous system (CNS) disorders and muscle
spasms) or in oncology.[6] Benzodiazepinones are prepared
from isatoic anhydride and amino acids,[7] and the multistep
synthesis of benzodiazepinones and BDZs has also been
[a] Dipartimento di Biotecnologie, Chimica e Farmacia, Università
degli Studi di Siena,
Scheme 1. Proposal for a new simple 2,3,4,5-tetrahydro-1H-1,4-
benzodiazepine (TH-BDZ) synthesis.
Via A. Moro 2, 53100 Siena, Italy
E-mail: maurizio.taddei@unisi.it
http://www.dbcf.unisi.it/en/department/people/academic-staff/
maurizio-taddei
[b] Dipartimento di Chimica e Farmacia, Università degli Studi di
Sassari,
Results and Discussion
For a test reaction, benzyl alcohol 1 and phenylalaninol
(2a) were chosen as model substrates, and treated with dif-
Via Vienna 2, 07100 Sassari, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403261.
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V. R. Jumde, E. Cini, A. Porcheddu, M. Taddei
FULL PAPER
ferent ruthenium-based catalysts to investigate the feasibil- Table 2. Assessment of the reaction conditions.[a]
ity of the reaction. Various catalytic species obtained by
Entry
[Ru(p-cymene)Cl2]2
Xantphos
[mol-%]
Time Yield
[h]
[mol-%]
[%][b]
mixing different ruthenium precursors and phosphorus li-
gands were explored, working in toluene at 160 °C in a
closed vial (Table 1). Among the metal catalysts tested,
[Ru(p-cymene)Cl2]2 and [Ru(CO)(PPh3)3HCl] turned out to
be compatible with all the bidentate P-ligands used, provid-
ing the product (i.e., 5a) in moderate yields (Table 1, En-
tries 9–13 and 14–17). Interestingly, [Ru(CO)(PPh3)3HCl]
also worked without any added ligand (Table 1, Entry 13),
while [Ru(benzene)Cl2]2 and [Ru(COD)Cl2]n required the
presence of Xantphos to achieve acceptable yields of TH-
BDZ 5a (Table 1, Entries 5 and 18).
1
2
3
4
5
6
7
8
9
2.5
5
5
10
5
5
5
5
2.5
5
10
10
5
5
5
5
15
15
15
15
3
42
69
55
60
25
6
51
48
15
1 + 1
15
51
32[c]
25[d]
36[e]
5
5
10
5 (2.5 + 2.5)
5 (2.5 + 2.5)
[a] Reaction conditions: under nitrogen,
1 (0.5 mmol), 2a
(0.5 mmol), catalyst (as stated) in toluene at 160 °C for the time
indicated. [b] Isolated yields [%]. [c] In degassed toluene. [d] Reac-
tion at 160 °C under microwave irradiation in the presence of an
ionic liquid. [e] The catalyst was added in two portions: the first
half at the beginning, and the remainder after an interval of 6 h.
Table 1. Optimization of reaction conditions.[a]
Keeping this ratio constant, the catalyst loading was
modified between 2.5 and 10 mol-%, and also the timing
of the addition of the catalyst to the reaction mixture was
examined. The best result was obtained starting with 5 mol-
% of catalyst at the beginning of the process (69% yield;
Table 2, Entry 2). The use of degassed toluene was also
tried, but this had no influence on the yield (Table 2, En-
try 8). Finally, microwave (MW) dielectric heating was ap-
plied, which was expected to speed up the reaction. How-
ever, when the reaction was carried out in toluene in the
presence of one drop of [bmim][BF4] so that the required
temperature could be reached, only 25% of 5a was formed
after 2 h of heating (Table 2, Entry 9). The influence of the
solvent was also investigated. Switching from toluene to di-
oxane, THF, or 2-methyl-2-butanol (TAA) resulted in a de-
crease in the yield of 5a. The cyclization was also attempted
in the presence of various bases without any further im-
provement in the yield. On the basis of these experiments,
the most efficient procedure was heating the reaction mix-
ture at 160 °C in toluene (sealed vial) in the presence of
Entry
Ru catalyst
Ru3(CO)12
Ligand[b]
Yield of 5a [%][c]
1
2[d]
3
Xantphos
Xantphos
DPEphos
dppf
9
–
Յ 5
Յ 5
4
5
6
7
8
[Ru(benzene)Cl2]2
Xantphos
dppf
DPEphos
BIPHEP
58
–
–
–
9
[Ru(CO)(PPh3)3HCl]
Xantphos
DPEphos
BIPHEP
dppf
20
30
51
45
15
10
11
12
13
–
14
15
16
17
[Ru(p-cymene)Cl2]2
Xantphos
BIPHEP
dppf
65
40
32
22
DPEphos
18
19
20
21
[Ru(COD)Cl2]n
Xantphos
DPEphos
BIPHEP
dppf
52
5 mol-% of
a
1:1 mixture of [Ru(p-Cymene)Cl2]2/
Յ 5
Յ 5
Յ 5
Xanthphos for 15 h. This gave compound 5a in 69% yield
(Table 2, Entry 2).
The composition of the reaction mixture was analyzed at
different times using TLC, HPLC–MS, and GC–MS, and
[a] Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), and catalyst
(5 mol-%) in toluene (1 mL) under nitrogen at 160 °C for 12–16 h.
[b] Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; the most significant components are reported in Table 3.
DPEphos = bis[(2-diphenylphosphino)phenyl] ether; dppf = 1,1Ј-
After 3 h, most of the starting materials (i.e., 1 and 2a)
bis(diphenylphosphino)ferrocene; BIPHEP
= 2,2Ј-bis(diphenyl-
had been consumed, with the exclusive formation of com-
pounds 5a (30%), 4a (25%), and 6a (35%). No trace of
homocondensation products 7 (derived from the reaction
of postulated amino aldehydes 3 or 3Ј; see Scheme 1) was
phosphino)-1,1Ј-biphenyl; COD
= cyclooctadiene. [c] Isolated
yields [%]. [d] In refluxing toluene.
High temperature (160 °C) was always necessary for observed. As the reaction proceeded, intermediates 4a and
these reactions, as only traces of product could be observed 6a were slowly converted into 5a, which was finally isolated
in refluxing toluene (Table 1, Entry 2). To improve the with a maximum 69% yield after a reaction time of 15 h,
product yields, we focused on the Ru loading and the li- together with a mixture containing unreduced diazepine 6a
gand/catalyst ratio (Table 2). With [Ru(p-cymene)Cl2]2 and and different amounts of oligomeric products (see the Sup-
Xantphos as the catalytic system, several fine-tuning experi- porting Information). Increasing the reaction time to 48 h
ments indicated that a 1:1 ligand/Ru ratio is the optimum resulted in a decrease in the yield of 5a as a result of oligo-
choice for obtaining TH-BDZ 5a.
mer formation. To verify whether 4a was an intermediate
2
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Metal-Catalyzed Tandem 1,4-Benzodiazepine Synthesis
Table 3. Composition of the mixture at different reaction times.[a]
Time
[h]
7
[%]
4a
[%]
6a
[%]
5a
[%]
Oligomers[b]
[%]
3
6
15
48
0
0
0
0
25
10
Ͻ 5
Ͻ 5
35
23
13
5
30
55
69
51
Ͻ 5
8
10
35
[a] Values determined by HPLC–MS (ESI) analysis using benzyl-
amine as internal standard. [b] From HPLC–MS (ESI) analysis (see
Supporting Information).
Scheme 3. Proposed mechanism for the TH-BDZ domino synthe-
sis.
in the reaction, its preparation was undertaken by conden-
sation of 2-nitrobenzaldehyde (8) with 2a, followed by imine
reduction with H2 in the presence of Pd/C. The isolated
4a was treated with [Ru(p-cymene)Cl2]2 and Xantphos in
toluene at 160 °C for 12 h, and TH-BDZ 5a was formed in
45% yield (Scheme 2). This procedure was also extended to
amino alcohols 2b–2e to give the corresponding TH-BDZs
(i.e., 5b–5e) in moderate yields.
Having established a clarified picture of the reaction, we
went on to examine the scope and generality of the process
by treating different 2-aminobenzyl alcohols (1, 9, 10) with
aromatic and aliphatic β-amino alcohols (2a–2e,
Scheme 4).[12]
To our delight, in all the tested reactions, our procedure
gave the desired products in good to moderate yields (69–
36% based on the amount of starting benzyl alcohols). In
the reaction of 2-aminobenzyl alcohol (1), all the aromatic
and aliphatic β-amino alcohols (2a–2e) reacted smoothly,
and a high yield of the product was obtained with phenyl-
alaninol (2a). On the other hand, in the reactions with 2-
amino-3-methylbenzyl alcohol (9), the moderate yields of
12a–12e were probably due to a slight steric hindrance of-
fered by the aromatic ring substituent. The reactions with 2-
amino-4-chlorobenzyl alcohol (10) showed that the reaction
conditions are compatible with electron-withdrawing sub-
stituents (Scheme 4). A comparison between the one-pot
domino process and the multistep procedure, both devel-
oped in this work, was also possible. Comparing the yields
Scheme 2. Multistep procedure to BDZ 5. DCM = CH2Cl2.
Based on these results, a tentative reaction mechanism obtained for compounds 5a–5e in Schemes 2 and 4 shows
could be postulated (Scheme 3).
that the one-pot tandem process was superior.
A first borrowing hydrogen process (BH-1) occurs with
These reaction conditions were also used for the synthe-
the formation of intermediate 4a based on the fact that the sis of 1,3-disubstituted TH-BDZs. Thus, starting from
benzylic alcohol is oxidized more quickly than the aliphatic aminobenzyl alcohol (1), N-alkylated aminobenzyl alcohol
one. The more nucleophilic amino group condenses with 11 was obtained according to a reported procedure[13]
the aldehyde, and this is followed by imine reduction (BH- (Scheme 5). Ru-mediated cyclocondensation with amino
1). Then, a second borrowing hydrogen process starts (BH- alcohols 2a, 2b, and 2d gave products 15a, 15b, and 15d in
2) with oxidation to the aldehyde followed by cycloconden- acceptable overall yields (Scheme 5). These products are
sation to give dihydrodiazepine 6a. A second hydrogen more easily functionalizable on the single nucleophilic ni-
transfer completes the process to give the product (i.e., trogen atom using acyl chlorides or other standard electro-
5a).[11]
philes for diversity-oriented synthesis.
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V. R. Jumde, E. Cini, A. Porcheddu, M. Taddei
FULL PAPER
consistent results with secondary aminobenzyl alcohols.
Moreover, the final products could be isolated without any
extractive workup, they were stable to silica gel purification,
and they could be handled without extra precautions. Fur-
ther studies on the extension of this method to the synthesis
of unsaturated 1,4-benzodiazepines is currently underway.
Experimental Section
General Remarks: All reagents and solvents were used as purchased
from commercial suppliers without further purification. Reactions
were carried out in oven- or flame-dried vessels (vials) under nitro-
gen. Flash column chromatography was carried out with Merck
silica gel 60, 0.040–0.063 mm (230–400 mesh). TLC plates were vis-
ualized by staining with a solution of Ninhydrin in EtOH then
heating to develop the color. 1H (400 MHz) and 13C (100 MHz)
NMR spectra were recorded with an NMR spectrometer. Deuter-
ated chloroform was used as the solvent, and chemical shift values
(δ) are reported in parts per million (ppm). The residual signals of
the solvent (δ = 7.26 ppm for 1H, and δ = 77.16 ppm for 13C) were
used as an internal standard. The data are presented as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet and/or multiple resonances, br. s = broad
singlet), coupling constant (J) in Hz, and integration. Mass spec-
trometry data were collected with GC–MS or LC–MS ESI mass
spectrometers. GC conditions: ion-trap detector equipped with a
30 m OV-101 capillary column, splitting injector at 280 °C, method:
45 °C, 5 min; 45–100 °C, 5 °Cmin–1, 12 min at 100 °C; 100–280 °C,
50 °Cmin–1, 13 min at 280 °C. LC–MS conditions: ESI ionization
after passage through a C-18, 35ϫ5 mm, 3 μm column; elution:
mixture A (99.9% water, 0.1% HCOOH), mixture B (99.9% aceto-
nitrile, 0.1% HCOOH); 0–20 min, 20–60% mixture B; 20–25 min
60% mixture B; 25–30 min 60–20% mixture B; flow 0.6 mLmin–1,
room temperature. Reactions using MW dielectric heating were
carried out with a microwave oven (Discover from CEM) under
monomode irradiation in a 10 mL sealed vial. The internal tem-
perature was monitored using an internal IR sensor, and the maxi-
mum internal pressure was monitored and kept under 300 psi.
Compounds 1, 2, 8, 9, and 10 are commercially available. Com-
pound 11 was prepared using the reported procedure.[13] Ru cata-
lysts and ligands were purchased and used as received. Dry toluene
purchased from Sigma–Aldrich was used for reactions.
Scheme 4. Domino synthesis of 1,2,3,4-tetrahydro-1,4-benzodi-
azepines under Ru catalysis.
3-(Phenylmethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
(5a).
General Procedure: Under nitrogen, 2-aminobenzyl alcohol (1;
61 mg, 0.5 mmol), β-amino alcohol 2a (75 mg, 0.5 mmol), catalyst
[Ru(p-cymene)Cl2]2 (16 mg, 0.025 mmol, 5 mol-%), and Xantphos
(15 mg, 0.025 mmol, 5 mol-%) were added to a glass vial with a
magnetic stirrer bar. Toluene (1.0 mL) was added, and the glass
vial was sealed. The mixture was stirred at 160 °C in a sand bath
for 16 h. Then, the mixture was cooled to room temperature, and
the reaction was checked by TLC (CH2Cl2/MeOH, 9:1). Additional
dichloromethane was added, and the reaction mixture was concen-
trated under reduced pressure. This crude reaction mixture was
loaded directly onto a column for flash chromatographic purifica-
tion (CH2Cl2 to CH2Cl2/MeOH, 97:3), which gave pure benzo-
Scheme 5. Synthesis of TH-BDZs 15.
Conclusions
The first example of cyclization of β-amino alcohols with
2-aminobenzyl alcohols to give TH-BDZs through a tan-
dem borrowing hydrogen reaction is reported. Even though
the TH-BDZs products were obtained in moderate to good
yields, the direct formation of saturated benzodiazepines
without using any external hydrogenation source is an eye-
catching aspect of the reported method, which shows good
1
diazepine 5a (82 mg, 69%) as a yellowish waxy material. H NMR
(400 MHz, CDCl3): δ = 7.39–7.18 (m, 5 H), 7.07–7.03 (m, 2 H),
6.80 (t, J = 7.4 Hz, 1 H), 6.70 (d, J = 8.0 Hz, 1 H), 3.92, 3.83 (ABq,
J = 14.5 Hz, 2 H), 3.32 (dd, J = 13.0, 2.0 Hz, 1 H), 3.19–3.13 (m, 1
H), 2.78–2.67 (m, 3 H), 1.78 (br. s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 150.2, 139.1, 132.1, 130.1, 129.8, 129.0, 128.1, 127.0,
efficiency and high atom economy. The method also gave 121.1, 119.1, 62.4, 54.6, 53.0, 41.0 ppm. MS (ESI): m/z = 239 [M +
4
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Metal-Catalyzed Tandem 1,4-Benzodiazepine Synthesis
H]+. HRMS (ESI): calcd. for C16H19N2 [M + H]+ 239.1548; found
239.1544.
(dd, J = 13.4, 8.3 Hz, 1 H), 2.18 (s, 3 H), 1.87–1.62 (m, 1 H), 1.38
(dt, J = 13.7, 6.9 Hz, 1 H), 1.30–1.15 (m, 1 H), 2.0–1.6 (br. s, 2 H),
0.93 (d, J = 6.5 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
148.1, 130.1, 129.5, 128.2, 124.9, 120.1, 58.4, 53.6, 51.7, 42.6, 24.9,
22.97, 22.89, 17.7 ppm. MS (ESI): m/z = 219 [M + H]+. HRMS
(ESI): calcd. for C14H23N2 [M + H]+ 219.1861; found 219.185.
3-Phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
(5b):
Yield
61 mg (54%). 1H NMR (400 MHz, CDCl3): δ = 7.49–7.21 (m, 5
H), 7.19–7.03 (m, 2 H), 6.86 (t, J = 7.4 Hz, 1 H), 6.77 (d, J =
7.8 Hz, 1 H), 4.14–3.86 (m, 3 H), 3.42 (dd, J = 13.0, 2.3 Hz, 1 H),
2.97 (dd, J = 13.0, 9.5 Hz, 1 H), 2.29 (br. s, 2 H) ppm. 13C NMR 3-Ethyl-9-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (12d):
(100 MHz, CDCl3): δ = 149.7, 143.0, 132.3, 129.8, 128.6, 128.3
127.9, 127.5, 127.1, 126.8, 121.0, 118.9, 66.5, 56.7, 53.8 ppm. MS
(ESI): m/z = 225 [M + H]+. HRMS (ESI): calcd. for C15H17N2 [M
+ H]+ 225.1392; found 225.1389.
Yield 45 mg (46%). 1H NMR (400 MHz, CDCl3): δ = 6.99–6.64
(m, 2 H), 6.71 (t, J = 7.4 Hz, 1 H), 4.05, 3.90 (ABq, J = 14.6 Hz,
2 H), 3.68 (br. s, 2 H), 3.46 (dd, J = 13.4, 1.9 Hz, 1 H), 2.88 (d, J
= 6.8 Hz, 1 H), 2.73 (dd, J = 13.4, 8.4 Hz, 1 H), 2.18 (s, 3 H), 1.68–
1.38 (m, 2 H), 0.98 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 148.2, 129.7, 129.4, 128.3, 125.0, 120.2, 62.1, 52.5,
51.6, 26.1, 17.7, 10.9 ppm. MS (ESI): m/z = 191 [M + H]+. HRMS
(ESI): calcd. for C12H19N2 [M + H]+ 191.1548; found 191.1544.
3-Isobutyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (5c): Yield
43 mg (42%). 1H NMR (400 MHz, CDCl3): δ = 7.10–7.06 (m, 2
H), 6.82 (t, J = 7.1 Hz, 1 H), 6.74 (d, J = 7.6 Hz, 1 H), 4.03, 3.90
(ABq, J = 14.8 Hz, 2 H), 3.53 (br. s, 2 H), 3.35 (dd, J = 13.3,
2.5 Hz, 1 H), 3.0 (td, J = 9.0, 2.4 Hz, 1 H), 2.71–2.65 (m, 1 H),
3,9-Dimethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (12e): Yield
1.81–1.65 (m, 1 H), 1.37 (m, 1 H), 1.25 (m, 1 H), 0.95 (d, J = 36 mg (39%). 1H NMR (400 MHz, CDCl3): δ = 6.97 (dd, J = 21.9,
6.6 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.9, 132.1,
129.6, 127.7, 120.6, 118.6, 58.7, 55.3, 52.5, 43.5, 24.9, 23.2,
22.7 ppm. MS (ESI): m/z = 205 [M + H]+. HRMS (ESI): calcd. for
C13H21N2 [M + H]+ 205.1705; found 205.1700.
7.4 Hz, 2 H), 6.72 (t, J = 7.4 Hz, 1 H), 4.02, 3.89 (ABq, J =
14.6 Hz, 2 H), 3.78 (br. s, 2 H), 3.39 (dd, J = 13.5, 2.5 Hz, 1 H),
3.27–2.99 (m, 1 H), 2.70 (dd, J = 13.5, 8.7 Hz, 1 H), 2.19 (s, 3 H),
1.20 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
148.2, 130.6, 129.6, 128.1, 124.6, 121.3, 56.4, 55.5, 51.7, 19.3,
17.9 ppm. MS (ESI): m/z = 177 [M + H]+. HRMS (ESI): calcd. for
C11H17N2 [M + H]+ 177.1392; found 177.1387.
3-Ethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (5d): Yield 44 mg
1
(49%). H NMR (400 MHz, CDCl3): δ = 7.13–7.08 (m, 2 H), 6.83
(t, J = 7.4 Hz, 1 H), 6.74 (d, J = 7.8 Hz, 1 H), 5.15 (br. s, 2 H),
4.19, 3.94 (ABq, J = 14.5 Hz, 2 H), 3.39 (dd, J = 13.8, 1.9 Hz, 1
H), 3.03 (dd, J = 13.9, 6.0 Hz, 1 H), 2.91–2.85 (m, 1 H), 1.85–1.58
3-Benzyl-8-chloro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (13a):
Yield 87 mg (64%). 1H NMR (400 MHz, CDCl3): δ = 7.40–7.12
(m, 2 H), 1.01 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (100 MHz, (m, 5 H), 6.95 (d, J = 8.0 Hz, 1 H), 6.83–6.63 (m, 2 H), 3.87, 3.75
CDCl3): δ = 150.2, 131.0, 129.3, 126.5, 121.5, 119.2, 62.6, 51.3,
50.8, 25.2, 10.9 ppm. MS (ESI): m/z = 177 [M + H]+. HRMS (ESI):
calcd. for C11H17N2 [M + H]+ 177.1392; found 177.138.
(ABq, J = 14.6 Hz, 2 H), 3.30 (d, J = 11.7 Hz, 1 H), 3.15–3.09 (m,
1 H), 2.84–2.58 (m, 3 H), 2.0–1.5 (br. s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 150.9, 138.6, 132.7, 130.8, 130.3, 129.4,
128.7, 126.6, 120.4, 118.5, 61.9, 54.2, 52.1, 40.6 ppm. MS (ESI):
m/z = 273 [M + H]+. HRMS (ESI): calcd. for C16H18ClN2 [M +
H]+ 273.1158; found 273.1155.
3-Methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (5e): Yield
38 mg (47%). 1H NMR (400 MHz, CDCl3): δ = 7.13 (m, 2 H), 6.87
(t, J = 7.4 Hz, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 4.08, 3.95 (ABq, J
= 14.6 Hz, 2 H), 3.36 (dd, J = 13.4, 2.4 Hz, 1 H), 3.23–3.12 (m, 1
H), 2.90 (br. s, 2 H), 2.76 (dd, J = 13.3, 8.8 Hz, 1 H), 1.38–1.17
8-Chloro-3-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (13b):
Yield 60 mg (45%). 1H NMR (400 MHz, CDCl3): δ = 7.39–7.15
(m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.0, 130.4, (m, 5 H), 7.04 (d, J = 8.0 Hz, 1 H), 6.91–6.69 (m, 2 H), 4.04–3.88
128.9, 128.5, 121.2, 119.0, 56.5, 54.6, 51.3, 18.8 ppm. MS (ESI):
m/z = 163 [M + H]+. HRMS (ESI): calcd. for C10H15N2 [M +
H]+ 163.1235; found 163.1232.
(m, 3 H), 3.39 (d, J = 12.4 Hz, 1 H), 2.96 (dd, J = 13.1, 9.4 Hz, 1
H), 2.05 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.7,
142.7, 132.8, 130.9, 130.5, 128.6, 127.6, 127.0, 120.6, 118.7, 66.2,
56.4, 53.1 ppm. MS (ESI): m/z = 259 [M + H]+. HRMS (ESI):
calcd. for C15H16ClN2 [M + H]+ 259.1002; found 259.1097.
3-Benzyl-9-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (12a):
Yield 68 mg (54%). 1H NMR (400 MHz, CDCl3): δ = 7.41–7.18
(m, 5 H), 6.97 (m, 2 H), 6.72 (m, 1 H), 3.95, 3.85 (ABq, J = 8-Chloro-3-isobutyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (13c):
1
14.5 Hz, 2 H), 3.40 (dd, J = 13.1, 2.3 Hz, 1 H), 3.18 (qd, J = 7.3,
2.5 Hz, 1 H), 2.79 (m, 1 H), 2.68 (m, 2 H), 2.19 (s, 3 H), 1.94 (br.
Yield 48 mg (39%). H NMR (400 MHz, CDCl3): δ = 6.95 (d, J =
8.0 Hz, 1 H), 6.83–6.59 (m, 2 H), 3.93, 3.79 (ABq, J = 14.9 Hz, 2
s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.1, 138.9, 131.6, H), 3.30 (dd, J = 13.2, 2.5 Hz, 1 H), 2.93–2.87 (m, 1 H), 2.63–2.58
129.5, 129.3, 128.7 (2 C), 128.0 (2 C), 126.5, 125.0, 120.1, 61.9, (m, 1 H), 1.71 (br. s, 2 H), 1.40–1.07 (m, 3 H), 0.91 (d, J = 6.5 Hz,
53.6, 52.6, 40.6, 17.7 ppm. MS (ESI): m/z = 253 [M + H]+. HRMS
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.0, 132.7, 130.7,
130.3, 120.3, 118.4, 58.5, 55.0, 51.9, 43.3, 24.9, 23.2, 22.7 ppm. MS
(ESI): m/z = 239 [M + H]+. HRMS (ESI): calcd. for C13H20ClN2
[M + H]+ 239.1315; found 239.1312.
(ESI): calcd. for C17H21N2 [M + H]+ 253.1705; found 253.170.
9-Methyl-3-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (12b):
Yield 55 mg (46%). 1H NMR (400 MHz, CDCl3): δ = 7.46–7.17
(m, 5 H), 7.04 (d, J = 7.4 Hz, 2 H), 6.78 (t, J = 7.5 Hz, 1 H), 4.10– 8-Chloro-3-ethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
(13d):
1
3.97 (m, 3 H), 3.52 (dd, J = 13.1, 2.5 Hz, 1 H), 2.95 (dd, J = 13.1,
Yield 38 mg (36%). H NMR (400 MHz, CDCl3): δ = 6.95 (d, J =
9.4 Hz, 1 H), 2.23 (s, 3 H), 2.0 (br. s, 2 H) ppm. 13C NMR 7.9 Hz, 1 H), 6.77–6.62 (m, 2 H), 3.94, 3.80 (ABq, J = 14.8 Hz, 2
(100 MHz, CDCl3): δ = 147.9, 143.0, 132.1, 129.4, 128.6, 128.1, H), 3.34 (dd, J = 13.0, 1.7 Hz, 1 H), 2.78–2.73 (m, 1 H), 2.66–2.61
127.5, 127.1, 125.2, 120.4, 66.3, 56.1, 53.6, 17.8 ppm. MS (ESI):
m/z = 239 [M + H]+. HRMS (ESI): calcd. for C16H19N2 [M +
H]+ 239.1548; found 239.1544.
(m, 1 H), 1.87 (br. s, 2 H), 1.44–1.39 (m, 2 H), 0.96 (t, J = 7.5 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.0, 130.8, 130.2,
128.9, 120.3, 118.4, 62.2, 54.3, 51.9, 27.1, 11.0 ppm. MS (ESI): m/z
= 211 [M + H]+. HRMS (ESI): calcd. for C11H16ClN2 [M + H]+
211.1002; found 211.1000.
3-Isobutyl-9-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (12c):
Yield 47 mg (43%). 1H NMR (400 MHz, CDCl3): δ = 7.06–6.87
(m, 2 H), 6.81–6.59 (m, 1 H), 4.03, 3.89 (ABq, J = 14.8 Hz, 2 H), 8-Chloro-3-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (13e):
1
3.42 (dd, J = 13.4, 2.2 Hz, 1 H), 3.01 (d, J = 6.3 Hz, 1 H), 2.67 Yield 40 mg (40%). H NMR (400 MHz, CDCl3): δ = 6.96 (d, J =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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/KAP1
Date: 20-12-14 11:19:48
Pages: 8
V. R. Jumde, E. Cini, A. Porcheddu, M. Taddei
FULL PAPER
7.6 Hz, 1 H), 6.83–6.60 (m, 2 H), 3.94, 3.81 (ABq, J = 14.5 Hz, 2 3.13–2.60 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.8,
H), 3.29 (d, J = 12.8 Hz, 1 H), 3.10–3.01 (m, 1 H), 2.79–2.54 (m, 138.2, 129.4, 128.8, 128.1, 125.9, 123.5, 117.6, 115.5, 63.0, 59.4,
1 H), 1.12 (d, J = 5.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): 49.7, 37.5 ppm. MS (ESI): m/z = 257.16 [M + H]+. HRMS (ESI):
δ = 151.0, 133.0, 131.0, 120.6 (2 C), 118.6, 56.1, 55.5, 51.6,
29.8 ppm. MS (ESI): m/z = 197 [M + H]+. HRMS (ESI): calcd. for
C10H14ClN2 [M + H]+ 197.0845; found 197.0841.
calcd. for C16H21N2O [M + H]+ 257.1654; found 257.1651.
2-[(2-Aminobenzyl)amino]-2-phenylethanol (4b): Yield 102 mg
(64%). 1H NMR (400 MHz, CDCl3): δ = 7.44–7.25 (m, 5 H), 7.13–
3-Benzyl-1-isobutyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (15a): 7.03 (m, 1 H), 6.92 (dd, J = 7.9, 6.9 Hz, 1 H), 6.73–6.58 (m, 2 H),
Yield 63 mg (43%). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.07 3.87–3.65 (m, 3 H), 3.65–3.50 (m, 2 H), 3.48–2.81 (br. s, 2 H) ppm.
(m, 7 H), 6.97–6.75 (m, 2 H), 3.95–3.85 (m, 1 H), 3.13–3.09 (m, 3
13C NMR (100 MHz, CDCl3): δ = 145.8, 140.0, 129.7, 128.3, 128.1,
H), 2.83–2.33 (m, 6 H), 1.71–1.64 (m, 1 H), 0.91 (d, J = 6.5 Hz, 3 127.3, 127.1, 126.9, 123.6, 117.7, 115.5, 66.4, 63.8, 49.6 ppm. MS
H), 0.86 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): (ESI): m/z = 243.15 [M + H]+. HRMS (ESI): calcd. for C15H19N2O
δ = 152.5, 138.6, 133.8, 129.8, 129.4, 128.7, 127.9, 126.6, 121.2,
117.5, 62.5, 61.1, 60.8, 52.3, 40.3, 27.0, 20.8, 20.6 ppm. MS (ESI):
m/z = 295 [M + H]+. HRMS (ESI): calcd. for C20H27N2 [M +
H]+ 295.2174; found 295.2170.
[M + H]+ 243.1497; found 243.1491.
2-[(2-Aminobenzyl)amino]-4-methylpentan-1-ol (4c): Yield 85 mg
(58%). 1H NMR (400 MHz, CDCl3): δ = 7.15–6.92 (m, 2 H), 6.80–
6.48 (m, 2 H), 4.55 (br. s, 2 H), 3.94–3.84 (m, 2 H), 3.70 (dd, J =
11.3, 3.0 Hz, 1 H), 3.45–3.40 (m, 1 H), 2.87–2.75 (m, 1 H), 1.70–
1.51 (m, 1 H), 1.44–1.23 (m, 2 H), 0.83 (d, J = 6.5 Hz, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 145.8, 130.3, 128.8, 121.3, 118.0,
116.1, 62.5, 56.1, 48.2, 39.2, 24.5, 22.5, 22.0 ppm. MS (ESI): m/z =
223.18 [M + H]+. HRMS (ESI): calcd. for C13H23N2O [M + H]+
223.1810; found 223.1807.
1-Isobutyl-3-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (15b):
Yield 83 mg (59%). 1H NMR (400 MHz, CDCl3): δ = 7.41–7.15
(m, 7 H), 7.01–6.85 (m, 2 H), 4.11–3.90 (m, 1 H), 3.15 (m, 2 H),
2.91–2.70 (m, 2 H), 1.96 (br. s, 1 H), 1.90–1.76 (m, 2 H), 1.38–1.17
(m, 1 H), 1.0 (d, J = 6.6 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 151.9, 142.3, 134.1, 129.2, 128.1,
127.3, 127.0, 126.6, 120.7, 117.1, 64.7, 62.8, 62.0, 52.8, 26.7, 20.3,
20.1 ppm. MS (ESI): m/z = 281 [M + H]+. HRMS (ESI): calcd. for
C19H25N2 [M + H]+ 281.2018; found 281.2015.
2-[(2-Aminobenzyl)amino]butan-1-ol (4d): Yield 90 mg (70%). 1H
NMR (400 MHz, CDCl3): δ = 7.14–6.95 (m, 2 H), 6.76–6.55 (m, 2
H), 3.91–3.65 (m, 5 H), 3.43 (dd, J = 11.3, 6.3 Hz, 1 H), 2.66–2.61
(m, 1 H), 1.65–1.36 (m, 2 H), 0.89 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 145.8, 130.0, 128.5, 122.2, 117.9,
115.9, 62.2, 59.5, 48.7, 22.9, 9.9 ppm. MS (ESI): m/z = 195 [M +
H]+. HRMS (ESI): calcd. for C11H19N2O [M + H]+ 195.1497;
found 195.1495.
3-Ethyl-1-isobutyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (15d):
Yield 45 mg (39%). 1H NMR (400 MHz, CDCl3): δ = 7.24–7.04
(m, 2 H), 6.98–6.80 (m, 2 H), 4.08, 3.95 (ABq, J = 13.7 Hz, 2 H),
3.78 (br. s, 1 H, NH), 3.14–2.84 (m, 3 H), 2.64 (dd, J = 13.9, 9.6 Hz,
2 H), 1.90–1.73 (m, 1 H), 1.66–1.32 (m, 2 H), 1.08–0.74 (m, 9 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 152.4, 130.2, 128.5, 121.4,
117.5, 62.5, 60.8, 60.1, 51.3, 27.0, 26.1, 20.8, 20.6, 10.8 ppm. MS
(ESI): m/z = 233 [M + H]+. HRMS (ESI): calcd. for C15H25N2 [M
+ H]+ 233.2018; found 233.2016.
2-[(2-Aminobenzyl)amino]propan-1-ol (4e): Yield 80 mg (67%). 1H
NMR (400 MHz, CDCl3): δ = 7.14–6.93 (m, 2 H), 6.75–6.58 (m, 2
H), 3.94 (d, J = 12.7 Hz, 1 H), 3.76 (d, J = 12.7 Hz, 1 H), 3.71 (s,
2 H), 3.60 (dd, J = 11.1, 3.9 Hz, 1 H), 3.40–3.35 (m, 1 H), 2.93–
2.77 (m, 1 H), 1.11 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 145.8, 129.7, 128.3, 123.0, 117.8, 115.8, 65.4, 53.7,
48.9, 16.0 ppm. MS (ESI): m/z = 181.13 [M + H]+. HRMS (ESI):
calcd. for C10H17N2O [M + H]+ 181.1341; found 181.1337.
Multistep Procedure for the Synthesis of Benzodiazepines 5a–e
Step 1: Under nitrogen, β-amino alcohol 2a–2e (0.66 mmol) and 2-
nitrobenzaldehyde (8; 0.66 mmol) were dissolved in dry dichloro-
methane (8 mL), and then Na2SO4 (2.5 equiv.) was added. The
mixture was stirred at room temperature for 12 h, then it was fil-
tered, and the Na2SO4 was washed with CH2Cl2. The solvent was
evaporated to dryness to give the crude imine, which was used in
the next step without further purification. The formation of the
Supporting Information (see footnote on the first page of this arti-
cle): General, HPLC MS (ESI) analysis, 1H and 13C NMR spectra.
1
Acknowledgments
product was confirmed by TLC, MS, and H NMR spectroscopic
analysis of the crude material. The imine was dissolved in methanol
under nitrogen, and then Pd/C (catalytic amount) was added. The
reaction mixture was stirred at room temperature under hydrogen
(1 atm) for 16 h. The reaction mixture was then filtered through
Celite, and the solvent was evaporated. The crude material was
purified by flash column chromatography on silica gel (eluent
CH2Cl2/MeOH) to give pure amine 4a–4e.
Financial support from the Ministero dell’Università e della
Ricerca (MIUR), Rome (PRIN project 2009RMW3Z5_006) and
the Regione Toscana (Project POR CRO FSE 2007-2013 Asse IV,
Capitale Umano) is gratefully acknowledged.
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(t, J = 7.6 Hz, 1 H), 6.96 (d, J = 7.4 Hz, 1 H), 6.75–6.47 (m, 2 H),
3.77 (s, 2 H), 3.63 (dd, J = 10.9, 4.0 Hz, 1 H), 3.54–3.30 (m, 1 H),
1
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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[11] The presence of unsaturated compound 6a in the reaction mix-
ture, even after 15 h, suggests that the Ru-mediated hydrogena-
tion of BDZ is slower than the oxidation/condensation step.
We cannot exclude the possibility that this sluggish reactivity
could also be due to degradation of the catalyst after a long
time at 160 °C. Attempts to promote the hydrogenation by the
addition of hydrogen donors (such as iPrOH, HCOOH, trieth-
ylsilane, or the Hantzsch ester) were unsuccessful.
[12] When (S)-2a was submitted to these reaction conditions, prod-
uct 5a was recovered as a racemic mixture. All the products
prepared in this work were obtained as mixtures of enantio-
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Received: September 25, 2014
Published Online: ᭿
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Job/Unit: O43261
/KAP1
Date: 20-12-14 11:19:48
Pages: 8
V. R. Jumde, E. Cini, A. Porcheddu, M. Taddei
FULL PAPER
Hydrogen Transfer
V. R. Jumde, E. Cini, A. Porcheddu,
M. Taddei* ....................................... 1–8
A Metal-Catalyzed Tandem 1,4-Benzodi-
azepine Synthesis Based on Two Hydrogen-
Transfer Reactions
Keywords: Hydrogen transfer
/ Homo-
geneous catalysis / Ruthenium / Cycli-
zation / Domino reactions
Two consecutive Ru-catalyzed borrowing hydrogen processes offer an efficient method for
benzodiazepine synthesis.
8
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Eur. J. Org. Chem. 0000, 0–0