A trifluoroacetic acid catalyzed domino reaction as an approach to amino acid derived 2,3-dihydro-1 H -1,5-benzodiazepines

Article abstract of DOI:10.1055/s-0033-1340837

Trifluoroacetic acid catalyzed condensation of aromatic amines with substituted benzaldehydes followed by intramolecular cyclization furnishes a highly effective synthesis of amino acid derived 2,3-dihydro-1H-1,5- benzodiazepines. The strategy provides an

Full text of DOI:10.1055/s-0033-1340837

LETTER
▌939
lAetteTr rifluoroacetic Acid Catalyzed Domino Reaction as an Approach to Amino
Acid Derived 2,3-Dihydro-1H-1,5-benzodiazepines
Synthesis of Amino Acid Derived 2,3-Dihydro-1H-1,5-benzodiazepines
Saurav Bera,a Pancham S. Kandiyal,b Ravi S. Ampapathi,b Gautam Panda*a
a
Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
E-mail: gautam.panda@gmail.com; E-mail: gautam_panda@cdri.res.in
b
Sophisticated Analytical Instrumental Facility Division, CSIR-Central Drug Research Institute, Lucknow 226031, UP, India
Received: 14.12.2013; Accepted after revision: 28.01.2014
This paper is dedicated to Prof. M. Periasamy on his 60th birthday.
curs.14 The salient features of cascade or domino reactions
Abstract: Trifluoroacetic acid catalyzed condensation of aromatic
are simplicity, efficiency, and shortened timing for diversi-
amines with substituted benzaldehydes followed by intramolecular
ty-oriented synthesis in one pot.15 Several approaches to
cyclization furnishes a highly effective synthesis of amino acid de-
rived 2,3-dihydro-1H-1,5-benzodiazepines. The strategy provides
benzodiazepines have been reported.16 The most general
an efficient access to a library of benzodiazepines that can be ex- and simplest method for accessing 1,5-benzodiazepines in-
plored for potential pharmaceutical or biological activities.
volves the acid-catalyzed reaction of o-phenylenediamine
with α,β-unsaturated carbonyl compounds, β-haloketones
or ketones. Many reagents including BF3·OEt2,17 polyphos-
phoric acid–SiO2,18 NaBH4,19 MgO/POCl3,20 Yb(OTf)3,21
Al2O3–P2O5,22 and acetic acid under microwave
conditions23 have been reported for this reaction. Recently,
these condensations have been reported even in monosac-
charide and ionic liquid media.24,25
Key words: amino acids, heterocycles, benzodiazepine, domino re-
action, intramolecular cyclization
Benzannulated nitrogen-containing heterocycles are core
structures of numerous biologically active compounds
that display a wide range of pharmacological activities.1
Among them, benzodiazepines (Figure 1) are widely used
in medicinal chemistry.2 They belong to the class of
psychotropics3 that have notable central nervous system
depressant activity,4 along with various other biologically
important activities5 such as anticancer,6 antiviral (HIV),7
and cardiovascular activity.8 Many members of this fami-
ly are known as antianxiety, analgesic, antidepressive,
sedative, and hypnotic agents9 and other applications in-
clude dyes for acrylic fibers10 and as anti-inflammatory
agents.11 In addition, 1,5-benzodiazepines are key inter-
mediates for fused benzodiazepines, such as triaxol12 and
oxadiazol.13
The synthesis and biology of (S)-amino acid based chiral
heterocyles and natural product like molecules26 have
been reported by our group. Recently, we synthesized a
novel series of amino acid derived benzoxazepines as
potential antitumor agents26e and diversity-oriented
benzannulated heterocyclic scaffolds employing inter-
and intramolecular Mitsunobu reactions.26g Herein we
disclose an innovative route towards the synthesis of chi-
ral 2,3-dihydro-1H-1,5-benzodiazepines through an acid-
catalyzed domino reaction.
(S)-Amino acids 2a,b were reacted with 1-fluoro-2-nitro-
benzene (1) in the presence of K2CO3 and dry DMF at
80 °C to furnish the corresponding 2-nitrophenyl N-pro-
tected amino acid derivatives which were converted into
methyl esters 3a,b in the presence of SOCl2 and MeOH
(Scheme 1). Nucleophilic aromatic substitution of 2-nitro-
fluorobenzene with amino acids occurs without any
racemization26h (ee > 99%). LiBH4 reduction of esters
3a,b gave carbinols 4a,b in 80–90% yield. The nitro
group was reduced to an amine by hydrogenation to pro-
vide carbinols 5a,b in 65–75% yield. Selective protection
of the primary amine using Boc anhydride and sodium bi-
carbonate in ethanol afforded 6a,b both in 95% yield.
Swern oxidation at –78 °C gave aldehydes 7a,b which un-
derwent one-carbon Wittig olefination to afford 8a,b.
R5
R4
Me
O
O
N
O
O
N
Cl
N
R1
N
Cl
R3
N
N
H
Ph
R2
Me
diazepam
triflubazam
prophylactic agent
Figure 1 Examples of medicinally important benzodiazepine deriva-
tives
One of the most practical strategies for the synthesis of such
heterocyclic compounds could be a cascade reaction in
which multiple-bond formation and/or bond cleavage oc-
With intermediate 8a in hand, we targeted enantiomerical-
ly pure tetrahydro-5H-isoquinolino[2,3-a]quinoxaline 11
in one pot via an inverse electron-demand Diels–Alder re-
action (Scheme 2). However, when 8a was treated with
trifluoroacetic acid (TFA) followed by addition of substi-
tuted benzaldehydes at room temperature, dihydrobenzo-
diazepines 12 were unexpectedly isolated instead of 11.
SYNLETT 2014, 25, 0939–0944
Advanced online publication: 11.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340837; Art ID: ST-2013-D1140-L
© Georg Thieme Verlag Stuttgart · New York

940
S. Bera et al.
LETTER
CO2Me
R
i. anhyd K2CO3, dry DMF
80 °C, 4 h
HN
NO2
F
H2N
CO2H
LiBH4 (2 M)
O2N
+
R
anhyd THF, 1 h
80–90%
ii. SOCl2, MeOH
2a, R = CHMe2
2b, R = Bn
1
60–70%
based on two steps
3a, b
CH2OH
CH2OH
H2, Pd/C, MeOH,
CH2OH
HN
R
HN
HN
R
R
Boc2O, NaHCO3
50 psi, 1 h
H2N
O2N
BocHN
EtOH, 1 h
95%
65–75%
4a,b
5a,b
6a,b
H
O
R
NHBoc
HN
Ph3P+Mel–
(COCl)2, DMSO
BocHN
KHMDS, dry THF
–78 °C
Et3N, dry CH2Cl2
–78 °C
N
H
R
74%
8a,b
85%
7a,b
Scheme 1 Synthesis of substrate 8
This was confirmed by 1H–1H homonuclear, 13C–1H and the seven-membered ring formation. This is further con-
15N–1H heteronuclear long-range correlations for the rep- firmed by the long-range correlation between N4 and C6H.
resentative compound 12g. Long-range correlation be-
tween H5′ (δ = 2.78 ppm) and C6 (δ = 28.3 ppm), supports
During optimization of this TFA-catalyzed domino reac-
tion, varying solvents and stoichiometries of reagents, no-
ticeable results were examined (Table 1). The maximum
Scheme 2 Strategy for preparation of benzodiazepines. (A) 13C–1H HMBC correlation of 12g is shown between H5′ ↔ C6 with blue arrow and
labelled as 1. (B) 15N–1H HMBC correlation of 12g is shown between N4 ↔ C6H with red arrow and labelled as 2.
Synlett 2014, 25, 939–944
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Amino Acid Derived 2,3-Dihydro-1H-1,5-benzodiazepines
941
yield (92%) was obtained with two equivalents TFA at
room temperature for 30 minutes. With one equivalent
TFA and 8 yields were lower.
Table 2 Synthesis of 2,3-Dihydro-1H-1,5-benzodiazepine
Entry
R
ArCHO
Product Time (min) Yield (%)
1
2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
Bn
4-FC6H4
12a
12b
12c
12d
12e
12F
12g
12h
12i
35
30
32
38
40
32
30
35
45
40
45
42
34
38
89
92
90
65
68
91
92
88
82
79
78
80
61
60
Table 1 Screening of the Substrates and Optimization of the Reac-
tion
4-NCC6H4
2-FC6H4
3
R2
CHO
R2
4
3-MeC6H4
2-MeC6H4
3-O2NC6H4
4-O2NC6H4
3-FC6H4
NHBoc
N
(1 equiv)
5
TFA (catalyst)
solvent, r.t.
N
H
8
R1
6
N
R1
12
60–92%
7
Entry Substrate TFA
(equiv)
Solvent
Time
(min)
Yield
(%)a
8
9
4-ClC6H4
3-ClC6H4
3-thiophene
4-NCC6H4
4-MeC6H4
4-MeOC6H4
1
2
8a
8a
8a
8a
8a
8b
8b
8b
8b
8a
8a
8b
0.0
CH2Cl2
50
45
48
48
30
38
44
50
35
50
45
55
0
51
65
72
92
62
53
69
85
0
10
11
12
13
14
12j
0.1
1.0
1.5
2.0
0.1
1.0
1.5
2.0
0.1
1.0
2.0
CH2Cl2
12k
12l
3
CH2Cl2
4
CH2Cl2
CHMe2
CHMe2
12m
12n
8
CH2Cl2
6
CH2Cl2
7
CH2Cl2
NO2
8
CH2Cl2
NHBoc
H
N
COOEt
COOEt
9
CH2Cl2
Ph3P
OHC
7a
dry CH2Cl2, reflux
5 h
10
11
12
MeCN
TFA, dry CH2Cl2
r.t., 30 min
13
MeCN
15
42
82%
92%
MeCN–H2O (1:1)
NO2
NO2
a Isolated yield after column chromatography.
COOEt
N
N
N
To explore this synthetic strategy, substituted benzalde-
hydes with a variety of electron-releasing groups; that is,
Me, OMe, and electron-withdrawing groups, such as NO2
and CN, were reacted with substrates 8 under similar con-
ditions (Table 2). The three-step reaction proceeded very
efficiently under mild conditions at room temperature to
produce the corresponding 2,3-dihydro-1H-1,5-benzodi-
azepines 12a–n in high yields in each case.
COOEt
N
not obtained
14
Scheme 3 Synthesis of compound 14
The probable mechanism for the TFA-catalyzed transfor-
mation of compounds 8a,b into benzodiazepines 12a–n27
is shown in Scheme 4. Initially, the iminium ion 15,
formed from condensation between the benzaldehyde and
amine, undergoes sigmatropic 1,5-H shift (NH → CH)28
to furnish the intermediate o-quinonediimine (type 16
without anion). Subsequently, intermediate 16through an-
other 1,5-H shift (CH → NH) generates the intermediate
18. Of the two reaction pathway possible from 18, intra-
molecular 7-endo-trig aza-Michael addition onto the most
activated α,β-unsaturated iminium ion followed by 1,7-
electrocyclization and final rearomatisation affords ben-
zodiazepine 14. Intermediate 18 does not furnish 20.
To examine the mechanism of the reaction, further inves-
tigations were undertaken under the optimized reaction
conditions. With intermediate aldehyde 7a in hand,
Horner–Wadsworth–Emmons olefination was performed
in the presence of Ph3P=CHCO2Et in dry CH2Cl2 to give
13 (Scheme 3). Upon treatment of 13 with 4-nitrobenzal-
dehyde and TFA in dry CH2Cl2, (S)-ethyl4-isopropyl-1-
(4-nitrobenzyl)-2,3-dihydro-1H-1,5-benzodiazepine-2-
carboxylate (14) was isolated. NMR analysis of com-
pound 14 also displayed similar, long-range correlations
as detected in 12g, supporting the same mechanistic route
like compound 12.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 939–944

942
S. Bera et al.
LETTER
O2N
H+
O2N
– H+
O2N
H
N
+
N
N
N
NH
N
+
+
–
EtOOC
EtOOC
EtOOC
H
H
H
15
16
17
O2N
O2N
O2N
+
H
N
H
N
NH
N
N
N
EtOOC
EtOOC
path a
X
EtOOC
H+
18
19
X
NO2
NO2
COOEt
N
N
N
*
COOEt
N
20
not obtained from path a
14
Scheme 4 Possible mechanism for the formation of product 14
In conclusion, we have established a new strategy for the
synthesis of 1,5-benzodiazepines from amino acid derived
substrates and substituted benzaldehydes through TFA-
catalyzed domino transformation. This synthesis proceeds
via Boc deprotection, imine formation, and intramolecu-
lar cyclization to form the seven-membered heterocycle.
Ths simple, convenient, easily reproducible, and high-
yielding procedure for accessing functionalized 1,5-ben-
zodiazepine scaffolds may be useful in both synthetic and
medicinal chemistry.
Acknowledgment
This research project was supported by the Department of Science
and Technology, New Delhi, India. SB and PSK are thankful to
CSIR for providing fellowships. Instrumental facilities from SAIF,
CDRI (communication no 174/2013/GP), Lucknow is acknowl-
edged.
Figure 2 Confirmation of stereochemistry of 14 by NOESY (400
MHz, CDCl3). Characteristic NOE values and average structure from
1nS MD run. (A) NOE enhancements are shown in blue arrows and
support the proposed twist-chair conformation of the seven-mem-
bered ring. (B) Average of the 15 lowest-energy structures resulted
from the restrained molecular dynamics (MD) run. For clarity, the
nitrophenyl group is replaced with a methyl group after the MD run.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
For compound 14, a vicinal coupling constant of 11.8 Hz
between H6a and H7 suggests their diaxial relative disposi-
tion. Additionally, NOE enhancements between H7 → Ph
(ortho), H6a → Ph (ortho), CH3(γ) → H6e and CH3(γ) →
H6a (weak) further support the proposed conformation for
the seven-membered ring. Restrained molecular dynam-
ics (MD) calculations were performed with a Discovery
Studio 3.0 client program using CHARMm force field29
with default parameters throughout the simulation. The
average structure, given in Figure 2, suggests that the cy-
cloheptadiene ring adopts the proposed twisted-chair con-
formation, which is flattened at the Val residue due to the
double bond.
References and Notes
(1) For a book chapter: Gilchrist, T. L. In Heterocyclic
Chemistry; Addison Wesley: Essex, England, 1997, 3rd ed.,
414.
(2) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893.
(3) Michelini, S.; Cassano, G. B.; Frare, F.; Perugi, G.
Pharmacopsychiatry 1996, 29, 127.
(4) Parola, A. L.; Yamamura, H. I.; Laird, H. E. Life Sci. 1993,
52, 1329.
(5) Knabe, J.; Buech, H. P.; Bender, S. Arch. Pharm. 1995, 328,
59.
Synlett 2014, 25, 939–944
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