Catalyst-free chemo-/regio-/stereo-selective amination of alk-3-ynones. Synthesis of 1,5-benzodiazepines and 3-amino-2-alkenones

Article abstract of DOI:10.1039/c3gc41898g

Reaction of alk-3-yn-1-ones with o-phenylenediamines provides an effective method with high atom economy for the synthesis of diversely substituted benzodiazepines and conjugated enaminones. This microwave-accelerated reaction proceeds in ethanol in the absence of a catalyst and leads to benzyl-substituted 1,5-benzodiazepines with good yields (70-92%). A room temperature protocol with the same set of reagents (stabilized with triethylamine) leads to enaminones (3-amino-2-alkenones, 70-99%). The tautomer formed and the regio- and stereochemistry of the process are confirmed by the X-ray crystallographic structure determination of 2-(4-methylbenzyl)-4-phenyl-3H-benzo[b][1,5]diazepine and (Z)-3-[(2-amino-4,5-dimethylphenyl)amino]-4-(4-tert-butylphenyl)-1-(4- chlorophenyl)but-2-en-1-one.

Full text of DOI:10.1039/c3gc41898g

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Catalyst-free chemo-/regio-/stereo-selective
amination of alk-3-ynones. Synthesis of
1,5-benzodiazepines and 3-amino-2-alkenones†
Cite this: Green Chem., 2014, 16,
1120
Received 10th September 2013,
Accepted 29th November 2013
Agnes Solan,a Bilal Nişanci,‡b Miranda Belcher,a Jonathon Young,a
Christian Schäfer,b Kraig A. Wheeler,c Béla Török*b and Roman Dembinski*a
DOI: 10.1039/c3gc41898g
www.rsc.org/greenchem
Reaction of alk-3-yn-1-ones with o-phenylenediamines provides recent protocol includes in situ generation of an alk-2-ynone
an effective method with high atom economy for the synthesis of (from acyl chloride and terminal alkyne via a palladium
diversely substituted benzodiazepines and conjugated enami- catalyzed cross-coupling). Subsequent addition of the o-phenyl-
nones. This microwave-accelerated reaction proceeds in ethanol in enediamine occurs in water or in acetic acid/THF, both at 100 °C
the absence of a catalyst and leads to benzyl-substituted 1,5- and involves conjugate addition to an activated alkyne.4,7
benzodiazepines with good yields (70–92%). A room temperature While these methods provide access to benzodiazepines,
protocol with the same set of reagents (stabilized with triethyl- our interests were directed to improving the sustainability of
amine) leads to enaminones (3-amino-2-alkenones, 70–99%). The synthesis of these pharmaceutically important structures.
tautomer formed and the regio- and stereochemistry of the Thus we turned our attention to amination reactions, which
process are confirmed by the X-ray crystallographic structure are of particular significance.8 Starting from readily accessible
determination of 2-(4-methylbenzyl)-4-phenyl-3H-benzo[b][1,5]- substrates such as alkynes, the hydroamination offers an
diazepine
and
(Z)-3-[(2-amino-4,5-dimethylphenyl)amino]-4- atom-efficient pathway towards formation of a C–N or CvN
(4-tert-butylphenyl)-1-(4-chlorophenyl)but-2-en-1-one.
bond, but proceeds mostly with the use of a catalyst.8
Alk-3-ynones (propargyl ketones, 1),9 which could formally
be viewed as containing an isolated alkyne function, represent
versatile bifunctional materials for the synthesis of hetero-
cycles. Their cycloisomerization or related electrophilic cycliza-
tion reactions lead to substituted furans,10 halofurans,11 and
pyrazoles.12 Building on the observation of a hydrazination
reaction in the latter case, we envisioned the synthesis of
1,5-benzodiazepines as a reaction of alk-3-ynone 1 with
o-phenylenediamine 2.
A non-catalytic preparative synthesis for a series of 1,5-
benzodiazepines 3 was developed as illustrated in Scheme 1.
The reactions were carried out in reagent grade ethanol,
usually at 80 °C (1 h), using microwave heating. The process
also progresses in the presence of water, but is less selective;
water serves as a heat transfer medium due to solubility
Diazepines are known for their pharmaceutical applications
and commercial success.1 Derivatives of this seven-membered
ring system exhibit a wide range of biological activities. Among
them, the 1,5-benzodiazepines have received less attention
than other homologs.2 An example of active 1,5-benzo-
diazepines includes the widely prescribed antioxidant and
anticonvulsant medication, Clobazam.3 Due to their potential
in pharmaceutical or materials chemistry, new synthetic
methods for producing new homologs of benzodiazepines are
of considerable interest.4
The most commonly used strategies for the synthesis of
1,5-benzodiazepines include cyclocondensation reactions of
o-phenylenediamines with 1,3-dicarbonyl compounds, 3-haloalk-
2-enones, and alk-2-ynones.5,6 A more straightforward and
aDepartment of Chemistry, Oakland University, 2200 N. Squirrel Rd., Rochester,
Michigan 48309-4477, USA. E-mail: dembinsk@oakland.edu, bela.torok@umb.edu
bDepartment of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd.,
Boston, Massachusetts 02125, USA
cDepartment of Chemistry, Eastern Illinois University, 600 Lincoln Avenue,
Charleston, Illinois 61920-3099, USA
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for diazepines 3, enaminones 4 and 6, and cif files for 3aa and 4cb. CCDC
929588 and 950049. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3gc41898g
Scheme 1 The synthesis of 1,5-diazepines 3 from alk-3-ynones 1 and
o-phenylenediamines 2.
‡Current address: Atatürk University, Erzurum, Turkey.
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Table 1 Preparation of 1,5-benzodiazepines 3 from alkynones 1
Entry Ynone
R
R′
R″
Product Yielda [%]
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
Ph
Ph
p-MeC6H4
p-MeC6H4
H
Me
H
Me
H
3aa
3ab
3ba
3bb
3ca
3cb
3da
3db
87
88
87
90
92
80
77b
70b
p-BrC6H4 p-MeC6H4
p-BrC6H4 p-MeC6H4
p-ClC6H4 p-t-BuC6H4
p-ClC6H4 p-t-BuC6H4 Me
Et
Et
Ph
Ph
H
Me
a 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. b At 50 °C, reaction
time 12 min.
problems. The products were isolated using silica gel column
chromatography (or crystallization). Although we focused on
aryl/benzyl-substituted diazepines (entries 1–6), ethyl/benzyl
compounds were also introduced (entries 7 and 8). With this
substituents the reaction required only 50 °C and 12 min
(microwave acceleration). Such an outcome can be attributed
to increased reactivity of a carbonyl group in an alkyl-substituted
ketone 1d. In the absence of a catalyst the reaction proceeded in
almost quantitative yields, as determined by GC/MS. Results
from the reaction of ketones 1 with o-phenylenediamine 2a and
its 4,5-dimethyl homolog 2b are provided in Table 1.13
The structure of the new benzodiazepines was confirmed by
NMR and MS. The characteristic NMR features for aryl-substi-
tuted diazepines 3aa–cb include the 1H H–3 and CH2Ar
(benzyl) signals (C6D6, 2.93–2.72 and 3.66–3.58 ppm) and 13C
CvN signals (160.6.3–151.7 ppm). Intense molecular ions and
accurate HRMS M + H+ peaks were observed in the mass
spectra for 3.
As the NMR data indicate, we observed only formation of
the commonly predominant diimine (3H) tautomeric
form.4,6,14 This observation was confirmed by X-ray crystallo-
graphy.15 The structure of p-methylbenzyl-1,5-benzodiazepine
3aa is shown in Fig. 1.
To gain insight into the mechanistic details and to
compare the reactivity of the carbonyl and alkyne functions,
the reaction was carried out at room temperature (22 °C,
EtOH). The reaction of alkynones 1 with monoamines yielding
Fig. 1 An ORTEP view of the 3aa illustrating atom labeling scheme and
thermal ellipsoids (50% probability level). Selected interatomic distances
(Å): N1–C2 1.288(3), N1–C10 1.412(3), C2–C3 1.520(3), C3–C4 1.505(3),
C4–N5 1.283(3), C4–C18, 1.515(3), N5–C11 1.404(3), C10–C11 1.420(3).
Key angles (°): C2–N1–C10, 121.95(17), N1–C2–C3 120.21(18), C2–C3–
C4 106.32(16), C3–C4–N5 123.08(19), C4–N5–C11 120.25(18), N5–
C11–C10 125.55(18), N1–C10–C11 124.86(17).
Scheme 2 Synthesis of enaminones 4.
mixtures occasionally revealed the presence of diazepines or
decomposition products (as determined by NMR). Due to their
limited stability, isolation of enaminones has become proble-
matic. Thus, concluding that traces of acids may accelerate the
imination/cyclization reaction as well as product protonation
processes, triethylamine (2 equiv.) was added to the reaction
mixture (Scheme 2). Such modification resulted in near quan-
titative formation of enaminones 4. The use of triethylamine
is not required to facilitate the reaction, but is preparatively
advantageous, enabling reproducibility and effective iso-
lation.21 In the most successful case, the reaction of ketone 1a
with diamine 2b (ethanol, 22 °C, 2 h) proceeded with quanti-
tative yield (Table 2, entry 2). Removal of volatiles from the
post-reaction mixture was sufficient to obtain enaminone
4ab with reasonable purity as indicated by NMR (see ESI†).
enaminones (3-amino-2-alkenones)
4 has been reported
earlier, supported by limited spectroscopic data.16 When ali-
phatic diamines have been used, linked bis-enaminones were
obtained.
The enaminones represent useful building blocks for the
synthesis of a variety of heterocyclic compounds.17–19 Their
therapeutic potential has also been recognized.20 The available
methods for the preparation of enaminones have been ele-
gantly summarized by Katritzky.17,19g The majority of methods
directed at the construction of the C–N bond lack regioselec-
tivity or show numerous limitations including moderate yields.
Our initial results indicated almost quantitative formation
of monoenaminones, as determined by GC/MS (vide infra)
and NMR. However, further examination of the post-reaction
Other enaminones
crystallization.22
4 (entries 1, 3–6) were isolated via
The characteristic NMR signals for enaminones 4 include
the 1H NH and NH2 (13.08–12.99 and 3.10–2.85 ppm), H–2
(vCH) and H–4 (CH2Ar) signals (6.04–5.82 and 3.49–3.40 ppm);
13C C–3 (vC–N) and C–4 (CH2Ar) signals (168.4–166.6 and
39.2–38.3 ppm). Monitoring the reaction using GC/MS may
be misleading since elevated injector/column temperature
leads to the cyclization reaction and frequently the base peak
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Table 2 Preparation of enaminones 4 from alkynones 1
Table 3 Preparation of enaminones 6 from alkynones 1d and mono-
amines 5
Entry Ynone
R
R′
R″
Product Yielda [%]
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
Ph
Ph
p-MeC6H4
p-MeC6H4
H
Me
H
Me
H
4aa
4ab
4ba
4bb
4ca
4cb
85
>99b
70
83
70
p-BrC6H4 p-MeC6H4
p-BrC6H4 p-MeC6H4
p-ClC6H4 p-t-BuC6H4
p-ClC6H4 p-t-BuC6H4 Me
93
Entry Monoamine 5
Product Temp [°C] Time
Yielda [%]
a Isolated yield; reactions were carried out on a 0.18 mmol scale with
1.0 equiv. of diamine, 2 equiv. of triethylamine, in ethanol, at 22 °C,
reaction time 2 h. b Without recrystallization.
1
2
3
C6H5NH2
p-ClC6H4NH2
C6H5CH2NH2
6a
6b
6c
45
45
50
2.5 h
4 h
5 min
93
92
85
4
6d
50
5 min
97
5
6
7
6e
6f
50
50
50
5 min
5 min
5 min
85
93
97
6g
a Isolated yield; reactions were carried out on a 1.0 mmol scale with
1.05 equiv. of amine, in ethanol.
Fig. 2 An ORTEP view of the 4cb illustrating atom labeling scheme and
thermal ellipsoids (50% probability level). Selected interatomic distances
(Å): O1–C1 1.2588(19), C1–C2 1.420(2), C2–C3 1.373(2), C3–C4 1.509(2),
N1–C3 1.338(2), O1–N1 2.6520(17). Key angles (°): O1–C1–C2
122.31(14), C1–C2–C3 124.15(15), C2–C3–C4 120.96(14), C2–C3–N1
121.62(15), N1–C3–C4 117.37(13), C3–C4–C11 111.38(13), C3–N1–C21
125.65(13).
corresponding to [M − H2O]+ (diazepine) is observed as the
highest m/z ion.
We observed almost exclusive formation of the Z isomer
presumably due to hydrogen-bond stabilization. Predomi-
nance of this stereoisomer has also been observed in other
synthetic investigations.19g,23 Its structure was confirmed with
the use of X-ray crystallography (Fig. 2).15
Scheme 3 Mechanistic outline for the synthesis of diazepines 3.
The reaction of alkynone decorated with an ethyl group 1d
proceeds effectively to benzodiazepines 3d; thus far we have
not been able to isolate enaminones 4d when diamines were
used. To monitor the formation of enaminones, and to confirm
reactivity of alkyl substituted alkynones, compound 1d was
combined with a variety of monoamines 5.16 Such an approach
excluded the forthcoming cyclization reaction. Anilines (entries
1 and 2), primary (entries 3–5), and secondary (entries 6 and 7)
aliphatic amines gave corresponding enaminones 6a–g in high
yield (Table 3). For aliphatic amines the reaction was completed
at 50 °C after 5 min and for aromatic amines at 45 °C after
2–4 h, all using microwave irradiation. The analytically pure
products with aliphatic amines 6c–g were isolated after rinsing
with a water etheral solution of the post reaction mixture.
Presumably the reaction mechanism includes the initial for-
mation of allene 7 corresponding to alk-3-ynone 1, which would
subsequently undergo conjugate addition and isomerization to
a conjugated enaminone 4 (Scheme 3). Comparable sequence
via initial isomerization of 1 to alk-2-ynone (not illustrated)
can also be considered. Consecutive formation of an imine in
an intramolecular cyclization reaction and isomerization of
vinamidine form 8, driven by higher stability of the CvN bond,
lead to the final product 3 (Scheme 3). Alkyne reaction and
accompanying hydrogen migrations proceed at room temp-
erature, while reaction of the carbonyl group requires an elevated
temperature thus allowing for chemoselectivity. Although a
sequence involving anti-Markovnikov direct hydroamination of
alkyne 1 (not illustrated) cannot be excluded, such a pathway
is less likely since the formation of the C–N bond proceeds
under very mild and non-catalytic conditions. Solvent-free
intramolecular cyclization of the pure isolated enaminone 4aa
proceeded to benzodiazepine 3aa at the melting point temp-
erature indicating that the reaction is thermal.
In summary, we have demonstrated that the combination
of an amination reaction with subsequent condensation
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provides an effective access to diverse 2,4-disubstituted
1,5-benzodiazepines. The methodology allows introduction of
benzyl-type substituents at the C-2 position of benzodiazepine
that is not easily carried out by currently available methods.
The catalyst-free conditions provide an appealing protocol that
includes formation of two CvN bonds and does not require
the isolation of the enaminone. The overall formal amination
reaction proceeds with anti-Markovnikov regiochemistry
relative to the initial alkyne bond. With a high degree of
C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier,
New York, 2008, vol. 13, pp. 183–235.
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rearrangement, this reaction provides
a convenient and
temperature-controlled synthetic method for the synthesis of
benzodiazepines and enaminones. En route, enaminones with
the stereoselective positioning of o-phenylenediamine across
the double bond can be manufactured with no need to protect
the second amino function. Determination of scope of the
reaction with alkyl-only substituted ketones 1 is the subject of
further investigation in our laboratory. The major advantages
of the reported protocol as a sustainable process are as
follows: (i) the reaction does not require the presence of any
catalyst; (ii) it proceeds with high (over 90%) atom economy;
(iii) no organic or inorganic waste is produced; the only
by-product, water, is easily miscible with the solvent applied;
thus its removal does not require an extra separation step;
(iv) ethanol is the greenest solvent possible for the reaction
due to the solubility of aromatic starting materials and
products. The use of reagent grade ethanol, which is an easily
recoverable and recyclable solvent, ensures that no moisture-
free reaction conditions are necessary; (v) the reaction occurs
with high yields and selectivity; (vi) the reaction is a low energy
consumption process; it either occurs at ambient temperature
(enaminones) or with a moderate temperature microwave
irradiation (benzodiazepines). In fact, with the appropriate
selection of the activation method, the formation of the
desired product can be easily achieved; (vii) finally, the reac-
tion occurs via a step-by-step mechanism that allows an easy
and selective preparation of diverse compounds from the same
starting materials.
4 B. Willy, T. Dallos, F. Rominger, J. Schönhaber and
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Acknowledgements
9 A. Sniady, M. S. Morreale and R. Dembinski, Org. Synth.,
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R. Dembinski, Org. Synth., 2007, 84, 199–208.
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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. A.S. is grateful for Provost’s
Graduate Student Research Award. M.B. and J.Y. were sup-
ported by the OU Department of Chemistry and Dershwitz
Summer Fellowship, respectively. B.N. is grateful for the pre-
doctoral fellowship received from the Turkish National Science
Foundation (TUBITAK).
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13 Representative procedure. Synthesis of benzodiazepine
3bb. A 10 mL round bottom microwave vial equipped
with a stir bar was charged with alkynone 1b (0.222 g,
0.709 mmol), 4,5-dimethyl-1,2-phenylenediamine 2b
(0.101 g, 0.745 mmol), and ethanol (2 mL). The vial was
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evaporation. Crystallization (methanol) gave 3bb as a white
solid (0.246 g, 0.571 mmol, 81%). Silica gel column chrom-
atography of the filtrate (20 × 2.5 cm; hexanes–ethyl acetate
80 : 20) gave a yellowish fraction. The solvent was removed
by rotary evaporation and the residue was dried by oil
pump vacuum to give 3bb as a colorless solid (second crop
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0.028 g, 0.064 mmol; total 0.274 g, 0.635 mmol, 90%): mp
174–175 °C. MS (EI, m/z): 430 (M+, 100%), 415 (M − CH3 , 20 I. O. Edafiogho, S. B. Kombian, K. V. V. Ananthalakshmi,
+
58%), 275 (M − C6H4Br+, 40%), 246 (M − C8H7 − Br+, 24%),
N. N. Salama, N. D. Eddington, T. L. Wilson, M. S. Alexander,
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105 (C8H9 , 24%). HRMS (ESI-TOF) [M + H]+ calcd for
+
C25H24BrN2 431.1123, found 431.1122. IR (cm−1, solid):
1630 m, 1613 m, 1484 s, 1308 s, 1098 m, 1087 s, 1007 s, 21 The removal of triethylamine via evaporation was quantitat-
1
884 s, 809 s. NMR (C6D6, δ): H: 7.60 (s, 1H), 7.55 (s, 1H),
7.34 (AA′XX′, 2H, J = 8.6 Hz), 7.14 (AA′XX′, 2H, J = 8.7 Hz),
6.80 (AA′XX′, 2H, J = 7.9 Hz), 6.68 (AA′XX′, 2H, J = 7.8 Hz),
ive and the presence of its non-volatile derivatives was not
observed in NMR. Further optimization of its amount is in
progress.
3.62 (s, 2H), 2.78 (br s, 2H), 2.10 (s, 6H), 2.05 (s, 3H); 13C: 22 Representative procedure. Synthesis of enaminone 4ab. A
158.2, 151.9, 139.6, 139.1, 136.7, 136.3, 134.6, 134.3, 133.2,
131.4 (2C), 130.1(2C), 129.8, 129.8(2C), 129.5(2C), 129.4,
124.6, 47.0, 36.0, 21.0, 19.5, 19.4.
50 mL round bottom flask equipped with a stir bar was
charged with 1a (0.0464 g, 0.198 mmol), 4,5-dimethyl-1,2–
phenylenediamine 2b (0.062 g, 0.20 mmol), triethylamine
(0.06 mL, 0.43 mmol), and ethanol (8 mL). The reaction
mixture was stirred for 2 h at rt. The solvent was removed
by rotary evaporation and the residue was dried by oil
pump vacuum for 2 h to give a yellow solid (0.0733 g,
0.198 mmol, >99%), mp 111–112 °C. MS (EI, m/z): 352
([M − H2O]+, 100%), 337 ([M − H2O − CH3]+, 35%). HRMS
(ESI-TOF) [M + H]+ calcd for C25H27N2O 371.2123, found
371.2123. IR (cm−1, solid) 3420 w, 3400 w, 1637 w, 1591 m,
1571 s, 1532 s, 1502 m, 1481 m, 734 s, 508 s. NMR (C6D6,
14 V. A. Chebanov, S. M. Desenko, O. V. Shishkin, N. N. Kolos,
S. A. Komykhov, V. D. Orlov and H. Meier, J. Heterocycl.
Chem., 2003, 40, 25–28.
15 Crystals of 3aa and 4cb were grown from the ethyl acetate–
hexanes by layering. CCDC 929588 and 950049 contain the
supplementary crystallographic data for this paper.
16 R. L. Bol’shedvorskaya, G. A. Pavlova, L. D. Gavrilov,
N. V. Alekseeva and L. I. Vereshchagin, J. Org. Chem. USSR,
1972, 8, 1927–1931.
17 A. R. Katritzky, A. E. Hayden, K. Kirichenko, P. Pelphrey
and Y. Ji, J. Org. Chem., 2004, 69, 5108–5111, and references
therein.
18 Reviews: (a) A.-Z. A. Elassar and A. A. El-Khair, Tetrahedron,
2003, 59, 8463–8480; (b) P. Lue and J. V. Greenhill, Adv.
Heterocycl. Chem., 1996, 67, 207–343.
1
δ): H: 13.07 (s, 1H), 8.17–8.14 (m, 2H), 7.14–7.12 (m, 3H),
6.94 (d, 2H, J = 8.2 Hz), 6.90 (d, 2H, J = 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.
19 Recent representative advances: (a) S. Cacchi, G. Fabrizi
and A. Goggiamani, Chim. Ind. (Milan, Italy), 2012, 23 See for example: A. Jezierska, L. B. Jerzykiewicz, J. Kołodziejczak
94, 69–73; (b) M. S. Sargsyan, S. S. Hayotsyan,
and J. M. Sobczak, J. Mol. Struct., 2007, 839, 33–40.
1124 | Green Chem., 2014, 16, 1120–1124
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