Regioselective “hydroamination” of alk-3-ynones with non-symmetrical o-phenylenediamines. Synthesis of diversely substituted 3H-1,5-benzodiazepines via (Z)-3-amino-2-alkenones

Article abstract of DOI:10.1039/c6ra24291j

The reaction of alk-3-yn-1-ones (a bifunctional reagent) with o-phenylenediamines provides an effective synthetic method with high atom economy for the preparation of diversely substituted 1,5-3H-benzodiazepines. The reaction initially leads to the formation of conjugated enaminones (3-amino-2-alkenones, 51-99%), at room temperature, which constitutes a formal non-catalyzed hydroamination of the non-conjugated alkyne. Non-symmetrical o-phenylenediamines react in a regioselective fashion with respect to amino groups. Both the direct microwave-accelerated reaction of o-phenylenediamines with alkynones in ethanol and the intramolecular cyclization of intermediate enaminones in ethanol/acetic acid lead to substituted 1,5-benzodiazepines with good yields (39-92 and 26-99%). The regio- and stereochemical outcomes of these processes are confirmed by the X-ray structure determination of (Z)-3-[(2-amino-4-methylanilino)-4-(4-methylphenyl)-1-phenylbut-2-en-1-one], 4-[(4-methylphenyl)methyl]-7-nitro-2-phenyl-3H-1,5-benzodiazepine and 6,8-dimethyl-4-(4-methylbenzyl)-2-phenyl-3H-benzo[b][1,5]diazepine.

Full text of DOI:10.1039/c6ra24291j

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PAPER
Regioselective “hydroamination” of alk-3-ynones
with non-symmetrical o-phenylenediamines.
Synthesis of diversely substituted 3H-1,5-
benzodiazepines via (Z)-3-amino-2-alkenones†
Cite this: RSC Adv., 2016, 6, 107081
Jonathon Young,a Christian Schafer,b Agnes Solan,a Anthony Baldrica,a
¨
a
b
c
a
b
*
Miranda Belcher, Bilal Nisanci,‡ Kraig A. Wheeler, Evan R. Trivedi, Bela Torok
¸
´
¨ ¨
ad
*
and Roman Dembinski
The reaction of alk-3-yn-1-ones (a bifunctional reagent) with o-phenylenediamines provides an effective
synthetic method with high atom economy for the preparation of diversely substituted 1,5-3H-
benzodiazepines. The reaction initially leads to the formation of conjugated enaminones (3-amino-2-
alkenones, 51–99%), at room temperature, which constitutes a formal non-catalyzed hydroamination of
the non-conjugated alkyne. Non-symmetrical o-phenylenediamines react in a regioselective fashion
with respect to amino groups. Both the direct microwave-accelerated reaction of o-phenylenediamines
with alkynones in ethanol and the intramolecular cyclization of intermediate enaminones in ethanol/
acetic acid lead to substituted 1,5-benzodiazepines with good yields (39–92 and 26–99%). The regio-
and stereochemical outcomes of these processes are confirmed by the X-ray structure determination of
Received 29th September 2016
Accepted 21st October 2016
(Z)-3-[(2-amino-4-methylanilino)-4-(4-methylphenyl)-1-phenylbut-2-en-1-one],
4-[(4-methylphenyl)
DOI: 10.1039/c6ra24291j
methyl]-7-nitro-2-phenyl-3H-1,5-benzodiazepine and 6,8-dimethyl-4-(4-methylbenzyl)-2-phenyl-3H-
benzo[b][1,5]diazepine.
www.rsc.org/advances
effects,8 there is a critical need to expand the current range of
available compounds. Due to the potential pharmaceutical
Introduction
impact or the need to develop new functionalities for materials
chemistry,9 novel synthetic methods for accessing diversely
substituted benzodiazepines are of considerable interest.
The synthetic strategies leading to 3H-benzo[b][1,5]dia-
zepines (containing two imino groups) are mostly based upon
cyclocondensation reactions of o-phenylenediamines (1,2-dia-
minobenzenes) with 1,3-dicarbonyl compounds and alk-2-
ynones (including in situ generation), in the presence of an
acid, a base, or a catalyst (Fig. 1).3,9–14 While these methods
provide effective access to benzodiazepines, their scope largely
has been limited to symmetrical o-phenylenediamines or
mostly resulted in production of mixtures of regioisomers. Our
interest has focused on investigating the regioselective
Benzodiazepines are molecules of high pharmacological
interest and are versatile clinical tools for the treatment of
various conditions, including alcohol withdrawal, insomnia,
and anxiety disorders.1,2 Active derivatives of 1,5-benzodiaze-
pines, with two nitrogen atoms located adjacent to an aromatic
ring,3–5 provide a common framework for the widely prescribed
antioxidant and anticonvulsant medication clobazam, as well as
arfendazam, clozapine, olanzapine, and lofendazam.6,7 Since
diazepines carry unsolicited psychotropic and other side
aDepartment of Chemistry, Oakland University, 146 Library Drive, Rochester, Michigan
48309-4479, USA. E-mail: dembinsk@oakland.edu
bDepartment of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd.,
Boston, Massachusetts 02125, USA. E-mail: bela.torok@umb.edu
cDepartment of Chemistry, Eastern Illinois University, 600 Lincoln Avenue, Charleston,
Illinois 61920-3099, USA
dCentre of Molecular and Macromolecular Studies, Polish Academy of Sciences,
´ ´
Department of Bioorganic Chemistry, Sienkiewicza 112, 90-363 Łodz, Poland
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for enaminones
5 and diazepines 8, cif les for 5ad, 8ae and 8ah, and
crystallographical tables for 2, 3, 5ad, 5cb, 8aa, 8ae and 8ah. DSC and
deuterated experiment MS data. CCDC 929587, 929589 and 1477555–1477557.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c6ra24291j
Fig.
1 Representative methods for synthesis of 3H-benzo[b][1,5]
¨
diazepines.
‡ Current address: Ataturk University, Erzurum, Turkey.
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synthesis of these pharmaceutically important structures that may be generated from alkynones 1 and monoamines.20 Further
incorporate broad selection of pendant substituents, developments are of interest since enaminones have proven
a
including non-symmetrically decorated o-phenylenediamines. useful as synthetic building blocks.21–23 Even so, the majority of
Considering that the reactivity patterns of the two amino groups preparative approaches that focus on the construction of C–N
may be different, the synthetic strategy of this study includes bonds lack regioselectivity or exhibit numerous limitations
the use of a bifunctional reagent where the more reactive amino such as moderate yields.24 Our initial studies conrmed the
group will react rst with one function, followed by an intra- regio- and stereoselectivity of this reaction using mono-
molecular process engaging the residual amine function.
amines.25 Further crystallographic investigations have high-
lighted the presence of well-dened intermolecular hydrogen
bonds, conjugated ene tautomer (of a formal imine function),
and the stereochemical control of formation of alkyl/aryl-
substituted (Z)-enaminones 2 and 3 (Fig. 2).26
In order to investigate the reactivity and regioselectivity
patterns, the scope of the reaction was extended to o-phenyl-
enediamines. Although a report indicates that aliphatic diamines
yield linked bis-enaminones,20 the reaction of alkynones 1 with
equimolar amounts of symmetrical o-phenylenediamines 4a,b
(ethanol, 22 ꢀC, 2 h) produced enaminones 5 with high yield, as
determined by 1H NMR and LC/MS. In order to prevent the
formation of benzodiazepines, which were observed in small
quantities in the post reaction mixtures,27 triethylamine (ca. 2
equiv.) was added to inhibit imine bond formation. Enaminones
containing a free amino function 5aa–cb were isolated by
recrystallization in 70–99% yield (Table 1, entries 1–6).28
Results and discussion
Alk-3-ynones (propargyl ketones, 1, Scheme 1),15 contain a non-
conjugated alkyne function and offer versatile bifunctional
reagents leading to substituted furans,16 halofurans,17,18 and
pyrazoles.19 Literature report, supported by narrow spectroscopic
evidence (IR), indicates enaminones (3-amino-2-alkenones)
Syntheses of benzodiazepines commonly use a symmetrical
component within 1,3-diketones or o-phenylenediamines to
avoid the formation of a regioisomers mixture. To explore the
regioselectivity of enaminone formation, alkynone 1a was
combined with non-symmetrical o-phenylenediamines 4c–h in
Scheme 1 Synthesis of enaminones 5 from o-phenylenediamines 4.
ꢀ
similar conditions (ethanol, triethylamine, 22 C, 2 h; Scheme
1). Several commercially available o-phenylenediamines were
selected for this study. These reagents include pendant
substituents that differ in electronic properties, such as strongly
electron donating methoxy (4c, R4 ¼ OMe), weakly donating
methyl (4d, R4 ¼ Me and 4e, R4 ¼ R6 ¼ Me), moderately electron
withdrawing carboxamide (4f, R3
¼
CONH2; 2,3-dia-
minobenzamide) and benzoyl (4g, R5 ¼ COC6H5; benzophenone
skeleton), and strongly electron withdrawing nitro (4h, R5
¼
NO2) groups. In the case of substituents with strong electronic
effects, 1H NMR detected the formation of only one regioisomer
(in the region of the enaminone N–H signal), with respect to the
reactivity of the amino group. Two regioisomers were generally
observed for moderately to weakly activating/deactivating
substituents, with the exception of the ortho CONH2-
substituted diamine 4f, where only one regioisomer formed and
precipitated from the reaction mixture. Nevertheless, in almost
all cases where two regioisomers were formed, the major isomer
could be isolated via recrystallization in an analytically pure
form. Using these methods, compounds 5ac,ad,af–ah were ob-
tained in 51–82% yields (Table 1, entries 7, 8, 10–12). In the case
of 3,5-dimethyl o-phenylenediamine (4e) two regioisomers were
1
Fig. 2 An ORTEP view of the enaminones derived from monoamines: obtained in the ratio of 1.05 : 1.00 as determined by H NMR,
2 (top) and 3 (bottom), illustrating atom labeling scheme and thermal
and limited separation attempts were not successful (entry 9).
ꢀ
ellipsoids (50% probability level). Selected interatomic distances (A): 2:
O1–C3 1.2496(17), C3–C4 1.425(2), C4–C5 1.3811(19), C5–C6
1.5110(19), N1–C5 1.3451(17), O1–N1 2.6781(15); 3: O1–C1 1.258(2),
C1–C2 1.425(2), C2–C3 1.380(2), C3–C4 1.517(2), N1–C3 1.3457(19),
O1–N1 2.6235(15).
1
The characteristic H NMR signals for enaminones 5 (C6D6
or DMSO-d6) included the deshielded NH protons (13.08–
12.47 ppm, due to intramolecular hydrogen bonding), free NH2
groups (3.32–2.96 ppm), and H-2 (]CH) and H-4 (CH2R2)
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Table 1 Preparation of enaminones 5 from alkynones 1
Entry
Alkynone
R1
R2
R3/R6
R4
R5
Product
Yielda [%]
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1a
1a
1a
1a
1a
1a
Ph
Ph
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-t-BuC6H4
p-t-BuC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
H
H
H
H
H
H
H
H
H
Me
H
Me
H
Me
OCH3
Me
Me
H
H
Me
H
Me
H
Me
H
H
H
H
5aa
5ab
5ba
5bb
5ca
5cb
5ac
5ad
5ae
5af
85
99
70
83
70
93
65
51
p-BrC6H4
p-BrC6H4
p-ClC6H4
p-ClC6H4
Ph
Ph
Ph
Ph
Ph
b
9
H/Me
CONH2/H
H
H
—
10
11
12
66
67
82
H
H
COC6H5
NO2
5ag
5ah
Ph
a
Isolated yield. b Two regioisomers (not separated) were obtained in a ratio of 1.05 : 1.00 as determined by 1H NMR integration of the vinyl proton
signal.
signals (6.04–5.82 and 3.49–3.13 ppm). 13C NMR characteristic composed from two isomers. Subsequent migration of the
signals include C]O, C-2 (OCC]), C-3 (]C–N), and C-4 double bond, in turn, leads exclusively to the Z isomer of the
(CH2R2) (190.3–187.4, 96.0–93.2, 168.4–166.0 and 39.2– conjugated enaminone 5. The conformation of intermediate 7,
38.2 ppm, respectively). GC/MS spectra exhibited an m/z peak of imposed by the intramolecular six-membered ring hydrogen
[M ꢁ H2O]+ as molecular ions, presumably due to a condensa- bonding, enforces the stereospecicity of the isomerization.
tion reaction to corresponding diazepines 8 during acquisition. Involvement of a dienol tautomer (not illustrated) would clearly
As anticipated the more nucleophilic amino group of need an intermolecular proton transfer to g-carbon.29 Alterna-
diamines 4c–h reacted predominantly with the alkyne function. tively, isomerization of alk-3-ynone 1 to conjugated alk-2-ynone,30
This reaction pathway was conrmed for enaminone 5ad by followed by conjugate addition, cannot be excluded. X-ray crys-
crystallographic assessment. Fig. 3 shows that the electronically tallography conrmed the structures of enaminones 2, 3, and 5ad
richer amino group para to the methyl substituent participated (vide ante, Fig. 1 and 2), as well as earlier reported 5cb.26
in the formation of the enaminone moiety.26
Preparative synthesis of a series of 1,5-benzodiazepines 8
The reaction process likely takes place via isomerization of was carried out as a non-catalytic process in reagent grade
alk-3-ynone 1 to allenone 6, facilitated by the presence of an ethanol, usually at 80 ꢀC (1 h), with the aid of microwave heating
amine (Scheme 2). Conjugate addition (aza-Michael reaction) to accelerate the reaction (Scheme 3). When symmetrical o-
gives rise to the structure 7 (not isolated), which may be phenylenediamines 4a–b were used, aryl/benzyl-substituted
diazepines 8aa–cb (Table 2, entries 1–6) were obtained with
80–92% yields. Next, the scope of the reaction was extended to
alkyl substituents. Diazepines 8da–ga containing phenyl/alkyl
substituents, including n-butyl, t-butyl, and cyclopropyl-
methylene groups, were obtained using the same methodology
with 60–79% yields, respectively (entries 7–10). Ethyl/benzyl
compounds 8ga and 8gb were isolated with 70 and 77%
yields, respectively (entries 11 and 12).
The reactivity of non-symmetrical o-phenylenediamines 4c–h
was investigated next. Diamines with electron withdrawing
Fig. 3 An ORTEP view of the enaminone 5ad illustrating atom labeling
scheme and thermal ellipsoids (50% probability level). Selected inter-
ꢀ
atomic distances (A): O1–C1 1.2743(17), C1–C2 1.432(2), C2–C3 Scheme 2 Mechanistic outline for the synthesis of enaminones 2, 3,
1.3967(19), C3–C4 1.5183(19), N1–C3 1.3500(18), O1–N1 2.6342(15).
and 5.
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Scheme 3 The synthesis of 1,5-diazepines 8 from alk-3-ynones 1 and
o-phenylenediamines 4.
substituents were found to be detrimental to the formation of
the diazepines; the reaction did not progress beyond the
formation of enaminones 5, even at increased temperature
and with prolonged reaction time. Diamines containing elec-
tron donating groups led to the formation of two regioisomers.
LC/MS pointed occasionally to the formation of bis-enami-
nones. The reaction of alkynone 1a with 3,5-dimethyl
substituted o-phenylenediamine 4e resulted similarly in the
formation of two regioisomers (2.54 : 1 as determined by
integration of CH3 signals in the 1H NMR). The more electron
rich amino group, located in the vicinity (ortho) of the methyl
group, overcame steric hindrance and yielded a major isomer,
isolated by crystallization (39%; Table 2 entry 13). The regio-
chemistry of the reaction was conrmed by X-ray crystallog-
raphy for diazepine 8ae (Fig. 4).26
To further develop regioselectivity in the construction of 1,5-
benzodiazepines from non-symmetrical o-phenylenediamines,
the intramolecular imination reaction between the carbonyl
group and the free amino substituent of enaminones 5,
combined with enamino–imino tautomerization, which would
lead via vinamidine form 9 to 3H-benzo-1,5-diazepines, was
considered.27 The availability of single regioisomers of the
enaminones 5ac,ad,af–ah made this approach especially
appealing. Reaction conditions were optimized using enaminone
5aa as a model compound.31 When the reaction was carried out in
ethanol, even at an elevated temperature, little to no conversion
Fig. 4 An ORTEP view of the diazepines 8ae (left) and 8ah (right)
illustrating atom labeling scheme and thermal ellipsoids (50% proba-
ꢀ
bility level). Selected interatomic distances (A): N1–C2 1.2876(17)/
1.296(5), N1–C10 1.4094(16)/1.404(5), C2–C3 1.5148(17)/1.518(5), C3–
C4 1.5147(17)/1.511(5), C4–N5 1.2837(17)/1.284(4), C4–C20/18,
1.5004(19)/1.500(6), N5–C11 1.4054(17)/1.414(5), C10–C11 1.4101(18)/
1.422(5). Key angles (deg): C2–N1–C10, 121.52(11)/120.7(3), N1–C2–
C3 121.63(11)/119.4(3), C2–C3–C4 105.49(10)/104.2(3), C3–C4–N5
122.04(12)/120.9(3), C4–N5–C11 120.99(11)/119.7(3), N5–C11–C10
123.89(12)/124.5(3), N1–C10–C11 125.76(12)/124.4(3).
was observed. Since the imination reaction is oen successful at
a lower pH, the addition of a catalytic amount of acetic acid
brought the process to an effective completion in most cases. The
conversion of enaminone 5aa into the corresponding diazepine
ꢀ
8aa was accomplished at room temperature (22 C, 2 h) in an
ethanol/acetic acid mixture (98 : 2 v/v), with 91% yield. The
preparative synthesis of 1,5-benzodiazepines 8a–c,d,f,g from
corresponding enaminones derived from diamines 4c,d,f,g was
investigated next. For enaminones containing electron donating
groups, the reaction proceeded at rt (3 h). Non-symmetrical 1,5-
benzodiazepines 8ac and 8ad were isolated in almost quantitative
yields (99%; Table 3, entries 2 and 3). The removal of volatiles
Table 2 Preparation of 1,5-benzodiazepines 8 from alkynones 1
Entrya
Alkynone
R1
R2
R4
R5
R6
Product
Yieldb [%]
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1e
1e
1f
Ph
Ph
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-t-BuC6H4
p-t-BuC6H4
Bu
t-Bu
t-Bu
c-Pr
Ph
H
Me
H
Me
H
Me
H
H
Me
H
H
Me
Me
H
Me
H
Me
H
Me
H
H
Me
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
8aa
8ab
8ba
8bb
8ca
8cb
8da
8ea
8eb
8fa
87
88
87
90
92
80
60
68
79
65
77c
70c
39d
p-BrC6H4
p-BrC6H4
p-ClC6H4
p-ClC6H4
Ph
Ph
Ph
Ph
Et
9
10
11
12
13
1g
1g
1a
8ga
8gb
8ae
Et
Ph
Ph
p-MeC6H4
a
R3 ¼ H for all entries in the table. b Isolated yield; reactions were carried out in a microwave vial on a 1.0 mmol scale with 1.05 equiv. of diamine, in
ethanol, at 80 ꢀC, reaction time 2 h, unless referenced otherwise. c At 50 ꢀC, reaction time 12 min. d 0.300 mmol scale, reaction time 8 h (optimized
via LC-MS). Formation of two isomers was observed (2.54 : 1 ratio, as determined by 1H NMR – integration of CH3 signals). Yield of major
regioisomer isolated via crystallization.
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from the post-reaction mixture was sufficient to achieve reason-
The new benzodiazepines 8 structures were conrmed by
able purity as indicated by NMR.32 This methodology offers NMR and HRMS. The characteristic NMR features include 1H H-
access to diazepines in a two-reaction sequence, both proceeding 3 and CH2Ar (benzyl) signals (C6D6 or DMSO-d6, 2.93–2.60 and
at room temperature.
3.84–3.47 ppm) and 13C C]N signals (163.6–151.2 ppm).
Next, the cyclization of enaminones 5af and 5ag, which Intense molecular ions and accurate [M + H]+ peaks were
contain electron withdrawing substituents (an amido and observed in the HRMS spectra for compounds 8. In addition to
phenylcarbonyl group) in the o-phenylenediamine core, was NMR data, X-ray crystallography unambiguously conrmed the
attempted.33 A similar procedure as above resulted in the commonly predominant diimine (3H) tautomeric form9,35 of
formation of benzodiazepines 8af and 8ag in modest yields benzodiazepines 8aa,25 8ae, and 8ah, and it decisively dened
(Table 3, entries 4 and 5). The lower solubility of the amide- the regioisomer for the last two compounds (Fig. 4).
substituted benzodiazepine 8af, as well as competition of the
carbonyl functionality of diaminobenzophenone derivative 8ag diazepines 8aa, 8ae, and 8ah showed a half-boat conforma-
toward an imination reaction might affect the yields.
tion of the seven-membered ring with a folding angle of 89.5ꢀ,
Analysis of the X-ray crystal structures of 3H-benzo-1,5-
Several commercial 1,4-benzodiazepine drugs, such as clo- 84.7ꢀ, and 89.6ꢀ, respectively. The conformational interconver-
nazepam, unitrazepam, nimetazepam, and nitrazepam are sion levels out the non-equivalence of H-3a and H-3b methylene
derivatives of 4-nitroaniline (4h). In synthetic approaches to 3H- protons at room or elevated temperature.36 In addition, H-3
1,5-benzodiazepines, the presence of a strongly electron- signals blended with the baseline and were barely visible at
withdrawing nitro group in the o-phenylenediamine core room temperature. To conrm their presence variable temper-
dramatically decreases the nucleophilicity of the amino groups ature NMR studies were undertaken. 1H NMR spectra of 8ga
and is detrimental to the imination reaction. Whereas some were recorded at temperatures ranging from ꢁ50 to +50 ꢀC
studies have achieved successful synthesis of nitro-substituted (223–323 K; 400 MHz, CDCl3; Fig. 5). When the temperature was
1,5-benzodiazepines using 4-nitro-o-phenylenediamine 4h,14,27 increased to +50 ꢀC, H-3 diazepine protons coalesced to
others have reported a lack of reactivity for the same reagent.13,34 a singlet peak at d ¼ 2.70 ppm, common for rapid conforma-
When enaminone 5ah, derived from diamine 4h was stirred in tional interconversion. Lowering the temperature resulted in
ethanol with the addition of acetic acid (9% v/v) at 80 ꢀC for 6 h, substantial broadening, splitting the H-3 signal at ꢁ35 ꢀC.
the reaction afforded a 37% yield of nitro-substituted 1,5- Finally at ꢁ50 ꢀC two doublets of H-3a and H-3b at 3.48 and
benzodiazepine 8ah. The location of the nitro group at carbon 1.99 ppm were observed (separated by 593.8 Hz, with a geminal
C-7 of the benzene ring was unambiguously conrmed by X-ray coupling constant of J ¼ 11.1 Hz). The large signal separation
crystallography (Fig. 4).
can be attributed to anisotropic shielding by the annelated
benzene ring and to the different relative orientation of H-3a
Table 3 Preparation of 1,5-benzodiazepines 8 from enaminones 5
Entry Enaminone R3
R4
R5
Product Yielda [%]
1
2
3
4
5
6
5aa
5ac
5ad
5af
5ag
5ah
H
H
H
H
H
H
H
H
8aa
8ac
8ad
8af
91
99
99
43
26
37
OCH3
Me
H
H
H
CONH2
H
H
COC6H5 8ag
NO2 8ah
Fig. 5 Variable temperature 1H NMR study for diazepine 8ga (400
a
Isolated yields.
MHz, CDCl3).
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and H-3b with respect to the p-electron systems.37 The coales- recorded. Overall, the reaction showed a d3 dominant structure
cence temperature (Tc) for H-3 protons was at approximately in enaminone formation, whereas a diazepine d2 dominant
ꢀ
0 C. The evaluation of the kinetics from the variable temper- structure was observed in both direct synthesis and cycliza-
ature 1H NMR spectra resulted in a ring ip rate constant at Tc tion. The abundant presence of deuterium was noticed in two
equal to 1323 sꢁ1 and a ring inversion barrier DG‡ of 50.3 kJ benzyl and one vinyl/two H-3 locations in enaminone/
molꢁ1
molꢁ1].9,36–39
Additionally, the separation of the benzyl CH2 signal at process may also include enaminone NH hydrogen-bonded
reverse exchange to
,
in agreement with related studies [48.9–54.2 kJ benzodiazepine products, respectively, as conrmed by the
pronounced decrease of 1H NMR integration. The detection
3.89 ppm into an AB system with coupling constant J ¼ 13.3 Hz protons, which may withstand
a
as well as CH2 of ethyl group at ca. 1.6 ppm into two multiplets hydrogen during LC/MS analysis and are eliminated during the
separated by 128.0 Hz was also observed at ꢁ50 ꢀC. As the formation of the imine bond.40,41 The multiple products ratio is
temperature increased, a slight upeld shi of the benzyl related to reorganization of several bonds that takes place
protons and downeld shi of ethyl protons was observed.
during the reaction.
As outlined in the Scheme 2, the mechanism corresponding
Photophysical measurements were carried out for the
enaminones formation suggests that the conversion of the representative benzodiazepine 8aa. Major UV electronic
acetylenic carbon into a methylene group takes place during absorptions of equal intensity occurred at 228 nm and 266 nm (3
the early stage of the reaction. Formation of an imine in an ¼ 2.6 ꢃ 104, dichloromethane) with a shoulder of lesser inten-
intramolecular cyclization reaction and isomerization of sity at 320 nm (3 ¼ 7.5 ꢃ 103; Fig. 6). These values are in line
a vinamidine form H9 driven by the higher stability of the with literature values and represent typical p–p* transitions.42
C]N bond, lead to the nal product 8. To gain additional Fluorescence from the excited singlet state (S1) was observed
insight into mechanistic details, deuterium-incorporation both within the solution and in the solid state. In the solution,
studies were undertaken. The reactions between o-phenyl- uorescence was observed at 368 nm, representing a Stokes
enediamine 4a and alk-3-yn-1-one 1a were carried out in shi of 4100 cmꢁ1; a shi of such magnitude falls on the low
deuterated methanol-d1 in a similar way to that described in end of the range observed for a series of related compounds.9
the preparative protocol for 5aa and 8aa (Schemes 1 and 3). For The quantum yield of uorescence was measured in solution
these reactions, methanol has been shown to be a viable (ethanol) by the relative method, but was found to be below the
solvent option that awards similar yields to ethanol. The reliability of the measurement (Ff < 0.01). In the solid state, two
reaction resulted in the incorporation of predominantly three luminescence features were observed. Fluorescence similar to
deuterium atoms into enaminone 5aa, with the ratio of that observed in the solution persisted, and a relatively intense
d0 : d1 : d2 : d3 : d4 : d5
products
calculated
as band, consistent with phosphorescence, appeared at 400 nm at
2 : 9 : 34 : 55 : ꢂ0 : ꢂ0 (LC/MS of the crude product). For rt. A previous report describes long-wavelength uorescence
benzodiazepine 8aa, the ratio of d0 : d1 : d2 : d3 : d4 products (400–500 nm) attributed to conformational ring-ipping in the
was 6 : 26 : 47 : 19 : 2. Comparison of 1H NMR spectra inte- solid state;9 complex uorescence of this kind was not observed
gration between non-deuterated and deuterated enaminone here. Instead, the assignment of phosphorescence from the
5aa indicated incorporation of deuterium in 91% vinyl and excited triplet state (T1) at 400 nm was conrmed by collecting
85% benzyl protons. 1H NMR spectra of benzodiazepine 8aa a spectrum aer enforcing a 50 ms delay (Fig. 6).
corresponded to 89% incorporation of the benzyl protons. No
exchange occurred when non-deuterated enaminone 5aa was
stirred in MeOD for two hours (LC/MS). When non-deuterated
Conclusion
enaminone 5aa was converted into benzodiazepine 8aa in In summary, we have demonstrated that the use of alk-3-yn-1-
MeOD, the ratio of d0 : d1 : d2 : d3 : d4 of 5 : 19 : 34 : 30 : 12 was one, a bifunctional reagent that contains a non-conjugated
alkyne function, facilitates the regiospecic amination of the
alkyne function, leading to enaminones containing a free
amino function. Non-symmetrical o-phenylenediamines react
in regioselective manner, yielding a single isomer aer crystal-
lization. A subsequent imination reaction provides an effective
way to access diverse substituted 1,5-benzodiazepines. Current
synthetic approaches, such as the use of 1,3-diketones, do not
offer regioselectivity as referred to the non-symmetrically
substituted phenylenediamine-originating ring. The bifunc-
tional alkynones reaction is highly diverse. All alkyne reactions
proceed at room temperature, whereas reaction of the carbonyl
group does require an elevated temperature thus allowing for
chemoselectivity. The regioselectivity of phenylenediamines
was achieved for strongly directing substituents. 4-Nitro-o-
Fig. 6 Photophysical spectra for 8aa. Electronic absorption (black
nitrophenylenediamine, which occasionally fails in terms of
solid), S1 fluorescence (black dashed) in CH2Cl2, and phosphores-
cence in the solid state at rt with (blue) and without (red) a 50 ms delay. reactivity in route to 1,5-benzodiazepines, renders also the
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regioselective product in our protocol. The strategy eliminated solid (0.0560 g, 0.164 mmol, 85%), mp 94–95 C. MS (EI, m/z)
the need for a catalyst and took advantage of the use of 324 (M+ ꢁ H2O, 57%), 309 (M+ ꢁ H2O ꢁ CH3, 15%), 105 (C8H9
,
+
a reagent-grade benign and renewable solvent (ethanol). The 100%). HRMS (ESI-TOF) [M + H]+ calcd for C23H23N2O
formation of two C]N and two C–H bonds allowed for the 343.1810, found 343.1813. IR (cmꢁ1, ATR) 3444 w, 3350 w,
introduction of substituents such as benzyl or cyclopropyl- 1625 w, 1593 m, 1573 s, 1534 s, 1510 m, 1495 m, 1481 m, 1458
methylene at the C-2 of the diazepine, which is not easily m, 1431 s, 731 s, 502 s. NMR (C6D6, d): 1H 13.08 (s, 1H), 8.15–
carried out by currently available procedures. This appealing 8.11 (m, 2H), 7.15–7.10 (m, 3H), 6.88 (s, 4H), 6.87 (dt, 1H, J ¼
protocol provides a convenient and temperature-controlled 7.7, 1.4 Hz), 6.70 (dd, 1H, J ¼ 7.8, 1.2 Hz), 6.48 (dt, 1H, J ¼ 6.6,
synthetic method for the preparation of enaminones and 1.3 Hz), 6.24 (dd, 1H, J ¼ 6.7, 1.3 Hz), 6.02 (s, 1H), 3.43 (s, 2H),
benzodiazepines via divergent synthesis using the same starting 3.08 (br s, 2H), 2.07 (s, 3H); 13C 189.0, 166.6, 143.3, 140.4,
materials, with the regioselective positioning of substituted 135.9, 133.8, 130.7, 129.2, 129.0 (2C), 128.3 (2C), 128.2 (2C),
o-phenylenediamines.
126.4 (2C), 124.1, 119.9, 117.8, 115.4, 93.9, 38.3, 20.7.
(Z)-3-[(2-Amino-4,5-dimethylphenyl)amino]-1-phenyl-4-(4-
methylphenyl)but-2-en-1-one (5ab). From 1a (0.0464 g, 0.198
mmol), 4,5-dimethyl-1,2-phenylenediamine 4b (0.062 g, 0.20
mmol), triethylamine (0.06 mL, 0.4 mmol), and ethanol (8
mL). Recrystallization from ethyl acetate/hexanes (layering)
afforded 5ab as a yellow solid (0.0733 g, 0.198 mmol, >99%),
mp 111–112 ꢀC. DSC (Tm) 126 ꢀC. MS (EI, m/z) 352 (M+ ꢁ H2O,
100%), 337 (M+ ꢁ H2O ꢁ CH3, 35%). HRMS (ESI-TOF) [M +
Experimental section
General methods
The microwave reactions were carried out using capped vials in
a Biotage Initiator reactor equipped with a conventional
temperature IR sensor and stirring capabilities. NMR spectra
were obtained with a Bruker Avance III spectrometer (1H of 400
MHz and 13C of 100 MHz). The chemical shis were reported in
d (ppm) values relative to C6D6 (7.16 ppm, 128.06 ppm respec-
tively). Mass spectra were recorded on Agilent 6520 Q-TOF
LCMS (HRMS) and Hewlett Packard 5973 GC/MS instruments.
IR spectra were recorded on a Bruker Alpha-P ATR spectrom-
eter. Melting points (closed capillaries) were recorded on a Mel
Temp apparatus. DSC curves were recorded in DSC Q2000 (TA
Instruments) using aluminum crucibles containing 2–3 mg of
H]+ calcd for C25H27N2O 371.2123, found 371.2123. IR (cmꢁ1
,
ATR) 3420 w, 3400 w, 1637 w, 1591 m, 1571 s, 1532 s, 1502 m,
1
1481 m, 734 s, 508 s. NMR (C6D6, d): H 13.07 (s, 1H), 8.17–
8.14 (m, 2H), 7.14–7.12 (m, 3H), 6.94 (d, 2H, J ¼ 8.2 Hz), 6.90
(d, 2H, J ¼ 8.1 Hz), 6.46 (s, 1H), 6.09 (s, 1H), 6.04 (s, 1H), 3.49
(s, 2H), 3.02 (br s, 2H), 2.08 (s, 3H), 1.97 (s, 3H), 1.89 (s, 3H);
13C 188.8, 167.1, 140.9, 140.6, 136.0, 135.8, 134.1, 130.6,
129.2, 129.1 (2C), 129.0 (2C), 128.2 (2C), 127.4 (2C), 125.6,
121.8, 117.0, 93.6, 38.3, 20.7, 19.1, 18.3.
samples. The heating rate was 10 C minꢁ1. The DSC was cali-
ꢀ
brated with indium (mp 156.6 ꢀC, DHm ¼ 28.54 J gꢁ1). An empty
pan sealed with cover pan was used as a reference sample. The
analyses were done in triplicate. Luminescence measurements
were performed on a Horiba-Jobin-Yvon Fluorolog 3 spectro-
uorometer equipped with a visible photomultiplier (R928,
Hamamatsu). Samples were prepared in 2.5 mm i.d. quartz
capillaries and spectra were measured with an integrating
sphere (G8, General Microtechnology & Photonics). The solu-
tion data was collected in dichloromethane (3.1 ꢃ 10ꢁ5 M), and
solids were ground to a ne powder before measurements. The
excitation wavelength (275 nm) remained constant throughout
each measurement. Phosphorescence was measured by
enforcing a 50 ms delay with a 450 W xenon ash lamp. All
(Z)-3-[(2-Aminophenyl)amino]-1-(4-bromophenyl)-4-(4-methyl-
phenyl)but-2-en-1-one (5ba). From 1b15,16 (0.0446 g, 0.142 mmol),
o-phenylenediamine 4a (0.0153 g, 0.142 mmol), triethylamine
(0.06 mL, 0.4 mmol), and ethanol (8 mL). Recrystallization from
ethyl acetate/hexanes (layering) afforded 5ba as a yellow solid
ꢀ
(0.0419 g, 0.100 mmol, 70%), mp 107–108 C. MS (EI, m/z) 402
(M+ ꢁ H2O, 100%). HRMS (ESI-TOF) [M + H]+ calcd for
C23H21BrN2O 421.0916, found 421.0917. IR (cmꢁ1, ATR) 3678 w,
3343 w, 1631 w, 1584 m, 1569 s, 1530 m, 1511 m, 1494 m, 1476 m,
844 m, 832 m, 742 s. NMR (C6D6, d): 1H 13.00 (s, 1H), 7.74 (AA0XX0,
2H, J ¼ 8.5 Hz),43 7.21 (AA0XX0, 2H, J ¼ 8.5 Hz), 6.89 (AB, 2H, J ¼
8.0 Hz), 6.91–6.83 (m, 1H),44 6.85 (AB, 2H, J ¼ 8.1 Hz), 6.68 (dd,
1H, J ¼ 7.8, 0.9 Hz), 6.46 (dt, 1H, J ¼ 7.6, 1.2 Hz), 6.23 (dd, 1H, J ¼
8.0, 1.2 Hz), 5.82 (s, 1H), 3.40 (s, 2H), 3.07 (br s, 2H), 2.07 (s, 3H);
13C 188.5, 168.0, 144.1, 140.0, 137.0, 134.6, 132.4 (2C), 130.0 (2C),
129.93 (2C), 129.88 (2C), 129.3, 129.2, 126.4, 124.8, 118.8, 116.4,
94.5, 39.2, 21.6.
ꢀ
products were stored in a refrigerator (4 C).
Synthesis of enaminones 5. General procedure
A 50 or 100 mL round bottom ask equipped with a stir bar was
(Z)-3-[(2-Amino-4,5-dimethylphenyl)amino]-1-(4-bromophenyl)-
charged with alkynone 1 (0.2 mmol), diamine 4 (0.2 mmol), 4-(4-methylphenyl)but-2-en-1-one (5bb). From 1b (0.0578 g, 0.185
triethylamine (ca. 2 equiv.), and ethanol. The mixture was stir- mmol), 4,5-dimethyl-1,2-phenylenediamine 4b (0.026 g, 0.19
red at rt for 2 h. Crystallization (details below), followed by mmol), triethylamine (0.06 mL, 0.4 mmol), and ethanol (8 mL).
decanting and drying the solid with an oil pump vacuum, Recrystallization from ethyl acetate/hexanes (layering) afforded
afforded 5.
5bb as a yellow solid (0.0690 g, 0.154 mmol, 83%), mp 154–155 ꢀC.
(Z)-3-[(2-Aminophenyl)amino]-1-phenyl-4-(4-methylphenyl) MS (EI, m/z) 430 (M+ ꢁ H2O, 100%), 415 (M+ ꢁ H2O ꢁ CH3, 37%),
but-2-en-1-one (5aa). From 1a15,16 (0.047 g, 0.20 mmol), o- 275 (M+ ꢁ H2O ꢁ C6H4Br, 33%). HRMS (ESI-TOF) [M + H]+ calcd
phenylenediamine 4a (0.023 g, 0.21 mmol), triethylamine for C25H26BrN2O 449.1229, found 449.1231. IR (cmꢁ1, ATR) 3420
(0.06 mL, 0.4 mmol), and ethanol (8 mL). Recrystallization w, 3339 w, 1635 w, 1591 m, 1570 s, 1532 s, 1502 m, 1481 m, 734 s,
from ethyl acetate/hexanes (layering) afforded 5aa as a yellow 499 s. NMR (C6D6, d): 1H 13.02 (s, 1H), 7.78 (AA0XX0, 2H, J ¼ 8.56),43
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7.21 (AA0XX0, 2H, J ¼ 8.6), 6.91 (s, 4H), 6.44 (s, 1H), 6.07 (s, 1H),
5.86 (d, 2H), 3.47 (s, 2H), 2.96 (br s, 2H), 2.08 (s, 3H), 1.96 (s, 3H),
1.88 (s, 3H); 13C 187.4, 167.6, 140.8, 139.2, 136.2, 136.0, 133.9,
131.4 (2C), 129.1 (2C), 129.0 (2C), 128.9 (2C), 128.3, 125.7, 125.4,
121.6, 117.1, 93.2, 38.3, 20.7, 19.1, 18.2.
(Z)-3-[(2-Amino-4-methylanilino)-4-(4-methylphenyl)-1-phenyl-
but-2-en-1-one (5ad). From 1a (0.0462 g, 0.197 mmol), 3,4-dia-
minotoluene 4d (0.0246 g, 0.202 mmol), triethylamine (0.06 mL,
0.4 mmol), and ethanol (14 mL). Recrystallization from hot
ethanol afforded the major regioisomer (as referred to diamine 4)
5ad as a yellow solid (0.036 g, 0.101 mmol, 51%), mp 152–154 ꢀC.
MS (EI, m/z) 338 (M+ ꢁ H2O, 100%), 323 (M+ ꢁ H2O ꢁ CH3, 36%),
261 (M+ ꢁ H2O ꢁ C6H5, 17%), 247 (M+ ꢁ H2O ꢁ C7H7, 16%), 233
(M+ ꢁ H2O ꢁ C8H9, 28%). HRMS (ESI-TOF) [M + H]+ calcd for
C24H24N2O 357.1967, found 357.1965. IR (cmꢁ1, ATR) 3448 w,
3334 w, 1633 w, 1567 s, 1537 s, 1504 s, 1502 m, 1482 m. NMR
(C6D6, d): 1H 13.06 (s, 1H), 8.15–8.13 (m, 2H), 7.14–7.11 (m, 2H),
6.92–6.89 (m, 4H), 6.63 (d, 1H, J ¼ 7.9 Hz), 6.31 (dd, 1H, J ¼ 7.9,
1.4 Hz), 6.03 (s, 1H, presumably d obscured by singlet), 3.46 (s,
2H), 3.08 (br s, 2H), 2.07 (s, 3H), 2.05 (s, 3H); 13C 188.9, 166.8,
143.0, 140.5, 137.6, 135.9, 134.0, 130.6, 129.0 (2C), 128.3, 128.2
(2C), 128.1 (2C), 127.4 (2C), 121.7, 118.7, 116.1, 93.8, 38.2, 20.8,
20.7.
(Z)-3-[(2-Aminophenyl)amino]-4-(4-(tert-butyl)phenyl)-1-(4-
chlorophenyl)but-2-en-1-one (5ca). From 1c15,16 (0.0580 g, 0.186
mmol), o-phenylenediamine 4a (0.0202 g, 0.187 mmol), trie-
thylamine (0.06 mL, 0.4 mmol), and ethanol (8 mL). Recrystal-
lization from ethyl acetate/hexanes (layering) afforded 5ca as
a yellow solid (0.0545 g, 0.130 mmol, 70%), mp 109–110 ꢀC. MS
(EI, m/z) 400 (M+ ꢁ H2O, 100%), 385 (M+ ꢁ H2O ꢁ CH3, 62%),
343 (M+ ꢁ H2O ꢁ C4H9, 33%). HRMS (ESI-TOF) [M + H]+ calcd
for C26H27ClN2O 419.1890, found 419.1894. IR (cmꢁ1, ATR) 3428
w, 3345 w, 1634 w, 1587 m, 1569 s, 1530 m, 1496 m, 1480 m, 769
m, 742 m. NMR (C6D6, d): 1H 13.03 (s, 1H), 7.83 (AA0XX0, 2H, J ¼
8.5 Hz),43 7.14 (AA0XX0, 2H),44 7.07 (d, 2H, J ¼ 8.5 Hz), 6.91 (d, 2H,
J ¼ 8.5 Hz), 6.86 (dt, 1H, J ¼ 7.7, 1.2 Hz), 6.68 (d, 1H, J ¼ 7.1 Hz),
6.45 (dt, 1H, J ¼ 7.6, 1.0 Hz), 6.24 (dd, 1H, J ¼ 8.0, 1.0 Hz), 5.88
(s, 1H), 3.44 (s, 2H), 3.10 (br s, 2H), 1.18 (s, 9H); 13C 188.4, 168.0,
150.3, 144.2, 139.6, 137.8, 134.7, 134.7, 129.7 (2C), 129.6 (2C),
129.4 (2C), 129.2, 126.2 (2C), 124.8, 118.8, 116.4, 94.6, 39.0, 35.0,
32.0 (3C).
2-Amino-3-{[(2Z)-1-(methylphenyl)-4-oxo-4-phenylbut-2-en-2-
yl]amino}benzamide (5af). From 1a (0.0710 g, 0.303 mmol), 2,3-
diaminobenzamide 4f (0.0455 g, 0.301 mmol), triethylamine
(0.10 mL, 0.72 mmol), and ethanol (8.4 mL). Filtration of the
precipitate afforded the regioisomer (as referred to diamine 4)
5af as a white solid (0.0765 g, 0.199 mmol, 66%), mp 199–
201 ꢀC. HRMS (ESI-TOF) [M + H]+ calcd for C24H23N3O2
386.1869, found 386.1868. IR (cmꢁ1, ATR) 3380 w, 3330 w,
1652 s, 1599 s, 1574 s, 1551 s, 1514 m, 1455 m, 1277 m, 1226 m,
737 s. NMR (DMSO-d6, d): 1H 12.47 (s, 1H), 7.89 (br s, 1H), 7.82
(dd, 2H, J ¼ 8.1, 1.2 Hz), 7.58 (d, 1H, J ¼ 8.0 Hz), 7.50–7.43 (m,
3H), 7.28 (br s, 1H), 7.09 (d, 1H, J ¼ 7.6 Hz), 7.05 (AB, 2H, J ¼ 7.8
Hz), 6.99 (AB, 2H, J ¼ 7.9 Hz), 6.55 (t, 1H, J ¼ 7.8 Hz), 6.42 (s,
2H), 3.57 (s, 2H), 2.24 (s, 3H); 13C 188.4, 171.8, 167.9, 146.9,
140.4, 136.5, 134.5, 132.0, 131.7, 129.8 (2C), 129.7 (2C), 129.3
(2C), 128.9, 127.7 (2C), 125.1, 116.4, 115.2, 94.6, 38.3, 21.6.
(Z)-3-(2-Amino-5-benzoylanilino)-4-(4-methylphenyl)-1-phenyl-
but-2-en-1-one (5ag). From 1a (0.0436 g, 0.186 mmol), 3,4-dia-
minobenzophenone 4g (0.0398 g, 0.188 mmol), triethylamine
(0.50 mL, 3.6 mmol), and ethanol (15 mL). Recrystallization
from hot ethanol afforded the major regioisomer (as referred
to diamine) 5ag as a yellow solid (0.0552 g, 0.124 mmol, 67%),
(Z)-3-[(2-Amino-4,5-dimethylphenyl)amino]-4-(4-(tert-butyl)
phenyl)-1-(4-chlorophenyl)but-2-en-1-one (5cb). From 1c
(0.0560 g, 0.179 mmol), 4,5-dimethyl-1,2-phenylenediamine 4b
(0.0245 g, 0.180 mmol), triethylamine (0.06 mL, 0.4 mmol),
and ethanol (8 mL). Recrystallization from ethyl acetate/
hexanes (layering) afforded 5cb as a yellow solid (0.0747 g,
0.167 mmol, 93%; two crops total), mp 109–110 ꢀC. MS (EI, m/
z) 428 (M+ ꢁ H2O, 100%), 413 (M+ ꢁ H2O ꢁ CH3, 56%), 371 (M+
ꢁ H2O ꢁ C4H9, 36%). HRMS (ESI-TOF) [M + H]+ calcd for
C
28H31ClN2O 447.2203, found 447.2203. IR (cmꢁ1, ATR) 3430
w, 3345 w, 1633 w, 1586 s, 1567 s, 1530 m, 1515 m, 1479 m, 867
m, 807 m, 765 s. NMR (C6D6, d): 1H 12.99 (s, 1H), 7.86 (AA0XX0,
2H, J ¼ 8.6 Hz),43 7.14 (AA0XX0, 2H),44 7.08 (AA0XX0, 2H, J ¼ 8.6
Hz), 6.95 (AA0XX0, 2H, J ¼ 8.3 Hz), 6.38 (s, 1H), 6.08 (s, 1H), 5.90
(s, 1H), 3.49 (s, 2H), 3.00 (br s, 2H), 1.95 (s, 3H), 1.85 (s, 3H),
1.19 (s, 9H); 13C 188.2, 168.4, 150.2, 141.8, 139.7, 137.7, 137.1,
134.9, 130.2, 129.7 (4C), 129.4 (2C), 126.6, 126.2 (2C), 122.5,
118.0, 94.3, 39.2, 35.0, 32.0 (3C), 20.1, 19.2.
mp 161–165 ꢀC. HRMS (ESI-TOF) [M
C
+
H]+ calcd for
30H26N2O2 447.2073, found 447.2078. IR (cmꢁ1, ATR) 3457 w,
(Z)-3-[(2-Amino-4-methoxyanilino)-4-(4-methylphenyl)-1-phenyl-
but-2-en-1-one (5ac). From 1a (0.1499 g, 0.6406 mmol), 4-methoxy-
o-phenylenediamine 4c (0.0887 g, 0.642 mmol), triethylamine (0.18
mL, 1.3 mmol), and ethanol (40 mL).45 Recrystallization from hot
ethanol afforded 5ac as a yellow solid (0.156 g, 0.419 mmol, 65%),
3342 w, 1632 w, 1583 m, 1568 m, 1488 m, 1299 s, 1257 s, 1147
1
m, 1094 m, 1071 m, 1007 m. NMR (C6D6, d): H 12.89 (s, 1H),
8.12–8.10 (m, 2H), 7.72 (dd, 1H, J ¼ 8.4, 1.9 Hz), 7.68 (AA0XX0,
2H, J ¼ 6.9 Hz),43 7.44 (d, 1H, J ¼ 1.8 Hz), 7.15–7.05 (m, 3H),
6.83 (AB, 2H, J ¼ 8.0 Hz), 6.77 (AB, 2H, J ¼ 8.0 Hz), 6.02 (d, 1H, J
¼ 8.4 Hz), 5.98 (s, 1H), 3.34 (s, 2H), 3.32 (s, 2H), 2.05 (s, 3H);
13C 193.9, 190.0, 166.6, 147.8, 140.9, 139.6, 136.7, 134.1, 132.1,
131.7, 131.6, 131.5, 130.1 (2C), 129.8 (2C), 129.5 (2C), 129.0
(2C), 123.5, 114.9, 95.4, 39.2, 21.4.
+
ꢀ
mp 157–159 C. HRMS (ESI-TOF) [M + H] calcd for C24H24N2O2
373.1911, found 373.1915. IR (cmꢁ1, ATR) 3435 w, 3333 w, 3228 w,
2992 w, 1633 w, 1530 s, 1449 m, 1330 m, 1208 s, 1027 m, 825 s,
731 s, 636 m, 494 s. NMR (C6D6, d): 1H 12.92 (s, 1H), 8.16–8.13 (m,
2H), 7.14–7.12 (m, 3H), 6.93 (AB, 2H, J ¼ 8.4 Hz), 6.91 (AB, 2H, J ¼
8.3 Hz), 6.60 (d, 1H, J ¼ 8.3 Hz), 6.08 (dd, 1H, J ¼ 8.6, 2.7 Hz), 6.03
(s, 1H), 5.93 (d, 1H, J ¼ 2.7 Hz), 3.44 (s, 2H), 3.29 (s, 3H), 3.08 (s,
2H), 2.08 (s, 3H); 13C 189.6, 167.9, 160.6, 145.1, 141.3, 136.6, 134.7,
131.3, 130.0, 129.7 (2C), 129.0, 128.9 (2C), 2C signal presumably
obscured by solvent, 118.1, 104.0, 101.5, 94.4, 55.2, 39.0, 21.4.
Z-3-[(2-Amino-5-nitroanilino)-4-(4-methylphenyl)-1-phenylbut-
2-en-1-one (5ah). From 1a (0.1303 g, 0.557 mmol), 4-nitro-o-phe-
nylenediamine 4h (0.0853 g, 0.558 mmol), triethylamine (0.40
mL, 2.9 mmol), and ethanol (45 mL). Recrystallization from hot
ethanol afforded 5ah as a yellow solid (0.176 g, 0.456 mmol,
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82%), mp 177–179 ꢀC. HRMS (ESI-TOF) [M + H]+ calcd for anhydrous ethanol (1.1 mL). Stirred for 9 h. Recrystallization
C23H22N3O3 388.1661, found 388.1661. IR (cmꢁ1, ATR) 3420 w, from ethyl acetate/hexanes (layering) afforded 3ae as a yellow
3315 w, 3208 w, 1635 m, 1577 s, 1524 s, 1492 m, 1433 s, 1317 s. solid (0.0400 g, 0.114 mmol, 39%), mp 152–154 ꢀC. MS (EI, m/
NMR (C6D6, d): 1H 12.63 (s, 1H), 8.12–8.10 (m, 2H), 7.73 (dd, 1H, J z): 352 (M+, 100%), 337 (M+ ꢁ CH3, 40%), 275 (M+ ꢁ C6H5,
¼ 8.9, 2.5 Hz), 7.57 (d, 1H, J ¼ 2.4 Hz), 7.18 (signal obscured by 22%), 261 (M+ ꢁ C7H7, 21%), 247 (M+ ꢁ C8H9, 16%). HRMS
solvent, 3H), 6.83 (AB, 2H, J ¼ 7.8 Hz), 6.69 (AB, 2H, J ¼ 8.0 Hz), (ESI-TOF) [M + H]+ calcd for C25H25N2 353.2018, found
5.99 (s, 1H), 5.60 (d, 1H, J ¼ 8.9 Hz), 3.32 (s, 2H), 3.16 (s, 2H), 2.07 353.2012. IR (cmꢁ1, ATR): 1633 w, 1547 w, 1429 m, 1263 m,
(s, 3H); 13C 190.3, 166.0, 149.3, 140.5, 139.3, 137.0, 133.7, 131.9, 864 s, 767 s, 698 s, 498 s. NMR (C6D6, d): 1H 7.85–7.83 (m, 2H),
129.8 (2C), 129.3 (2C), 129.0 (2C), 2C signal presumably obscured 7.52 (s, 1H), 7.10–7.07 (m, 3H), 6.99 (AB, 2H, J ¼ 8.0 Hz), 6.94–
by solvent, 125.4, 124.6, 123.2, 113.8, 96.0, 39.2, 21.3.
6.94 (m, 1H), 6.82 (AB, 2H, J ¼ 7.8 Hz), 3.60 (s, 2H), 2.69 (s, 3H),
2.25 (s, 3H), 2.05 (s, 3H); 13C 157.1, 153.3, 141.5, 138.1, 137.7,
136.7, 136.0, 134.8, 134.2, 130.4, 129.9 (4C), 129.0 (2C), 128.8
(2C), 127.4, 47.0, 36.8, 21.4, 21.3, 19.1.
Synthesis of benzodiazepines 8aa–fa. General procedure
A 10 mL round bottom microwave vial equipped with a stir bar
2-(4-Bromophenyl)-4-(4-methylbenzyl)-3H-benzo[b][1,5]dia-
was charged with alkynone 1 (1 equiv. 1.00 mmol), diamine 4 zepine (8ba). From 1b (0.282 g, 0.905 mmol), o-phenylenedi-
(ca. 1 equiv.), and ethanol. The vial was sealed and the reaction amine 4a (0.103 g, 0.950 mmol), and ethanol (2 mL). Stirred for
ꢀ
was irradiated in the microwave reactor at 80 C for the time 1 h. Silica gel column chromatography (20 ꢃ 2.5 cm; hexanes/
specied for each compound. The solvent was removed by ethyl acetate 80 : 20) afforded 8ba as a colorless solid (0.317 g,
rotary evaporation. The product was puried by recrystallization 0.787 mmol, 87%), mp 182–182 ꢀC. MS (EI, m/z): 402 (M+,
from ethyl acetate/hexanes (layering) at 4 ꢀC or silica gel column 100%), 387 (M+ ꢁ CH3, 25%), 323 (M+ ꢁ Br, 23%), 247 (M+ ꢁ
chromatography, as indicated below. The solid was dried by C6H4Br, 26%), 233 (M+ ꢁ C7H7Br + 1, 24%), 218 (M+ ꢁ C8H9Br,
rotary evaporation followed with an oil pump vacuum to give 67%), 105 (C8H9+, 23%). HRMS (ESI-TOF) [M + H]+ calcd for
8aa–fa.
C
23H20BrN2 403.0810, found 403.0815. IR (cmꢁ1, ATR): 1622 m,
2-(4-Methylbenzyl)-4-phenyl-3H-benzo[b][1,5]diazepine (8aa). 1606 m, 1583 m, 1559 m, 1394 s, 1275 m, 1068 m 1004 s, 796 s,
From 1a (0.236 g, 1.01 mmol), o-phenylenediamine 4a (0.118 g, 769 s. NMR (C6D6, d): 1H 7.80–7.71 (m, 2H), 7.26 (AA0XX0, 2H, J
1.09 mmol), and ethanol (2 mL). Stirred for 1 h. Silica gel column ¼ 9.0 Hz),43 7.15–7.07 (m, 4H), 6.74 (AB, 2H, J ¼ 8.0 Hz), 6.65
chromatography (20 ꢃ 2.5 cm; hexanes/ethyl acetate 80 : 20) (AB, 2H, J ¼ 8.0 Hz), 3.57 (s, 2H), 2.67 (br s, 2H), 2.04 (s, 3H);
afforded 8aa as a colorless solid (0.287 g, 0.882 mmol, 87%), mp 13C 159.9, 153.2, 141.5, 140.9, 136.8, 136.0, 132.8, 131.4 (2C),
124–125 ꢀC. MS (EI, m/z): 324 (M+, 100%), 309 (M+ ꢁ CH3, 42%), 130.2 (2C), 129.6 (2C), 129.5 (2C), 129.3, 128.9, 125.8, 125.5,
1
219 (M+ ꢁ C8H5, 49%). HRMS (ESI-TOF) [M + H]+ calcd for 124.8, 47.1, 36.0, 21.0; (CDCl3, d): H 7.56–7.47 (m, 4H), 7.42
C23H21N2 325.1705, found 325.1702. IR (cmꢁ1, ATR): 1627 s, (AA0XX0, 2H, J ¼ 8.7 Hz),43 7.34–7.28 (m, 2H), 7.25 (AB, 2H, J ¼
1604 s, 1566 s, 1443 s, 1316 s, 1202 m, 1017 m, 842 s, 811 s, 758 s. 7.9 Hz), 6.92 (AB, 2H, J ¼ 7.8 Hz), 3.80 (s, 2H), 3.18 (br s, 2H),
NMR (C6D6, d): H 7.82–7.71 (m, 4H), 7.15–7.11 (m, 2H), 7.08– 2.25 (s, 3H); 13C 160.6, 153.9, 141.0, 140.2, 137.3, 135.9, 132.5,
1
7.01 (m, 3H), 6.91 (AA0XX0, 2H, J ¼ 7.9 Hz),43 6.76 (AA0XX0, 2H, J ¼ 131.8 (2C), 130.0 (2C), 129.73 (2C), 129.66 (2C), 129.6, 129.0,
7.8 Hz), 3.58 (s, 2H), 2.82 (br s, 2H), 2.01 (s, 3H); 13C 159.6, 154.1, 129.4, 125.8, 125.7, 125.2, 47.2, 36.5, 21.3.
141.7, 141.1, 137.4, 136.4, 133.4, 130.1, 129.6 (2C), 129.3, 128.8,
2-(4-Bromophenyl)-7,8-dimethyl-4-(4-methylbenzyl)-3H-benzo-
128.7 (2C), 128.4 (2C), 127.9 (2C), 125.5, 125.4, 46.8, 36.2, 21.0. [b][1,5]diazepine (8bb). From 1b (0.282 g, 0.905 mmol), 4,5-
7,8-Dimethyl-2-(4-methylbenzyl)-4-phenyl-3H-benzo[b][1,5] dimethyl-1,2-phenylenediamine 4b (0.129 g, 0.950 mmol), and
diazepine (8ab). From 1a (0.234 g, 1.00 mmol), 4,5-dimethyl- ethanol (2 mL). Stirred for 1 h. Silica gel column chromatography
1,2-phenylenediamine 4b (0.143 g, 1.05 mmol), and ethanol (20 ꢃ 2.5 cm; hexanes/ethyl acetate 80 : 20) afforded 8bb as a white
(2 mL). Stirred for 1 h. Silica gel column chromatography (20 solid (0.351 g, 0.814 mmol, 90%), mp 174–175 ꢀC. MS (EI, m/z): 430
+
ꢃ 2.5 cm; hexanes/ethyl acetate 80 : 20) afforded 8ab as (M+, 100%), 415 (M ꢁ CH3 , 58%), 275 (M ꢁ C6H4Br+, 40%), 246 (M
+
a yellow solid (0.311 g, 0.884 mmol, 88%), mp 130–131 ꢀC. MS ꢁ C8H7 ꢁ Br+, 24%), 105 (C8H9 , 24%). HRMS (ESI-TOF) [M + H]+
(EI, m/z): 352 (M+, 100%), 337 (M+ ꢁ CH3, 41%), 275 (M+
ꢁ
calcd for C25H24BrN2 431.1123, found 431.1122. IR (cmꢁ1, ATR):
C6H5, 21%), 261 (M+ ꢁ C7H7, 21%), 247 (M+ ꢁ C8H9, 29%). 1630 m, 1613 m, 1484 s, 1308 s, 1098 m, 1087 s, 1007 s, 884 s, 809 s.
HRMS (ESI-TOF) [M + H]+ calcd for C25H25N2 353.2018, found NMR (C6D6, d): 1H 7.60 (s, 1H), 7.55 (s, 1H), 7.34 (AA0XX0, 2H, J ¼
353.2027. IR (cmꢁ1, ATR): 1602 m, 1564 m, 1512 m, 1445 s, 8.6 Hz),43 7.14 (AA0XX0, 2H, J ¼ 8.7 Hz), 6.80 (AA0XX0, 2H, J ¼ 7.9
1271 m, 1005 m, 882 m, 769 s, 753 s, 690 s. NMR (C6D6, d): 1H Hz), 6.68 (AA0XX0, 2H, J ¼ 7.8 Hz), 3.62 (s, 2H), 2.78 (br s, 2H), 2.10
7.86–7.79 (m, 2H), 7.60 (s, 1H), 7.59 (s, 1H), 7.12–7.06 (m, 3H), (s, 6H), 2.05 (s, 3H); 13C 158.2, 151.9, 139.6, 139.1, 136.7, 136.3,
6.97 (AA0XX0, 2H, J ¼ 7.9 Hz),43 6.79 (AA0XX0, 2H, J ¼ 7.8 Hz), 134.6, 134.3, 133.2, 131.4 (2C), 130.1 (2C), 129.8, 129.8 (2C), 129.5
3.63 (s, 2H), 2.93 (br s, 2H) 2.11 (s, 3H), 2.11 (s, 3H), 2.03 (s, (2C), 129.4, 124.6, 47.0, 36.0, 21.0, 19.5, 19.4.
3H); 13C 158.3, 152.8, 139.8, 139.3, 137.7, 136.4, 134.3, 134.1,
133.8, 130.0, 129.9, 129.6 (2C), 129.4, 128.6 (2C), 128.4 (2C), diazepine (8ca). From 1c (0.280 g, 0.905 mmol), o-phenyl-
46.8, 36.2, 21.0, 19.5, 19.4. enediamine 4a (0.103 g, 0.950 mmol), and ethanol (2 mL).
2-(4-(tert-Butyl)benzyl)-4-(4-chlorophenyl)-3H-benzo[b][1,5]
6,8-Dimethyl-4-(4-methylbenzyl)-2-phenyl-3H-benzo[b][1,5] Stirred for 1 h. Silica gel column chromatography (20 ꢃ
diazepine (8ae). From 1a (0.0701 g, 0.300 mmol), 4,5-dimethyl- 2.5 cm; hexanes/ethyl acetate 80 : 20) afforded 8ca as a white
1,2-phenylenediamine 4e (0.0402 g, 0.296 mmol), and solid (0.333 g, 0.832 mmol, 92%), mp 121–122 ꢀC. MS (EI, m/z):
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400 (M+, 100%), 385 (M ꢁ CH3+, 62%), 343 (M ꢁ C4H9+, 33%), 141.2, 137.9, 130.6, 129.8, 128.8 (2C), 128.7 (2C), 128.5, 125.4,
218 (C15H10N2+, 39%), 117 (C9H9+, 24%). HRMS (ESI-TOF) [M + 125.1, 52.8, 39.2, 32.4, 30.1 (3C).
H]+ calcd for C26H26ClN2 401.1785, found 401.1784. IR (cmꢁ1
,
7,8-Dimethyl-2-(2,2-dimethylpropyl)-4-phenyl-3H-benzo[b]
ATR): 1633 m, 1590 m, 1559 m, 1314 m, 1090 s, 1008 m, 814 s, [1,5]diazepine (8eb). From 1e (0.100 g, 0.499 mmol), 4,5-
761 s. NMR (C6D6, d): 1H 7.81–7.75 (m, 1H), 7.74–7.69 (m, 1H), dimethyl-1,2-phenylenediamine 4b (0.081 g, 0.60 mmol) and
7.43 (AA0XX0, 2H, J ¼ 8.7 Hz),43 7.16–7.12 (m, 2H), 6.99 (AA0XX0, ethanol (2 mL). Stirred for 1 h. Silica gel column chroma-
2H, J ¼ 6.9 Hz), 6.96 (AA0XX0, 2H, J ¼ 7.2 Hz), 6.89 (AA0XX0, 2H, J tography (20 ꢃ 2.5 cm; hexanes/ethyl acetate 80 : 20) afforded
¼ 8.3 Hz), 3.61 (s, 2H), 2.72 (br s, 2H), 1.17 (s, 9H); 13C 160.0, 8eb as a yellow oil (0.126 g, 0.396 mmol, 79%). MS (EI, m/z):
153.3, 150.2, 141.8, 141.4, 136.8, 136.0, 133.3, 130.2 (2C), 129.7 318 (M+, 7%), 303 (M+ ꢁ CH3, 3%), 261 (M+ ꢁ C4H9, 100%),
(2C), 129.2, 128.9 (2C), 128.3, 126.1, 126.1 (2C), 125.9, 47.5, 247 (M+ ꢁ C5H11, 8%), 77 (C6H5+, 3%). HRMS (ESI-TOF) [M +
36.5, 34.7, 31.8 (3C).
H]+ calcd for C22H27N2 319.2174, found 319.2178. IR (cmꢁ1
,
2-(4-(tert-Butyl)benzyl)-4-(4-chlorophenyl)-3H-benzo[b][1,5] ATR): 1608 w, 1567 w, 1517 m, 1447 s, 1364 m, 1218 w, 1008 m,
diazepine (8cb). From 1c (0.283 g, 0.905 mmol), 4,5-dimethyl- 879 m, 760 m, 690 s. NMR (C6D6, d): 1H 8.12–8.07 (m, 2H), 7.64
1,2-phenylenediamine 4b (0.129 g, 0.950 mmol), and ethanol (s, 1H), 7.52 (s, 1H), 7.22–7.10 (m, 5H), 2.22 (s, 2H), 2.12 (s,
(2 mL). Stirred for 1 h. Silica gel column chromatography (20 3H), 2.10 (s, 3H), 1.45 (s, 2H), 1.05 (s, 9H); 13C 157.9, 151.2,
ꢃ 2.5 cm; hexanes/ethyl acetate 80 : 20) afforded 8cb as 139.7, 139.3, 138.1, 134.2, 133.8, 130.4, 129.7, 129.0, 128.8
a white solid (0.310 g, 0.724 mmol, 80%), mp 137–139 ꢀC. MS (2C), 128.6 (2C), 52.8, 39.3, 32.5, 30.1 (3C), 19.5 (2C).
(EI, m/z): 428 (M+, 100%), 413 (M+ ꢁ CH3, 53%), 371 (M+
ꢁ
2-(Cyclopropylmethyl)-4-phenyl-3H-benzo[b][1,5]diazepine
C4H9, 27%), 246 (M+ ꢁ C11H15Cl, 19%). HRMS (ESI-TOF) [M + (8fa). From 1f15,16 (0.0448 g, 0.243 mmol), o-phenylenedi-
H]+ calcd for C28H30ClN2 429.2098, found 429.2096. IR (cmꢁ1
,
amine 4a (0.0283 g, 0.262 mmol), and anhydrous ethanol (1.1
ATR): 1632 m, 1580 m, 1484 s, 1314 s, 1090 s, 1007 s, 814 s, mL). Stirred for 1 h 45 min. Silica gel column chromatography
761 s. NMR (C6D6, d): 1H 7.62 (s, 1H), 7.55 (s, 1H), 7.51 (AA0XX0, (12 ꢃ 2 cm, hexanes/ethyl acetate 80 : 20) afforded 8fa as
2H, J ¼ 8.7 Hz),43 7.03 (AA0XX0, 2H, J ¼ 5.7 Hz), 7.00 (AA0XX0, a yellow solid (0.0435 g, 0.159 mmol, 65%), mp 94–96 C. MS
ꢀ
2H, J ¼ 6.0 Hz), 6.95 (AA0XX0, 2H, J ¼ 8.3 Hz), 3.66 (s, 2H), 2.83 (EI, m/z): 274 (M+, 100%), 259 (M+ ꢁ CH3, 70%), 245 (M+
ꢁ
(br s, 2H), 2.11 (s, 6H), 1.18 (s, 9H); 13C 158.4, 151.7, 149.8, C2H5, 33%), 233 (M+ ꢁ C3H5, 36%), 219 (M+ ꢁ C4H7, 35%).
139.6, 139.2, 136.2, 135.9, 134.6, 133.3, 129.9, 129.8 (2C), HRMS (ESI-TOF) [M + H]+ calcd for C19H18N2 275.1548, found
129.4, 129.4 (2C), 128.6 (2C), 125.8 (2C), 47.0, 36.2, 34.4, 31.4 275.1546. IR (cmꢁ1, ATR): 1626 m, 1605 m, 1569 m, 1460 m,
(3C), 19.5, 19.4.
1319 m, 1261 m, 1207 m, 1017 m, 755 s, 692 s. NMR (C6D6, d):
2-Pentyl-4-phenyl-3H-benzo[b][1,5]diazepine (8da). From 1d 1H 7.97–7.94 (m, 2H), 7.82–7.80 (m, 1H), 7.76–7.74 (m, 1H),
(0.098 g, 0.49 mmol), o-phenylenediamine 4a (0.063 g, 0.59 7.15–7.10 (m, 5H), 2.89 (br s, 2H), 2.16 (d, 2H, J ¼ 7.0 Hz),
mmol), and ethanol (2 mL). Stirred for 1 h. Silica gel column 0.83–0.74 (m, 1H), 0.23–0.18 (AA0XX0, 2H), ꢁ0.06 to ꢁ0.10
chromatography (20 ꢃ 2.5 cm; hexanes/ethyl acetate 80 : 20) (AA0XX0, 2H); 13C 160.7, 153.7, 141.9, 141.6, 138.4, 130.9,
afforded 8da as a yellow oil (0.085 g, 0.29 mmol, 60%). MS (EI, 129.6, 129.1 (2C), 129.0, 129.0 (2C), 125.8, 125.5, 45.6, 37.3,
m/z): 290 (M+, 10%), 275 (M+ ꢁ CH3, 1%), 261 (M+ ꢁ C2H5, 3%), 9.0, 5.5 (2C).
247 (M+ ꢁ C3H7, 15%), 233 (M+ ꢁ C4H9, 100%), 219 (M+
ꢁ
+
C5H11, 12%), 77 (C6H5 , 5%). HRMS (ESI-TOF) [M + H]+ calcd for
Synthesis of 4-ethylbenzodiazepines 8ga/gb. General
procedure
C
20H23N2 291.1861, found 291.1858. IR (cmꢁ1, ATR): 1636 w,
1566 w, 1444 m, 1320 m, 1253 m, 1179 m, 1011 w, 758 s, 690 s.
1
NMR (C6D6, d): H 8.00–7.96 (m, 2H), 7.83–7.79 (m, 1H), 7.75– A 10 mL round bottom microwave vial equipped with a stir bar
7.72 (m, 1H), 7.18–7.09 (m, 5H), 2.25 (t, 2H, J ¼ 7.6 Hz), 1.52 (p, was charged with alkynone 1 (1.00 mmol), diamine 4 (1.1 mmol,
2H, J ¼ 7.5 Hz), 1.41–1.26 (m, 2H), 1.15–0.99 (m, 5H), 0.75 (t, 3H, 1.1 equiv.), and ethanol (5 mL). The vial was sealed and the
J ¼ 7.0 Hz); 13C 160.5, 153.2, 141.5, 137.7, 130.6, 129.2, 128.8 reaction was irradiated in the microwave reactor at 50 ꢀC for
(2C), 128.7 (2C), 128.6, 128.5, 125.5, 125.1, 40.3, 37.4, 31.5, 25.9, 12 min with stirring. The solvent was removed by rotary evap-
22.8, 14.1.
oration. Silica gel column chromatography (15 ꢃ 2.5 cm;
2-(2,2-Dimethylpropyl)-4-phenyl-3H-benzo[b][1,5]diazepine hexanes/ethyl acetate 80 : 20) gave a yellowish fraction. The
(8ea). From 1e (0.084 g, 0.42 mmol), o-phenylenediamine 4a solvent was removed by rotary evaporation and the residue was
(0.054 g, 0.50 mmol), and ethanol (2 mL). Stirred for 1 h. Silica dried with an oil pump vacuum to give 8ga/gb.
gel column chromatography (20 ꢃ 2.5 cm; hexanes/ethyl
2-Benzyl-4-ethyl-3H-benzo[b][1,5]diazepine (8ga). From 1g
a yellow oil (0.083 g, (0.166 g, 0.965 mmol) and o-phenylenediamine 4a (0.115 g, 1.03
acetate 80 : 20) afforded 8ea as
0.29 mmol, 68%). MS (EI, m/z): 290 (M+, 3%), 275 (M+ ꢁ CH3, mmol) afforded 8ga as a colorless oil (0.195 g, 0.743 mmol,
+
4%), 233 (M+ ꢁ C4H9, 100%), 219 (M+ ꢁ C5H11, 9%), 77 (C6H5
,
77%). MS (EI, m/z): 262 (M+, 100%), 247 (M+ ꢁ CH3, 72%), 233
+
25%). HRMS (ESI-TOF) [M + H]+ calcd for C20H23N2 291.1861, (M+ ꢁ C2H5, 39%), 171 (M+ ꢁ C7H7, 39%), 91 (C7H7 , 33%).
found 291.1858. IR (cmꢁ1, ATR): 1634 w, 1565 w, 1479 m, 1320 HRMS (ESI-TOF) [M + H]+ calcd for C18H19N2 263.1548, found
m, 1249 m, 1115 w, 1026 m, 764 s, 689 s. NMR (C6D6, d): H 263.1546. IR (cmꢁ1, ATR): 1633 s, 1600 m, 1493 m, 1454 m, 1421
1
1
8.05–8.00 (m, 2H), 7.82–7.79 (m, 1H), 7.67–7.63 (m, 1H), 7.18– m, 763 s, 734 s, 699 s. NMR (CDCl3, d): H 7.47–7.41 (m, 1H),
7.08 (m, 5H), 2.17 (s, 2H), 1.00 (s, 9H); 13C 159.3, 152.5, 141.5, 7.39–7.15 (m, 8H), 3.81 (s, 2H), 2.72 (br s, 2H), 1.79 (q, 2H, J ¼
7.3 Hz), 0.97 (t, 3H, J ¼ 7.3 Hz); 13C 163.6, 160.5, 140.8, 140.0,
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136.0, 129.6 (2C), 128.9 (2C), 128.0, 127.9, 127.3, 125.1, 124.8, 2.21 (s, 3H), 2.02 (s, 3H), 2.08 (s, 3H); 13C 159.1, 154.0, 141.9,
47.7, 40.0, 32.7, 10.5. 139.3, 137.9, 136.7, 135.3, 133.9, 130.4, 129.9 (2C), 129.6,
2-Benzyl-4-ethyl-7,8-dimethyl-3H-benzo[b][1,5]diazepine (8gb). 129.1, 129.0 (2C), 128.7 (2C), 2C signal presumably obscured
From 1g (0.156 g, 0.905 mmol) and 4,5-dimethyl-1,2- by solvent, 127.2, 47.1, 36.6, 21.4, 21.3.
phenylenediamine 4b (0.148 g, 1.09 mmol) afforded 8gb as
a colorless oil (0.183 g, 0.634 mmol, 70%). MS (EI, m/z): 290 (M+,
Synthesis of benzodiazepines with electron-withdrawing
substituents 8af–h from enaminones. General procedure
100%), 275 (M+ ꢁ CH3, 76%), 261 (M+ ꢁ C2H5, 36%), 199 (M+ ꢁ
+
C7H7, 37%), 91 (C7H7 , 25%). HRMS (ESI-TOF) [M + H]+ calcd for
C20H23N2 291.1861, found 291.1867. IR (cmꢁ1, ATR): 1628 s, 1600 A 10 mL round bottom microwave vial equipped with a stir bar
m, 1480 m, 1452 m, 1420 m, 1285 m, 881 s, 737 s, 701 s. NMR was charged with enaminone 5. The vial was sealed and evacu-
(CDCl3, d): 1H 7.36–7.23 (m, 5H), 7.21 (s, 1H), 7.13 (s, 1H), 3.84 (s, ated with an oil pump vacuum/lled with nitrogen three times.
2H), 2.72 (br s, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 1.85 (q, 2H, J ¼ 7.4 The vial was charged with anhydrous ethanol and acetic acid
Hz), 1.02 (t, 3H, J ¼ 7.4 Hz); 13C 162.6, 159.4, 138.9, 138.1, 136.5, (73–75 equiv.) and via syringe. The reaction was irradiated in the
134.3, 133.9, 129.8 (2C), 129.2 (2C), 128.7, 128.7, 127.4, 47.9, 40.1, microwave reactor at 80 ꢀC with stirring for the time specied for
32.9, 19.6, 19.6, 10.8.
each compound. The solvent was removed by rotary evaporation.
Silica gel column chromatography (18 ꢃ 2.5 cm; hexanes/ethyl
acetate 80 : 20 or 60 : 40 for 8af) gave a yellow/white fraction.
The solvent was removed by rotary evaporation and the residue
was dried with an oil pump vacuum to give 8af–h.
Synthesis of benzodiazepines with electron-donating or
without substituents 8aa,ac,ad from enaminones. General
procedure
2-(4-Methylbenzyl)-4-phenyl-3H-benzo[b][1,5]diazepine-6-
A 50 mL round bottom ask equipped with a stir bar was charged carboxamide (8af). From 5af (0.0380 g, 0.0987 mmol), acetic
with enaminone 5 and a solution of acetic acid in ethanol (2% v/ acid (0.42 mL, 7.3 mmol), and anhydrous ethanol (3.9 mL).
v). The reaction was stirred at rt for the time specied for each Stirred for 4.5 h to afford 8af as a white solid (0.0157 g,
compound. The solvent was removed by rotary evaporator fol- 0.0427 mmol, 43%), mp 206–209 ꢀC. HRMS (ESI-TOF) [M +
lowed with an oil pump vacuum to give 8aa,ac,ad.
H]+ calcd for C24H21N3O 368.1763, found 368.1762. IR (cmꢁ1
,
2-(4-Methylbenzyl)-4-phenyl-3H-benzo[b][1,5]diazepine (8aa). ATR): 1658 s, 1562 s, 1421 m, 1303 m, 1122 w, 776 m, 759 s,
From 5aa (0.143 g, 0.418 mmol) and a solution of acetic acid in 587 m. NMR (DMSO-d6, d): 1H 8.23 (s, 1H), 7.81 (AA0XX0, 2H, J
ethanol (2% v/v; 35 mL). Stirred for 2 h. Silica gel column chro- ¼ 7.2 Hz),43 7.75 (dd, 1H, J ¼ 5.8, 1.6 Hz), 7.57 (s, 1H), 7.52–
matography (19 ꢃ 2.5 cm; hexanes/ethyl acetate 80 : 20) afforded 7.49 (m, 2H), 7.43–7.35 (m, 3H), 7.03 (AB, 2H, J ¼ 8.0 Hz), 6.93
5aa as a yellow solid (0.124 g, 0.382 mmol, 91%). Spectral data (AB, 2H, J ¼ 7.8 Hz), 3.77 (s, 2H), 2.16 (s, 3H); 13C 169.2, 162.9,
were identical with those described above.
156.1, 140.8, 138.8, 137.1, 137.0, 133.8, 133.6, 132.0, 131.2,
7-Methoxy-2-(4-methylbenzyl)-4-phenyl-3H-benzo[b][1,5]dia- 130.4 (2C), 130.2 (2C), 129.8 (2C), 129.6 (2C), 127.5, 125.9,
zepine (8ac). From 5ac (0.0138 g, 0.0371 mmol) and a solution 46.8, 38.3, 21.8.
of acetic acid in ethanol (2% v/v; 30 mL). Stirred for 2 h to afford
4-(4-Methylbenzyl)-7-benzoylphenyl-2-phenyl-3H-benzo[b]
8ac as a yellow solid (0.0131 g, 0.0370 mmol, >99%), mp 134– [1,5]diazepine (8ag). From 5ag (0.0477 g, 0.107 mmol), acetic
136 ꢀC. MS (EI, m/z): 354 (M+, 100%), 339 (M+ ꢁ CH3, 24%), 324 acid (0.46 mL, 8.0 mmol), and anhydrous ethanol (3.7 mL).
(M+ ꢁ OCH3, 4%), 277 (M+ ꢁ C6H5, 17%), 263 (M+ ꢁ C7H7, Stirred for 4.5 h to afford 8ag as a yellow solid (0.0118 g,
12%). HRMS (ESI-TOF) [M + H]+ calcd for C24H22N2O 355.1810, 0.028 mmol, 26%), mp 217–219 ꢀC. HRMS (ESI-TOF) [M + H]+
found 355.1809. IR (cmꢁ1, ATR): 1656 m, 1569 m, 1436 m, 1339 calcd for C30H24N2O 429.1967, found 429.1967. IR (cmꢁ1
,
1
m, 1262 m, 1227 m, 798 s, 685 s. NMR (C6D6, d): H 7.78–7.75 ATR): 1651 m, 1597 m, 1404 m, 1242 m, 1075 m, 717 m, 688 s,
1
(m, 3H), 7.25 (d, 1H, J ¼ 2.8 Hz), 7.07–7.05 (m, 3H), 6.97–6.93 625 m. NMR (C6D6, d): H 8.36 (d, 1H, J ¼ 1.9 Hz), 7.87–7.84
(m, 3H), 6.77 (AB, 2H, J ¼ 7.8 Hz), 3.64 (s, 2H), 3.38 (s, 3H), 2.91 (m, 3H), 7.74 (AA0XX0, 2H, J ¼ 6.7 Hz), 7.70 (d, 1H, J ¼ 8.2 Hz),
(br s, 2H), 2.02 (s, 3H); 13C 157.8, 153.7, 142.1, 136.7, 7.12–7.02 (m, 7H), 6.87 (AB, 2H, J ¼ 8.0 Hz), 6.76 (AB, 2H, J ¼
135.5134.0, 130.6, 130.5, 129.2 (2C), 129.1 (2C), 128.7 (2C), 7.8 Hz), 3.53 (s, 2H), 2.77 (br s, 2H), 2.02 (s, 3H); 13C 195.3,
128.3 (2C), 115.2, 111.3, 58.4, 55.4, 47.0, 36.6, 21.3, 18.9.
161.1, 156.0, 144.7, 140.6, 138.9, 137.3, 137.0, 135.4, 133.4,
7-Methyl-2-(4-methylbenzyl)-4-phenyl-3H-benzo[b][1,5]dia- 132.3, 132.0, 130.1, 130.6 (2C), 130.0 (2C), 129.9 (2C), 129.6,
zepine (8ad). From 5ad (0.0360 g, 0.101 mmol) and a solution 129.2 (2C), 128.8 (2C), 128.8 (2C), 126.9, 47.1, 36.8, 21.3.
of acetic acid in ethanol (2% v/v; 17 mL). Stirred for 3 h to
4-(4-Methylbenzyl)-7-nitro-4-phenyl-3H-benzo[b][1,5]dia-
afford 8ad as a yellow solid (0.0342 g, 0.101 mmol, >99%), mp zepine (8ah). From 5ah (0.0348 g, 0.0900 mmol), acetic acid
89–92 ꢀC. MS (EI, m/z): 338 (M+, 100%), 323 (M+ ꢁ CH3, 40%), (0.38 mL, 6.6 mmol), and anhydrous ethanol (4.0 mL). Stirred
261 (M+ ꢁ C6H5, 19%), 247 (M+ ꢁ C7H7, 19%), 233 (M+ ꢁ C8H9, for 6 h to afford 8ah as a yellow solid (0.012 g, 0.033 mmol,
35%). HRMS (ESI-TOF) [M + H]+ calcd for C24H22N2 339.1861, 37%), mp 138–141 ꢀC. MS (EI, m/z): 369 (M+, 100%), 354 (M+ ꢁ
found 339.1858. IR (cmꢁ1, ATR): 1628 w, 1571 w, 1445 m, 1419 CH3, 29%), 292 (M+ ꢁ C6H5, 10%), 278 (M+ ꢁ C7H7, 11%), 264
m, 1300 m, 1272 m, 1125 m, 1130 m, 763 s, 690 s. NMR (C6D6, (M+ ꢁ C8H9, 13%). HRMS (ESI-TOF) [M + H]+ calcd for
d): 1H 7.79–7.77 (m, 2H), 7.74 (d, 1H, J ¼ 8.2), 7.59 (s, 1H),
C
23H19N3O2 370.1556, found 370.1562. IR (cmꢁ1, ATR): 1631 s,
7.09–7.05 (m, 3H), 6.98 (dd, 1H, J ¼ 8.2, 1.9 Hz), 6.93 (AB, 2H, J 1588 m, 1510 s, 1450 m, 1340 s, 1077 m, 882 m, 687 s. NMR
1
¼ 7.9 Hz), 6.77 (AB, 2H, J ¼ 7.8), 3.61 (s, 2H), 2.88 (br s, 2H), (C6D6, d): H 8.54 (d, 1H, J ¼ 2.6 Hz), 7.82 (dd, 1H, J ¼ 8.9, 2.6
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Hz), 7.68 (AA0XX0, 2H, J ¼ 6.9 Hz),43 7.36 (d, 1H, J ¼ 8.9 Hz), 7.10–
7.00 (m, 3H), 6.85 (AB, 2H, J ¼ 8.0 Hz), 6.78 (AB, 2H, J ¼ 7.8 Hz),
3.47 (s, 2H), 2.60 (br s, 2H), 2.02 (s, 3H); 13C 162.3, 157.0, 145.8,
145.3, 140.6, 137.2, 136.8, 133.0, 131.4, 130.1 (2C), 130.0, 129.9
(2C), 129.1 (2C), 128.9 (2C), 124.9, 120.0, 47.0, 36.9, 21.3.
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Acknowledgements
Acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund (PRF #52858) for
the support of this research. The NSF awards (CHE-0821487,
CHE-0722547, and CHE-1048719) and OU Research Excellence
Fund are also acknowledged. J. Y. and M. B. were supported by
Dershwitz Summer Fellowship and the OU Department of
Chemistry, respectively. B. N. is grateful for the predoctoral
fellowship received from the Turkish National Science Foun-
dation (TUBITAK).
¨
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at ꢁ50 ꢀC is about twice as much (1131 Hz). This
difference could be explained by presence of a benzyl
system in compound 8ga, which provides conformational
exibility that causes deshielding of the second H-3 proton
by the phenyl ring.
28 Occasionally only removal of volatiles from the post-reaction
mixture was sufficient to obtain enaminones with
reasonable purity as indicated by NMR. Limited attempts
to purify enaminones using silica gel column
chromatography were unsuccessful.
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ꢀ
30 A recent study found that mixture of alk-3-ynone and
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126 C within the rst heating curve indicating absence of 43 Six peaks exhibiting a splitting pattern of pseudo triplet of
¼
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ꢀ
the thermal process at the specic conditions. Cf. DSC
scan in ESI.†
32 Cf. NMR spectra in ESI.†
doublet were observed. The estimated values were
determined as nA ¼ (d2 + d5), JAX z d2 ꢁ d5.
44 A part of the signal was obscured.
45 Limited solubility of 4-methoxy-o-phenylenediamine 4c
required additional amount of solvent.
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