Diversity-oriented synthesis of 1,3-benzodiazepines

Article abstract of DOI:10.1016/j.tet.2017.09.034

A concise assembly of the 1,3-benzodiazepine core from A³-coupling-derived propargylamines and ortho-bromophenylisocyanates is described. The developed synthetic sequence involves the addition of propargylamine to isocyanate followed by palladium-catalyzed intramolecular alkyne hydroarylation that could be accomplished in a stepwise or one-pot manner.

Full text of DOI:10.1016/j.tet.2017.09.034

Tetrahedron xxx (2017) 1e9
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Tetrahedron
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Diversity-oriented synthesis of 1,3-benzodiazepines
,
,
Gaigai Wang a 1, Chao Liu a 1, Binbin Li a, Yingchun Wang a, Kristof Van Hecke b,
Erik V. Van der Eycken c d, Olga P. Pereshivko a **, Vsevolod A. Peshkov a
,
,
, *
a College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Dushu Lake Campus, Suzhou, 215123, China
b XStruct, Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281-S3, B-9000, Ghent, Belgium
c Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F,
3001, Leuven, Belgium
d Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow, 117198, Russia
a r t i c l e i n f o
a b s t r a c t
A concise assembly of the 1,3-benzodiazepine core from A3-coupling-derived propargylamines and
ortho-bromophenylisocyanates is described. The developed synthetic sequence involves the addition of
propargylamine to isocyanate followed by palladium-catalyzed intramolecular alkyne hydroarylation
that could be accomplished in a stepwise or one-pot manner.
Article history:
Received 26 June 2017
Received in revised form
13 September 2017
Accepted 18 September 2017
Available online xxx
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
A3-coupling
Propargylamines
Isocyanates
Reductive Heck reaction
1,3-Benzodiazepines
Medium-rings
1. Introduction
1,3-Benzodiazepine skeleton, which results from a small struc-
tural deviation from the above scaffolds (Fig. 1), has been relatively
Nitrogen-containing seven-membered heterocyclic systems
such as 3-benzazepine1 and 1,4-benzodiazepine2 constitute a core
structural elements of many natural and biologically active mole-
cules and therefore could be rightfully designated as privileged
structures (Fig. 1).3 Fenoldopam, a representative 3-benzazepine-
containing medication, is the first selective peripheral dopamine
receptor agonist approved for clinical use for the treatment of se-
vere hypertension.4 Diazepam belongs to a large family of 1,4-
benzodiazepine-based psychoactive drugs whose mechanism of
action involves the enhancement of the inhibitory activity of the
gamma-aminobutyric acid (GABA) neurotransmitter at the GABAA
receptor, resulting in sedative, sleep-inducing, anxiolytic, alcohol
withdrawal, anticonvulsant, and muscle relaxant therapeutic
properties.5
less studied in terms of synthesis6 and potential biological and
therapeutic applications.7 Therefore, we set a goal to develop a
combinatorial route to provide a diversity-oriented entry to this
medium-ring-containing class of heterocycles.
Recently, others and we made substantial efforts on exploiting
A3-coupling-derived propargylamines in heterocyclic chemistry.8,9
Subjecting secondary propargylamines 1 to a palladium-catalyzed
intramolecular alkyne hydroarylation process, we were able to
attain a small set of 3-benzazepines 2 (Scheme 1).10,11 Using pri-
mary propargylamines 3, we have developed a series of protocols
that selectively convert in situ generated propargylureas 4 into
imidazol-2-ones 5,12,13 imidazolidin-2-ones 6,14 oxazolidin-2-
imines 7,15 and pyrimidin-2-ones 816 via silver- or gold-catalyzed
cycloisomerizations (Scheme 1).
2. Results and discussion
* Corresponding author.
** Corresponding author.
Inspired by these processes, we envisaged that the 1,3-
benzodiazepine core 9 could be assembled by a palladium-
catalyzed intramolecular alkyne hydroarylation of propargylic
E-mail addresses: olga@suda.edu.cn (O.P. Pereshivko), vsevolod@suda.edu.cn
(V.A. Peshkov).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.tet.2017.09.034
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G. Wang et al. / Tetrahedron xxx (2017) 1e9
bond carbopalladation and subsequent trapping of the resulting
vinyl-palladium species A with sodium formate as reducing agent.
The carbopalladation step is crucial for the whole process and al-
lows to control the ring size and the double bond geometry in the
forming 1,3-benzodiazepine product 9 (Scheme 2).17 The required
secondary propargylamines 3 are readily accessible from primary
amines 12, aldehydes 13 and terminal acetylenes 14 through a
CuBr-catalyzed A3-coupling protocol (Scheme 2).18
Reacting propargylamine 3a with ortho-bromophenyl isocya-
nate (11a) gave propargylurea 10a in 98% yield. In turn, this sub-
strate was selected to perform the optimization of the Pd-catalyzed
intramolecular alkyne hydroarylation that is also frequently
referred to as reductive Heck reaction (Table 1). Conducting this
transformation in DMF/H2O mixtures that previously proved to be
beneficial for such processes delivered desired 1,3-benzodiazepine
9a albeit in low yield of maximum 38% (Table 1, entries 1e3). At the
same time, this was accompanied by the degradation of significant
amounts of urea 10a back to the propargylamine 3a (Table 1, entries
1e3). Using DMF or iPrOH as solvent gave no or little of 3a, but the
yield of target 9a remained insufficient (Table 1, entries 4e6),
despite some enhancement observed when reaction in DMF was
conducted in the presence of phase-transfer catalyst (Table 1, entry
5). To our delight, the yield of 9a was substantially improved by
Fig. 1. Nitrogen-containing seven-membered heterocyclic systems.
ureas 10 derived from secondary propargylamines 3 and ortho-
bromophenyl isocyanates 11 (Scheme 2). The proposed hydro-
arylation process involves an oxidative insertion of the Pd(0)-
catalyst into the arylbromide moiety of 10, followed by a triple
Scheme 1. Synthesis of various heterocycles from the A3-coupling-derived propargylamines 1 and 3.
Scheme 2. Strategy towards 1,3-benzodiazepines 9.
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G. Wang et al. / Tetrahedron xxx (2017) 1e9
3
Table 1
Optimization of the Pd-catalyzed intramolecular alkyne hydroarylation (reductive Heck) step.a
Entry
Catalyst
Solvent
Time, h
Yield, %b
9a
3a
1
2
3
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
DMF/H2O (3:1)
DMF/H2O (3:1)
DMF/H2O (9:1)
DMF
DMF
iPrOH
iPrOH/H2O (3:1)
iPrOH/H2O (4:1)
tBuOH/H2O (3:1)
iPrOH/H2O (3:1)
iPrOH/H2O (3:1)
THF
1
1
1
1
2
4
4
4
4
4
4
18
13
38
21
36
46
34
62
57
55
54
28
ee
43
15
25
e
4
5c
6
e
9
7
8
9
10
11
12d
26
14
18
15
38
e
Pd(PPh3)2Cl2
3 mol% Pd(OAc)2/6 mol% PPh3
Pd(PPh3)4
10 mol% Ni(cod)2/20 mol% P(nBu)3
a
The reactions were run at 110 ꢀC on 0.25 mmol scale in 2 mL of solvent with 1.5 equiv od sodium formate as reducing agent.
b
c
The yields of 9a and 3a were determined by 1H NMR of the reaction mixture after work-up using 3,4,5-trimethoxybenzaldehyde as internal standard.
The reaction was conducted in the presence of 1 equiv of tetra-butylammonium bromide (TBAB).
d
e
The reaction was conducted at 100 ꢀC in 0.5 mL of THF with 1.2 equiv of triethylsilane as reducing agent.
65% of unreacted 10a was detected by 1H NMR analysis of reaction mixture after removal of nickel catalyst by filtration through a short plug of silica gel. cod ¼ 1,5-
cyclooctadiene.
switching to iPrOH/H2O or tBuOH/H2O mixtures as the reaction
media, although the competing degradation of 10a into 3a could
not be completely suppressed (Table 1, entries 7e9). The best result
was obtained for the reaction with Pd(PPh3)2Cl2 as a catalyst and
iPrOH/H2O (3:1) as solvent producing 9a in 62% yield as was
determined by 1H NMR analysis of reaction mixture (Table 1, entry
7). Pd(OAc)2/PPh3 and Pd(PPh3)4 showed lower efficiency under the
same settings (Table 1, entries 10 and 11) while an attempt to utilize
one of the literature protocols based on nickel catalysis19 was
completely unproductive (Table 1, entry 12).
Having effective conditions for the Pd-catalyzed alkyne hydro-
arylation step in hands, we moved to exploring the scope and
limitations of our strategy (Scheme 3). The required propargylurea
precursors 10 were obtained in high yields by reaction of prop-
argylamines 3 with ortho-bromophenyl isocyanates 11. The high
efficiency of this transformation motivated us to compare the
Scheme 3. Scope of the Pd-catalyzed intramolecular alkyne hydroarylation leading to 1,3-benzodiazepine 9.
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G. Wang et al. / Tetrahedron xxx (2017) 1e9
on this three-step methodology. The results obtained during 2016/
2017 academic year at Soochow University, China demonstrate that
the students from the intensive training class could satisfactorily
reproduce the procedures described in this study with a minimal
failure rate.22
In order to further extend the scope of our strategy and to
introduce an additional diversity point into target 1,3-benz-
odiazepine scaffold, we evaluated a base-promoted N-alkylation
reaction of 9 (Scheme 5a). Reacting 1,3-benzodiazepines 9 with
benzyl chlorides 17 or with methyl iodide (18) in the presence of
sodium hydride smoothly produced alkylated 1,3-benzodiazepines
19 in up to 96%. Another viable synthetic manipulation involved an
acid-promoted removal of the para-methoxybenzyl group23 from
the substrate 9f to afford 1,3-benzodiazepine 20 containing
two unprotected NH groups (Scheme 5b left). Interestingly, an
analogous transformation of 9e bearing phenyl group at the allylic
position was accompanied by a double-bond migration leading to
the formation of isomerized 1,3-benzodiazepine 21 (Scheme 5b
right).
Fig. 2. X-ray crystallographic molecular structure of 1,3-benzodiazepine 9d, showing
thermal displacement ellipsoids at the 50% probability level.
3. Conclusion
sequential and one-pot approaches, when combining it with the
final Pd-catalyzed alkyne hydroarylation process (Scheme 3). Using
propargylureas 10a-j bearing a (hetero)aromatic substituent on the
triple-bond and with no additional substituents on the isocyanate-
derived benzene ring (R4 ¼ H), the target 1,3-benzodiazepines 9a-j
were obtained in up to 62% and 52% for the stepwise and one-pot
approaches, respectively. The structure of the representative 1,3-
benzodiazepine 9d was confirmed by X-ray crystallographic anal-
ysis (Fig. 2).20 Conducting the Pd-catalyzed intramolecular alkyne
hydroarylation with substrates 10k,l bearing alkyl group on the
triple-bond, led to an unclean reaction hampering the isolation of
desired products 9k,l. Thus, 1,3-benzodiazepines 9k,l were ob-
tained in a lower purity. The reactions of propargylureas 10m,n
derived from branched isocyanate 11b (R4 ¼ 4,6-diMe) delivered
1,3-benzodiazepines 9m,n in 64% and 69%, respectively (stepwise
approach).
With not too many ortho-bromophenyl isocyanates 11 being
commercially available, we turned our attention to the corres-
ponding ortho-bromophenyl carboxylic acids 15a,b. Reacting later
with diphenylphosphoryl azide (DPPA) in the presence of trie-
thylamine gave rise to the desired isocyanates 11c,d through a
Curtius rearrangement of initially formed acyl azides 16a,b.21 The
reaction mixtures containing either 11c or 11d were directly treated
with propargylamine 3c allowing to attain propargylurea pre-
cursors 10o,p. Finally, Pd-catalyzed cyclization afforded 1,3-
benzodiazepines 9o,p featuring electron donating or electron
withdrawing R4 substituents (Scheme 4).
In summary, we have developed a diversity-oriented strategy
towards 1,3-benzodiazepines that involves a one-pot or sequential
reaction of A3-coupling-derived propargylamines with ortho-bro-
mophenylisocyanates, followed by a palladium-catalyzed intra-
molecular alkyne hydroarylation. An additional N-alkylation step
further enriches the overall strategy allowing to construct a 1,3-
benzodiazepine core featuring five points of diversity.
4. Experimental
4.1. General information
All starting materials and solvents were purchased from com-
mercial sources and used as received. Melting points were
measured using INESA WRR apparatus. Infrared (FT-IR) spectra
were recorded neat on a Bruker Vertex 70. 1H (400 MHz) and 13C
(100 MHz) NMR spectra were recorded using a Bruker Avance III HD
instrument. The 1H and 13C chemical shifts are reported relative to
TMS using the residual CDCl3 signal as internal reference. HRMS
were performed on a Bruker micrOTF-Q III.
4.2. General procedure for the synthesis of secondary
propargylamines 3
Copper (I) bromide catalyst (17 mg, 0.12 mmol) was placed in a
screw cap vial followed by addition of dry toluene (1.0 mL), amine
12 (0.8 mmol), aldehyde 13 (1 mmol), and phenyl acetylene 14
(1.6 mmol). The resulting mixture was flushed with argon, sealed
and stirred at 100 ꢀC for 5 h. Upon completion of this time, the
mixture was diluted with ethyl acetate and transferred to the round
bottom flask. Then the silicagel was added and the mixture was
concentrated under reduced pressure. Column chromatography on
It is important to stress, that despite the moderate efficiency in
the Pd-catalyzed alkyne hydroarylation step, the overall synthetic
sequence towards 1,3-benzodiazepines 9 starting from amines 12,
aldehydes 13 and acetylenes 14 proved to be operationally simple
and robust. In fact, we have developed and implemented a practical
exercise for the fourth year undergraduate students, which is based
Scheme 4. Extended scope of the Pd-catalyzed intramolecular alkyne hydroarylation leading to 1,3-benzodiazepine 9.
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5
Scheme 5. Base-promoted alkylation of 9 and PMB-deprotection of 9f and 9e.
silica gel using petroleum ether-ethyl acetate (9:1 / 8:2) mixture
as eluent provided pure propargylamine 3.
and transferred to the round bottom flask. Then the silicagel was
added and the mixture was concentrated under reduced pressure.
Column chromatography on silica gel using petroleum ether-ethyl
acetate (9:1 / 8:2 / 1:1) mixture as eluent provided 1,3-
benzodiazepine 9.
4.3. General procedure for the synthesis of propargylureas 10a-n
Propargylamine 3 (0.7 mmol) was placed in a screw cap vial
followed by addition of dry DCM (2.8 mL) and ortho-bromophenyl
isocyanate 11 (1.05 mmol). The resulting mixture was sealed and
stirred at rt for 0.5 h. Upon completion of this time, the mixture was
diluted with ethyl acetate and transferred to the round bottom
flask. Then the silicagel was added and the mixture was concen-
trated under reduced pressure. Column chromatography on silica
gel using petroleum ether-ethyl acetate (49:1 / 9:1) mixture as
eluent provided pure propargylurea 10.
4.6. General procedure for the one-pot synthesis of 1,3-
benzodiazepines 9
Propargylamine 3 (0.5 mmol) was placed in a screw cap vial
followed by addition of dry DCM (2 mL) and ortho-bromophenyl
isocyanate 11 (0.75 mmol). The resulting mixture was sealed and
stirred at rt for 0.5 h. Upon completion of this time, the vial was
open and the DCM was evaporated under the ambient condition.
The crude propargylurea 10 was transferred to the next step. Bis(-
triphenylphosphine)palladium(II) dichloride (10.5 mg, 0.015 mmol)
and sodium formate (51 mg, 0.75 mmol) were added to the vial
with the crude urea 10 followed by addition of isopropanol (3 mL)
and water (1 mL). The resulting mixture was flushed with argon,
sealed and stirred at 100 ꢀC for 4 h. Upon completion of
this time, the mixture was diluted with ethyl acetate and trans-
ferred to the round bottom flask. Then the silicagel was
added and the mixture was concentrated under reduced pressure.
Column chromatography on silica gel using petroleum ether-ethyl
acetate (9:1 / 8:2 / 1:1) mixture as eluent provided 1,3-
benzodiazepine 9.
4.4. General procedure for the synthesis of propargylureas 10o,p21c
2-Bromobenzoic acid 15 (2.5 mmol) was placed in a screw cap
vial followed by addition of dry dioxane (6 mL), diphenylphos-
phoryl azide (DPPA, 688 mg, 2.5 mmol) and triethylamine (273 mg,
2.7 mmol). The resulting mixture was sealed and stirred at rt for 1 h
followed by heating at 100 ꢀC for another 2 h. Then propargylamine
3c (459 mg, 2 mmol) in dry dioxane (4 mL) was added and the
mixture was continued to stir at rt for 1 h. Upon completion of this
time, the mixture was diluted with ethyl acetate and transferred to
the round bottom flask. Then the silicagel was added and the
mixture was concentrated under reduced pressure. Column chro-
matography on silica gel using petroleum ether-ethyl acetate (9:1
for 10o; 47:3 for 10p) mixture as eluent provided pure prop-
argylurea 10.
4.6.1. (Z)-3-Benzyl-5-benzylidene-4-propyl-1,3,4,5-tetrahydro-2H-
benzo[d][1,3]diazepin-2-one (9a)
Yield: 61% (stepwise from 10a); beige solid; mp: 127e129 ꢀC; 1H
NMR (400 MHz, CDCl3): d 7.76 (bs,1H), 7.44e7.33 (m, 4H), 7.27e7.12
4.5. General procedure for the synthesis of 1,3-benzodiazepines 9
through the Pd-catalyzed intramolecular alkyne hydroarylation
(m, 6H), 7.03e6.94 (m, 2H), 6.91e6.82 (m, 3H), 4.87 (d, J ¼ 14.5 Hz,
1H), 4.49 (dd, J ¼ 8.8, 7.0 Hz, 1H), 3.70 (d, J ¼ 14.5 Hz, 1H), 1.51e1.21
(m, 2H), 1.10e0.78 (m, 2H), 0.57 (t, J ¼ 7.3 Hz, 3H); 13C NMR
Propargylurea 10 (0.5 mmol), bis(triphenylphosphine)palladiu-
m(II) dichloride (10.5 mg, 0.015 mmol) and sodium formate (51 mg,
0.75 mmol) were placed to the screw cap vial followed by addition
of isopropanol (3 mL) and water (1 mL). The resulting mixture was
flushed with argon, sealed and stirred at 100 ꢀC for 4 h. Upon
completion of this time, the mixture was diluted with ethyl acetate
(100 MHz, CDCl3): d 157.2, 139.3, 137.7, 137.6, 137.2, 129.6, 129.1,
128.94, 128.92, 128.5, 128.3, 128.0, 127.4, 127.2, 125.3, 121.7, 118.6,
54.5, 53.9, 33.7, 19.5, 13.8; IR (ATR, neat): 3210, 3066, 3023, 2960,
n
2926, 2860, 1655, 1576, 1474, 1454, 1432, 1339, 1281, 1260, 1219,
830, 755, 721, 697 cmꢁ1; HRMS (ESI, [MþH]þ) for C26H27N2Oþ
calcd. 383.2118, found 383.2116.
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4.6.2. (Z)-5-Benzylidene-3-(4-methoxybenzyl)-4-propyl-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9b)
4.6.6. (Z)-4-Benzyl-5-benzylidene-3-(4-methoxybenzyl)-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9f)
After column chromatography, product 9f was additionally pu-
rified by washing with diethyl ether. Yield: 50% (stepwise from
10f); white solid; mp: 212e214 ꢀC; 1H NMR (400 MHz, CDCl3):
Yield: 51% (stepwise from 10b); white solid; mp: 220e222 ꢀC;
1H NMR (400 MHz, CDCl3):
d 7.71 (bs, 1H), 7.45e7.32 (m, 4H),
7.26e7.16 (m, 3H), 7.03e6.92 (m, 2H), 6.91e6.74 (m, 3H), 6.68 (d,
J ¼ 8.5 Hz, 2H), 4.81 (d, J ¼ 14.4 Hz, 1H), 4.49 (t, J ¼ 7.8 Hz, 1H), 3.77
(s, 1H), 3.64 (d, J ¼ 14.4 Hz, 1H), 1.50e1.26 (m, 2H), 1.12e0.82 (m,
d
7.99e7.78 (m,1H), 7.43e7.36 (m,1H), 7.33e7.26 (m, 2H), 7.26e7.19
(m, 2H), 7.19e7.11 (m, 3H), 7.10e7.02 (m, 1H), 7.00e6.93 (m, 1H),
6.89 (s, 1H), 6.78e6.68 (m, 4H), 6.61e6.54 (m, 2H), 6.54e6.46 (m,
2H), 4.91 (d, J ¼ 14.3 Hz, 1H), 4.55 (dd, J ¼ 10.6, 4.4 Hz, 1H), 3.81 (s,
3H), 3.42 (d, J ¼ 14.3 Hz, 1H), 2.86 (dd, J ¼ 12.8, 10.8 Hz, 1H), 2.44
2H), 0.59 (t, J ¼ 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 159.0,
156.7, 139.2, 137.7, 136.9, 130.3, 129.8, 129.7, 129.2, 129.0, 128.6,
128.1, 127.3, 125.3, 121.9, 118.3, 113.7, 55.3, 54.1, 53.1, 33.7, 19.6, 13.9;
IR (ATR, neat):
n
3325, 3210, 3071, 3022, 2960, 2926, 2853, 1655,
(dd, J ¼ 13.0, 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 159.2, 156.7,
1614,1575,1511,1474,1436,1323,1305,1281,1233,1305,1281,1233,
1220, 1173, 1029, 831, 761, 754, 699, 688, 658 cmꢁ1; HRMS (ESI,
[MþNa]þ) for C27H28N2O2Naþ calcd.435.2043, found 435.2055.
138.0, 137.3, 137.0, 130.5, 130.1, 129.6, 129.5, 129.2, 129.0, 128.7,
128.4, 128.3, 127.1, 126.7, 125.2, 122.1, 118.6, 113.8, 55.7, 55.4, 52.7,
38.5; IR (ATR, neat):
n 3219, 3079, 2961, 2923, 2851, 1656, 1606,
1577, 1509, 1462, 1438, 1352, 1297, 1236, 1221, 1176, 1031, 831, 765,
758, 746, 701 cmꢁ1; HRMS (ESI, [MþNa]þ) for C31H28N2O2Naþ
calcd. 483.2043, found 483.2034.
4.6.3. (Z)-5-Benzylidene-3-butyl-4-propyl-1,3,4,5-tetrahydro-2H-
benzo[d][1,3]diazepin-2-one (9c)
After column chromatography, product 9c was additionally
purified by washing with diethyl ether. Yield: 62% (stepwise from
10c), 52% (one-pot from 3c and 11a); white solid; mp: 243e245 ꢀC;
4.6.7. (Z)-3-Benzyl-5-(4-fluorobenzylidene)-4-isobutyl-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9g)
Yield: 53% (stepwise from 10g), 40% (one-pot from 3g and 11a);
1H NMR (400 MHz, CDCl3):
d 8.25 (bs, 1H), 7.45e7.35 (m, 3H),
beige solid; mp: 208e211 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.65 (bs,
7.34e7.17 (m, 4H), 7.01e6.94 (m, 1H), 6.94e6.87 (m, 2H), 4.57 (t,
J ¼ 7.9 Hz, 1H), 3.46e3.32 (m, 1H), 3.11e2.97 (m, 1H), 1.75e1.61 (m,
1H), 1.61e1.48 (m, 1H), 1.45e1.20 (m, 3H), 1.20e1.01 (m, 4H), 0.84 (t,
J ¼ 7.3 Hz, 3H), 0.71 (t, J ¼ 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
1H), 7.38 (dd, J ¼ 7.8, 1.2 Hz, 1H), 7.26e7.15 (m, 4H), 7.11e6.96 (m,
5H), 6.96e6.91 (m, 2H), 6.86 (s, 1H), 6.84 (dd, J ¼ 8.1, 0.6 Hz, 1H),
4.49e4.40 (m, 1H), 4.44 (t, J ¼ 7.3 Hz, 1H), 3.97 (d, J ¼ 14.6 Hz, 1H),
1.36e1.21 (m, 3H), 0.56 (d, J ¼ 6.1 Hz, 3H), 0.50 (d, J ¼ 6.0 Hz, 3H);
13C NMR (100 MHz, CDCl3):
d
162.0 (d, J ¼ 247.0 Hz), 157, 139.8,
d
156.1, 139.6, 137.5, 137.1, 129.7, 129.0, 128.9, 128.6, 128.3, 127.3,
125.3,121.6,118.2, 55.7, 51.2, 34.3, 30.3, 20.0,19.9,14.2,13.7; IR (ATR,
137.6, 137.0, 133.5 (d, J ¼ 3.4 Hz), 130.7 (d, J ¼ 7.9 Hz), 129.6, 129.1,
128.9, 128.4, 127.6, 127.0, 125.4, 121.9, 118.5 (d, J ¼ 1.3 Hz), 115.46 (d,
neat): n 3218, 3116, 3077, 3020, 2958, 2933, 2872, 1656, 1577, 1476,
1462, 1434, 1361, 1302, 1219, 1074, 817, 749, 699, 661 cmꢁ1; HRMS
J ¼ 21.4 Hz), 54.0, 53.4, 40.9, 24.9, 22.7, 22.6; IR (ATR, neat):
n 3213,
(ESI, [MþH]þ) for C23H29N2O calcd. 349.2274, found 349.2256.
3068, 2952, 2923, 2868, 1657, 1579, 1504, 1473, 1454, 1431, 1329,
1286, 1218, 1155, 832, 757, 745, 730, 700, 657, 618 cmꢁ1; HRMS (ESI,
[MþNa]þ) for C27H27FN2ONaþ calcd. 437.2000, found 437.2007.
4.6.4. (Z)-5-Benzylidene-4-isobutyl-3-(4-methoxybenzyl)-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9d)
4.6.8. (Z)-4-((3-Butyl-4-isobutyl-2-oxo-1,2,3,4-tetrahydro-5H-
benzo[d][1,3]diazepin-5-ylidene)methyl)benzonitrile (9h)
Yield: 62% (stepwise from 10h), 47% (one-pot from 3i and 11a);
After column chromatography, product 9d was additionally
purified by washing with diethyl ether. Yield: 42% (stepwise from
10d), 40% (one-pot from 3d and 11a); white solid; mp: 223e226 ꢀC;
beige solid; mp: 236e238 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.54 (bs,
1H NMR (400 MHz, CDCl3):
d 8.69 (bs, 1H), 7.48e7.32 (m, 4H),
1H), 7.71 (d, J ¼ 7.9 Hz, 2H), 7.42e7.32 (m, 3H), 7.29e7.20 (m, 1H),
7.04e6.91 (m, 2H), 6.86 (s,1H), 4.50 (t, J ¼ 7.3 Hz,1H), 3.52e3.37 (m,
1H), 3.11e2.97 (m, 1H), 1.72e1.50 (m, 2H), 1.44e1.31 (m, 1H),
1.23e1.04 (m, 4H), 0.91e0.79 (m, 6H), 0.75 (t, J ¼ 6.9 Hz, 3H); 13C
7.25e7.16 (m, 3H), 7.05e6.90 (m, 3H), 6.84 (d, J ¼ 8.4 Hz, 2H), 6.70
(d, J ¼ 8.4 Hz, 2H), 4.89 (d, J ¼ 14.4 Hz, 1H), 4.52 (t, J ¼ 7.0 Hz, 1H),
3.78 (s, 3H), 3.74 (d, J ¼ 14.5 Hz, 1H), 1.38e1.19 (m, 3H), 0.58 (d,
J ¼ 5.8 Hz, 3H), 0.49 (d, J ¼ 5.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d 156.0, 142.4, 142.2, 137.2, 132.4, 129.7,
d
159.0, 157.1, 139.7, 137.7, 137.1, 130.4, 129.8, 129.6, 129.2, 128.9,
129.61, 129.55, 125.7, 124.6, 121.8, 118.7, 118.5, 111.0, 54.4, 51.5, 41.2,
30.4, 25.1, 23.1, 22.9, 20.0, 13.8; IR (ATR, neat): 3198, 3056, 2955,
128.5, 127.8, 127.2, 125.5, 121.8, 118.5, 113.7, 55.4, 53.1, 52.8, 40.8,
24.9, 22.7, 22.6; IR (ATR, neat): 3210, 3071, 3022, 2960, 2902,1655,
n
n
2933, 2866, 2223, 1653, 1603, 1580, 1500, 1486, 1474, 1436, 1362,
1339, 1308, 1228, 876, 832, 781, 746, 662 cmꢁ1; HRMS (ESI,
[MþH]þ) for C25H30N3O calcd. 388.2383, found 388.2364.
1615, 1576, 1510, 1475, 1435, 1323, 1238, 1218, 1172, 1030, 834, 766,
755, 698, 659 cmꢁ1; HRMS (ESI, [MþNa]þ) for C28H30N2O2Naþ
calcd. 449.2199, found 449.2197.
4.6.9. (Z)-3-Benzyl-4-isobutyl-5-(4-(trifluoromethyl)benzylidene)-
1,3,4,5-tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9i)
After column chromatography, product 9i was additionally pu-
rified by washing with diethyl ether. Yield: 50% (stepwise from
10i); white solid; mp: 232e235 ꢀC; 1H NMR (400 MHz, CDCl3):
4.6.5. (Z)-5-Benzylidene-3-(4-methoxybenzyl)-4-phenyl-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9e)
After column chromatography, product 9e was additionally
purified by washing with diethyl ether. Yield: 39% (stepwise from
10e), 38% (one-pot from 3e and 11a); beige solid; mp: 246e248 ꢀC;
d
7.76e7.51 (m, 3H), 7.44e7.36 (m, 1H), 7.31e7.09 (m, 6H),
1H NMR (400 MHz, CDCl3):
d
7.58e7.47 (m, 2H), 7.36e7.28 (m, 3H),
7.05e6.97 (m, 1H), 6.90 (s, 1H), 6.89e6.77 (m, 3H), 4.71 (d,
J ¼ 14.7 Hz, 1H), 4.42 (t, J ¼ 7.3 Hz, 1H), 3.97 (d, J ¼ 14.7 Hz, 1H),
1.48e1.22 (m, 3H), 0.60 (d, J ¼ 6.2 Hz, 3H), 0.51 (d, J ¼ 6.1 Hz, 3H);
7.26e7.17 (m, 3H), 7.15e7.06 (m, 4H), 7.05e6.99 (m, 2H), 6.98e6.90
(m, 1H), 6.80 (d, J ¼ 8.5 Hz, 2H), 6.68e6.58 (m, 3H), 5.87 (s, 1H), 4.70
(d, J ¼ 14.4 Hz, 1H), 4.01 (d, J ¼ 14.4 Hz, 1H), 3.74 (s, 3H); 13C NMR
13C NMR (100 MHz, CDCl3):
d 157.0, 141.2, 141.0, 137.2, 137.1, 129.7,
(100 MHz, CDCl3):
d
159.1, 157.5, 138.5, 137.4, 137.2, 136.4, 130.6,
129.5, 129.3 (q, J ¼ 32.5 Hz), 128.8, 128.5, 127.7, 126.3, 125.5 (q,
129.7, 129.2, 129.0, 128.84, 128.82, 128.80, 128.2, 127.5, 127.0, 126.1,
125.8, 122.0, 118.8, 113.8, 57.53, 55.26, 53.00; IR (ATR, neat): 3212,
J ¼ 3.7 Hz),125.0,124.3 (q, J ¼ 271.9 Hz),122.0,118.6, 53.9, 53.1, 40.8,
n
25.0, 22.8, 22.6; IR (ATR, neat): n 3327, 3205, 3112, 3068, 2966, 2957,
3077, 3026, 2832,1661,1577,1510,1472,1436,1302,1237,1218,1174,
2936, 2902, 2872, 1655, 1580, 1508, 1472, 1456, 1436, 1361, 1321,
1226, 1160, 1107, 1067, 1017, 884, 875, 831, 818, 751, 731, 701,
668 cmꢁ1; HRMS (ESI, [MþNa]þ) for C28H27F3N2ONaþ calcd.
1028, 824, 766, 750, 737, 698, 655 cmꢁ1; HRMS (ESI, [MþNa]þ) for
C
30H26N2O2Naþ calcd. 469.1886, found 469.1878.
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7
487.1968, found 487.1959.
(d, J ¼ 3.5 Hz), 132.7, 131.7, 130.6, 130.5 (d, J ¼ 7.9 Hz), 128.4, 127.3,
125.7, 123.3, 115.5 (d, J ¼ 21.5 Hz), 54.4, 51.4, 41.7, 30.4, 25.0, 22.91,
4.6.10. (Z)-3-(4-Methoxybenzyl)-4-propyl-5-(thiophen-3-
ylmethylene)-1,3,4,5-tetrahydro-2H-benzo[d][1,3]diazepin-2-one
(9j)
22.90, 20.5, 20.0, 18.5, 13.7; IR (ATR, neat): n 3225, 2959, 2927, 2870,
1641,1505,1465,1430,1317,1220, 863, 836, 821, 781, 744, 612 cmꢁ1
;
HRMS (ESI, [MþNa]þ) for C26H33FN2ONaþ calcd. 431.2469, found
Yield: 36% (stepwise from 10j); beige solid; mp: 206e208 ꢀC; 1H
431.2473.
NMR (400 MHz, CDCl3): d 7.53 (bs, 1H), 7.41e7.32 (m, 2H), 7.26e7.18
(m, 1H), 7.03e6.89 (m, 5H), 6.83e6.79 (m, 1H), 6.78 (s, 1H), 6.74 (d,
J ¼ 8.5 Hz, 2H), 4.76 (d, J ¼ 14.5 Hz, 1H), 4.61 (dd, J ¼ 8.7, 7.0 Hz, 1H),
3.87 (d, J ¼ 14.5 Hz, 1H), 3.79 (s, 3H), 1.51e1.32 (m, 2H), 1.13e0.84
4.6.14. (Z)-3-Benzyl-4-isobutyl-7,9-dimethyl-5-(4-
(trifluoromethyl)benzylidene)-1,3,4,5-tetrahydro-2H-benzo[d][1,3]
diazepin-2-one (9n)
(m, 2H), 0.62 (t, J ¼ 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
159.0,
Yield: 69% (stepwise from 10n); beige solid; mp: 147e148 ꢀC; 1H
157.0, 139.2, 138.2, 136.9, 130.1, 129.8, 129.6, 128.97, 128.95, 125.8,
125.3, 123.2, 122.4, 121.9, 118.5, 113.8, 55.3, 54.7, 53.4, 33.7, 19.6,
NMR (400 MHz, CDCl3):
d
7.56 (d, J ¼ 8.1 Hz, 2H), 7.23e7.10 (m, 5H),
7.06 (s, 1H), 7.01 (s, 1H), 6.91e6.83 (m, 3H), 6.78 (s, 1H), 4.67 (d,
J ¼ 14.6 Hz, 1H), 4.41 (t, J ¼ 7.2 Hz, 1H), 4.07 (d, J ¼ 14.6 Hz, 1H), 2.35
(s, 3H), 2.30 (s, 3H), 1.42e1.19 (m, 3H), 0.60 (d, J ¼ 6.1 Hz, 3H), 0.54
13.9; IR (ATR, neat):
n 3322, 3220, 3114, 3079, 2990, 2968, 2936,
1656,1606,1577, 1509, 1462, 1437, 1352,1297, 1236, 1221, 1176, 1031,
831, 765, 758, 746, 702 cmꢁ1
C
;
HRMS (ESI, [MþNa]þ) for
(d, J ¼ 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 156.2, 141.3, 141.2,
25H26N2O2SNaþ calcd. 441.1607, found 441.1597.
137.2, 132.7, 132.1, 131.0, 129.3, 129.2 (d, J ¼ 32.6 Hz), 128.8, 128.5,
128.4,127.6,126.9,125.5,125.4 (q, J ¼ 3.7 Hz),124.3 (d, J ¼ 272.0 Hz),
4.6.11. (Z)-3-(4-Methoxybenzyl)-5-pentylidene-4-propyl-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9k)
123.7, 53.7, 53.2, 41.0, 24.9, 22.6, 22.6, 20.5, 18.5; IR (ATR, neat): n
3306, 3240, 2959, 2926, 2869, 1637, 1455, 1322 1292, 1163, 1125,
1103, 1066, 1017, 907, 862, 841, 760, 734, 714, 700 cmꢁ1; HRMS (ESI,
[MþNa]þ) for C30H31F3N2ONaþ calcd. 515.2281, found 515.2280.
The isolated product was contaminated with unidentified im-
purities. Yield: 53% (67% purity, stepwise from 10k); washing with
diethyl ether can improve the purity but leads to significant loses of
9k; yield after wash: 32% (78% purity); white solid; mp:
4.6.15. (Z)-5-Benzylidene-3-butyl-7,8-dimethoxy-4-propyl-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9o)
185e188 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.75 (bs, 1H), 7.30 (d,
J ¼ 8.5 Hz, 2H), 7.20e7.10 (m, 2H), 6.94e6.82 (m, 3H), 6.81e6.75 (m,
1H), 5.68 (t, J ¼ 7.3 Hz, 1H), 4.89 (d, J ¼ 14.8 Hz, 1H), 4.48 (d,
J ¼ 14.8 Hz, 1H), 4.24 (dd, J ¼ 8.9, 6.8 Hz, 1H), 3.80 (s, 3H), 1.91e1.77
(m, 1H), 1.70e1.59 (m, 1H), 1.47e1.36 (m, 2H), 1.29e1.17 (m, 4H),
1.06e0.92 (m, 2H), 0.90e0.83 (m, 3H), 0.68 (t, J ¼ 7.3 Hz, 3H); 13C
Yield: 64% (stepwise from 10o); brown solid; mp: 183e184 ꢀC;
1H NMR (400 MHz, DMSO-d6):
d 8.76 (bs, 1H), 7.46e7.38 (m, 2H),
7.34e7.24 (m, 3H), 6.90 (s, 2H), 6.83 (s, 1H), 4.52 (t, J ¼ 7.8 Hz, 1H),
3.75 (s, 3H), 3.72 (s, 3H), 3.35e3.24 (m, 1H), 2.85e2.74 (m, 1H),
1.72e1.58 (m, 1H), 1.57e1.43 (m, 1H), 1.41e1.17 (m, 2H), 1.02e0.87
(m, 4H), 0.82 (t, J ¼ 7.3 Hz, 3H), 0.61 (t, J ¼ 7.0 Hz, 3H); 13C NMR
NMR (100 MHz, CDCl3):
d 159.2, 156.1, 136.6, 136.1, 131.5, 130.2,
129.8, 129.4, 128.3, 126.6, 121.9, 117.8, 114.1, 55.4, 54.6, 53.3, 34.0,
32.1, 27.8, 22.6, 19.4, 14.1, 13.7; IR (ATR, neat): 3198, 3058, 2962,
(100 MHz, DMSO-d6) d 155.2, 149.4, 143.5, 138.5, 137.4, 131.2, 128.7,
n
128.4, 126.9, 125.3, 115.8, 112.0, 102.3, 55.8, 55.3, 54.4, 49.8, 33.5,
2932, 2861, 1653, 1581, 1512, 1461, 1434, 1336, 1249, 1226, 1176,
29.6, 19.27, 19.25, 14.0, 13.4; IR (ATR, neat): n 3342, 3212, 3090,
1036, 853, 830, 760, 732, 689 cmꢁ1; HRMS (ESI, [MþNa]þ) for
2950, 2929, 2857, 1664, 1444, 1251, 861, 697 cmꢁ1; HRMS (ESI,
C
25H32N2O2Naþ calcd. 415.2356, found 415.2348.
[MþH]þ) for C25H33N2O3þ calcd. 409.2486, found 409.2478.
4.6.12. (Z)-5-Butylidene-3-(4-methoxybenzyl)-4-propyl-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9l)
The isolated product was contaminated with unidentified im-
purities. Yield: 46% (60% purity, stepwise from 10l); washing with
diethyl ether can improve the purity but leads to significant loses of
9l; yield after wash: 25% (78% purity); beige solid; mp: 163e165 ꢀC;
4.6.16. (Z)-5-Benzylidene-3-butyl-7-fluoro-4-propyl-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9p)
Yield: 57% (stepwise from 10p); beige solid; mp: 187e188 ꢀC; 1H
NMR (400 MHz, DMSO-d6):
d 9.08 (s, 1H), 7.48e7.40 (m, 2H),
7.37e7.27 (m, 3H), 7.23 (dd, J ¼ 10.1, 2.7 Hz, 1H), 7.18e7.04 (m, 2H),
6.99 (s,1H), 4.52 (t, J ¼ 7.8 Hz,1H), 3.33e3.21 (m,1H), 2.92e2.79 (m,
1H), 1.69e1.53 (m, 1H), 1.53e1.39 (m, 1H), 1.38e1.12 (m, 2H),
1H NMR (400 MHz, CDCl3):
d
8.16 (bs, 1H), 7.32 (d, J ¼ 8.4 Hz, 2H),
7.21e7.10 (m, 2H), 6.94e6.81 (m, 4H), 5.68 (t, J ¼ 7.2 Hz, 1H), 4.91 (d,
J ¼ 14.8 Hz,1H), 4.50 (d, J ¼ 14.8 Hz,1H), 4.24 (dd, J ¼ 9.1, 6.5 Hz,1H),
3.80 (s, 3H),1.87e1.75 (m,1H),1.70e1.58 (m,1H),1.47e1.36 (m, 2H),
1.36e1.23 (m, 2H), 1.05e0.94 (m, 2H), 0.84 (t, J ¼ 7.3 Hz, 3H), 0.68 (t,
1.04e0.86 (m, 4H), 0.79 (t, J ¼ 7.3 Hz, 3H), 0.61 (t, J ¼ 6.9 Hz, 3H); 13
C
NMR (100 MHz, DMSO-d6)
d
156.7 (d, J ¼ 237.0 Hz), 154.7, 137.9 (d,
J ¼ 1.4 Hz), 136.8, 134.0 (d, J ¼ 1.9 Hz), 128.7, 128.5, 127.3, 125.8 (d,
J ¼ 7.3 Hz), 119.5 (d, J ¼ 8.1 Hz), 115.8 (d, J ¼ 22.7 Hz), 114.8 (d,
J ¼ 22.9 Hz), 54.2, 49.8, 33.5, 29.6, 19.3, 19.2, 13.9, 13.4; IR (ATR,
J ¼ 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 159.2, 156.3, 136.8,
136.4, 131.2, 130.3, 129.9, 129.2, 128.3, 126.6, 121.7, 118.0, 114.1, 55.4,
neat): n 3334, 3221, 3102, 3065, 2957, 2931, 2872, 1660, 1475, 1222,
54.6, 53.3, 34.0, 30.1, 23.1, 19.3, 14.0, 13.7; IR (ATR, neat):
n
3200,
1189, 862, 828, 763, 700 cmꢁ1
;
HRMS (ESI, [MþH]þ) for
3062, 2957, 2930, 2859, 1654, 1613, 1581, 1512, 1487, 1462, 1435,
C
23H28FN2Oþ calcd. 367.2180, found 367.2167.
1334, 1309, 1248, 1228, 1175, 1037, 853, 828, 762, 734, 689 cmꢁ1
;
HRMS (ESI, [MþNa]þ) for C24H30N2O2Naþ calcd. 401.2199, found
4.7. General procedure for the synthesis of 1,3-benzodiazepines 19
by base-promoted alkylation of 9
401.2201.
4.6.13. (Z)-3-Butyl-5-(4-fluorobenzylidene)-4-isobutyl-7,9-
dimethyl-1,3,4,5-tetrahydro-2H-benzo[d][1,3]diazepin-2-one (9m)
Yield: 64% (stepwise from 10m), 48% (one-pot from 3h and 11b);
beige solid; mp: 168e170 ꢀC; 1H NMR (400 MHz, CDCl3):
1,3-Benzodiazepine 9 (0.3 mmol) was placed in a screw cap vial
followed by addition of dry THF (1 mL), sodium hydride (19.2 mg,
60% dispersion in mineral oil, 0.48 mmol) and benzyl chloride 17
(0.6 mmol) or methyl iodide (18, 85 mg, 0.6 mmol). The resulting
mixture was sealed and stirred at 60 ꢀC for 3 h. Upon completion of
this time, the mixture was diluted with ethyl acetate and trans-
ferred to the round bottom flask. Then the silicagel was added and
the mixture was concentrated under reduced pressure. Column
chromatography on silica gel using petroleum ether-ethyl acetate
d
7.24e7.15 (m, 2H), 7.13e7.04 (m, 2H), 7.02 (s, 1H), 6.96 (s, 1H), 6.80
(s, 1H), 6.63 (bs, 1H), 4.50 (t, J ¼ 7.2 Hz, 1H), 3.48e3.33 (m, 1H),
3.09e2.96 (m, 1H), 2.29 (s, 3H), 2.27 (s, 3H), 1.61e1.47 (m, 2H),
1.38e1.02 (m, 5H), 0.86e0.78 (m, 6H), 0.73 (t, J ¼ 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3):
d
162.0 (d, J ¼ 247.2 Hz), 155.3, 140.6, 133.5
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8
G. Wang et al. / Tetrahedron xxx (2017) 1e9
(9:1 / 8:2) mixture as eluent provided pure 1,3-benzodiazepine
19.
1.40e1.04 (m, 4H), 0.98e0.82 (m, 4H), 0.69 (d, J ¼ 6.7 Hz, 3H), 0.39
(d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 162.1 (d,
J ¼ 246.9 Hz), 161.0, 139.4, 138.8, 136.8, 135.7, 132.6, 132.5 (d,
J ¼ 3.4 Hz), 131.5, 130.5 (d, J ¼ 8.0 Hz), 129.4, 125.5115.51 (d,
J ¼ 21.4 Hz), 63.0, 48.1, 42.0, 38.8, 30.8, 24.4, 24.0, 21.1, 20.9, 20.6,
4.7.1. (Z)-1-Benzyl-5-benzylidene-4-isobutyl-3-(4-
methoxybenzyl)-1,3,4,5-tetrahydro-2H-benzo[d][1,3]diazepin-2-
one (19a)
18.6, 14.0; IR (ATR, neat): n 2957, 2925, 2858, 1642, 1626, 1603, 1507,
Yield: 93%; white solid; mp: 141e143 ꢀC; 1H NMR (400 MHz,
1466, 1459, 1447, 1367, 1343, 1279, 1220, 1157, 1146, 1078, 858, 830,
817, 787, 759 cmꢁ1; HRMS (ESI, [MþH]þ) for C27H36FN2Oþ calcd.
423.2806, found 423.2819.
CDCl3): d 7.34e7.26 (m, 3H), 7.26e7.08 (m, 11H), 7.00e6.94 (m, 2H),
6.79 (d, J ¼ 8.6 Hz, 2H), 6.70 (s, 1H), 5.18 (d, J ¼ 15.4 Hz, 1H), 4.96 (d,
J ¼ 15.4 Hz, 1H), 4.60e4.49 (m, 2H), 4.27 (d, J ¼ 14.6 Hz, 1H), 3.82 (s,
3H),1.65e1.54 (m,1H),1.43e1.30 (m,1H),1.18e1.06 (m,1H), 0.59 (d,
J ¼ 6.6 Hz, 3H), 0.42 (d, J ¼ 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
4.8. General procedure for PMB-deprotection of 1,3-
benzodiazepines 9f,e23
d
159.3, 159.0, 141.7, 139.2, 138.8, 136.7, 134.7, 130.5, 130.3, 130.1,
128.6, 128.6, 128.5, 128.3, 127.7, 127.1, 126.8, 124.5, 121.7, 113.9, 58.6,
55.4, 55.1, 51.7, 42.1, 24.6, 23.1, 22.0; IR (ATR, neat): 3029, 2954,
1,3-Benzodiazepine 9f (92 mg, 0.2 mmol) was placed in a screw
cap vial followed by addition of DCM (1.5 mL), trifluoroacetic acid
n
2931, 2865, 1615, 1509, 1454, 1413, 1242, 1200, 1174, 1031, 770, 759,
700, 692 cmꢁ1; HRMS (ESI, [MþH]þ) for C35H37N2Oþ2 calcd.
517.2850, found 517.2860.
(0.5 mL) and triflic acid (12 mL). The resulting mixture was sealed
and stirred at 50 ꢀC for 3 h. Upon completion of this time, the
mixture was diluted with ethyl acetate and transferred to the round
bottom flask. Then the silicagel was added and the mixture was
concentrated under reduced pressure. Column chromatography on
silica gel using petroleum ether-ethyl acetate (1:1) mixture as
eluent provided 1,3-benzodiazepine 20. Starting from 9e (45 mg,
0.1 mmol), 1,3-benzodiazepine 21 was obtained following the same
procedure and using petroleum ether-ethyl acetate (9:1 / 8:2)
mixture as eluent for column chromatography.
4.7.2. (Z)-5-Benzylidene-3-(4-methoxybenzyl)-1-methyl-4-phenyl-
1,3,4,5-tetrahydro-2H-benzo[d][1,3]diazepin-2-one (19b)
Yield: 84%; white solid; mp: 144e147 ꢀC; 1H NMR (400 MHz,
CDCl3):
d 7.30e7.17 (m, 5H), 7.13e7.05 (m, 5H), 7.05e6.94 (m, 5H),
6.85e6.78 (m, 2H), 6.74 (d, J ¼ 8.6 Hz, 2H), 5.71 (s, 1H), 4.28 (d,
J ¼ 14.3 Hz, 1H), 4.17 (d, J ¼ 14.3 Hz, 1H), 3.79 (s, 3H), 3.05 (s, 3H);
13C NMR (100 MHz, CDCl3):
d 159.6, 159.1, 141.6, 140.0, 136.7, 136.6,
131.0, 130.8, 129.4, 128.84, 128.75, 128.6, 128.4, 128.2, 127.3, 127.0,
125.8, 123.4,119.8, 113.8, 61.2, 55.3, 51.0, 37.8; IR (ATR, neat): 2954,
2922, 2853, 1649, 1607, 1508, 1493, 1458, 1446, 1299, 1258, 1235,
1172, 1098, 1033, 851, 765, 749, 737, 725, 703, 609 cmꢁ1; HRMS (ESI,
[MþH]þ) for C31H29N2O2þ calcd. 461.2224, found 461.2231.
4.8.1. (Z)-4-Benzyl-5-benzylidene-1,3,4,5-tetrahydro-2H-benzo[d]
[1,3]diazepin-2-one (20)
n
Yield: 90%; white solid; mp: 154e155 ꢀC; 1H NMR (400 MHz,
DMSO-d6):
d
9.10 (bd, J ¼ 1.5 Hz, 1H), 7.58 (dd, J ¼ 7.2, 1.7 Hz, 1H),
7.37e7.14 (m, 9H), 7.14e7.08 (m, 2H), 7.02e6.94 (m, 1H), 6.93e6.85
(m, 2H), 6.73 (m, 1H), 4.52 (q, J ¼ 7.4 Hz, 1H), 2.76 (dd, J ¼ 13.4,
7.3 Hz, 1H), 2.64 (dd, J ¼ 13.4, 7.8 Hz, 1H); 13C NMR (100 MHz,
4.7.3. (Z)-5-Benzylidene-3-butyl-1-methyl-4-propyl-1,3,4,5-
tetrahydro-2H-benzo[d][1,3]diazepin-2-one (19c)
DMSO-d6): d 155.4, 139.4, 137.9, 137.4, 136.6, 129.8, 129.0, 128.8,
Yield: 89%; yellowish oil; 1H NMR (400 MHz, CDCl3):
d
7.51 (dd,
128.6, 128.3, 128.2, 127.8, 127.1, 126.3, 126.2, 121.3, 118.1, 50.0, 40.3;
J ¼ 7.7, 1.3 Hz, 1H), 7.43e7.35 (m, 2H), 7.35e7.25 (m, 4H), 7.15e7.03
(m, 2H), 6.92 (s, 1H), 4.49 (t, J ¼ 7.6 Hz, 1H), 3.31 (s, 3H), 3.20e3.07
(m, 2H), 1.88e1.73 (m, 1H), 1.47e1.18 (m, 5H), 1.18e1.04 (m, 2H),
0.79 (t, J ¼ 7.2 Hz, 3H), 0.76 (t, J ¼ 7.3 Hz, 3H); 13C NMR (100 MHz,
IR (ATR, neat): n ;
3215, 3027, 1683, 1480, 1421, 1231, 746, 697 cmꢁ1
HRMS (ESI, [MþH]þ) for C23H21N2Oþ calcd. 341.1648, found
341.1638.
CDCl3):
d
159.2,141.5,139.3,137.4,130.4,128.8,128.7,128.52,128.45,
4.8.2. 5-Benzyl-4-phenyl-1,3-dihydro-2H-benzo[d][1,3]diazepin-2-
one (21)
127.9, 127.2, 122.9, 119.1, 58.9, 50.4, 38.0, 34.9, 30.2, 20.1, 19.5, 14.0,
13.8; IR (ATR, neat):
n
2957, 2928, 2871,1649,1596,1459,1447,1300,
Yield: 43%; beige solid; mp: 179e180 ꢀC; 1H NMR (400 MHz,
1233, 1118, 1096, 1033, 753, 700 cmꢁ1; HRMS (ESI, [MþH]þ) for
DMSO-d6):
7.29e7.17 (m, 3H), 7.16e7.06 (m, 4H), 4.06e4.00 (m, 2H), 13C NMR
(100 MHz, DMSO-d6) 152.5, 140.7, 135.92, 135.85, 131.9, 129.2,
128.32, 128.28, 128.24, 128.0, 127.9, 125.9, 123.3, 121.1, 119.3, 115.5,
d 7.79e7.73 (m, 1H), 7.68 (bs, 1H), 7.52e7.36 (m, 7H),
C
24H31N2Oþ calcd. 363.2431, found 363.2443.
d
4.7.4. (Z)-5-Benzylidene-3-butyl-1-(3-chlorobenzyl)-4-propyl-
1,3,4,5-tetrahydro-2H-benzo[d][1,3]diazepin-2-one (19d)
112.6, 29.6; IR (ATR, neat):
n 3464, 3291, 3178, 2921, 1678, 1604,
Yield: 95%; yellowish oil; 1H NMR (400 MHz, CDCl3):
d
7.42e7.33
1452, 1388, 1338, 740, 698 cmꢁ1
;
HRMS (ESI, [MþH]þ) for
(m, 2H), 7.33e7.19 (m, 6H), 7.17e7.03 (m, 5H), 6.78 (s, 1H), 5.11 (d,
J ¼ 15.6 Hz, 1H), 4.91 (d, J ¼ 15.6 Hz, 1H), 4.41 (dd, J ¼ 8.6, 5.2 Hz,
1H), 3.34e3.20 (m, 1H), 3.19e3.05 (m, 1H), 1.71e1.56 (m, 1H),
1.52e1.35 (m, 2H), 1.25e0.94 (m, 5H), 0.81 (t, J ¼ 7.3 Hz, 3H), 0.68 (t,
C
22H19N2Oþ calcd. 327.1492, found 327.1479.
Acknowledgements
J ¼ 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
158.1, 141.5, 141.2,
This work was supported by the startup fund from Soochow
University (grant Q410900714), the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD) and
the project of scientific and technologic infrastructure of Suzhou
(grant SZS201708). K.V.H. thanks the Hercules Foundation (project
AUGE/11/029 ‘3D-SPACE: 3D Structural Platform Aiming for
Chemical Excellence’) and the Research Foundation - Flanders
(FWO) for funding. E.V.V.d.E. acknowledges the financial support
from The Ministry of Education and Science of the Russian Feder-
ation (the Agreement number 02.a03.0008). The authors are also
grateful to the undergraduate students of intensive training class of
Soochow University, China for their participation in the approba-
tion of the described methodology.
139.2, 136.7, 134.6, 134.2, 130.7, 129.6, 128.8, 128.61, 128.59, 128.4,
127.46, 127.45, 126.9, 125.6, 124.5, 121.4, 62.1, 54.7, 50.4, 35.8, 30.5,
20.3, 19.0, 14.0, 13.9; IR (ATR, neat): n 2957, 2930, 2871, 1626, 1596,
1576, 1455, 1355, 1286, 1241, 1210, 1077, 760, 699, 683 cmꢁ1; HRMS
(ESI, [MþH]þ) for C30H34ClN2Oþ calcd. 473.2354, found 473.2362.
4.7.5. (Z)-3-Butyl-5-(4-fluorobenzylidene)-4-isobutyl-1,7,9-
trimethyl-1,3,4,5-tetrahydro-2H-benzo[d][1,3]diazepin-2-one (19e)
Yield: 96%; white solid; mp: 131e133 ꢀC; 1H NMR (400 MHz,
CDCl3):
d 7.26e7.19 (m, 2H), 7.08e6.96 (m, 3H), 6.85 (s, 1H), 6.73 (s,
1H), 4.21 (dd, J ¼ 10.9, 2.5 Hz, 1H), 3.54e3.39 (m, 1H), 3.12 (s, 3H),
2.87e2.70 (m, 1H), 2.33 (s, 3H), 2.25 (s, 3H), 1.59e1.42 (m, 2H),
Please cite this article in press as: Wang G, et al., Diversity-oriented synthesis of 1,3-benzodiazepines, Tetrahedron (2017), https://doi.org/
10.1016/j.tet.2017.09.034

G. Wang et al. / Tetrahedron xxx (2017) 1e9
207e211;
9
Appendix A. Supplementary data
e) Fedoseev P, Sharma N, Khunt R, Ermolat'ev DS, Van der Eycken EV. RSC Adv.
2016;6:75202e75206;
f) Van Beek WE, Van Stappen J, Franck P, Tehrani KA. Org Lett. 2016;18:
4782e4785;
g) Rajesh UC, Gulati U, Rawat DS. ACS Sustainable Chem Eng. 2016;4:
3409e3419;
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2017.09.034.
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Please cite this article in press as: Wang G, et al., Diversity-oriented synthesis of 1,3-benzodiazepines, Tetrahedron (2017), https://doi.org/
10.1016/j.tet.2017.09.034