One pot conversion of azido arenes to N-arylacetamides and N-arylformamides: Synthesis of 1,4-benzodiazepine-2,5-diones and fused [2,1-b]quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2004.09.046

Sodium iodide in acidic media has been employed for the synthesis of N-arylformamides and N-arylacetamides. The NaI/acetic acid reagent system has also been extended for the synthesis of 1,4-benzodiazepine-2,5-diones, pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones, and fused [2,1-b]quinazolinones.

Full text of DOI:10.1016/j.tetlet.2004.09.046

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8187–8190
One pot conversion of azido arenes to N-arylacetamides and
N-arylformamides: synthesis of 1,4-benzodiazepine-2,5-diones
and fused [2,1-b]quinazolinones
*
Ahmed Kamal, A. Venkata Ramana, K. Srinivasa Reddy, K. Venkata Ramana,
A. Hari Babu and B. Rajendra Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 29 July 2004; revised 25 August 2004; accepted 3 September 2004
Available online 22 September 2004
Abstract—Sodium iodide in acidic media has been employed for the synthesis of N-arylformamides and N-arylacetamides. The NaI/
acetic acid reagent system has also been extended for the synthesis of 1,4-benzodiazepine-2,5-diones, pyrrolo[2,1-c][1,4]benzodiaze-
pine-5,11-diones, and fused [2,1-b]quinazolinones.
Ó 2004 Published by Elsevier Ltd.
1
. Introduction
factors, there has been considerable demand for the
development of novel and efficient methods for the prepa-
ration of these compounds.
1
In recent years, azides have attracted much attention
not only as excellent protecting groups, but also as key
intermediates for the synthesis of a large number of
organic compounds such as nucleosides, carbohy-
drates, and N-containing heterocycles like quinolines,
quinazolines, benzodiazepines, lactams, and cyclic imi-
des. The conversion of azido arenes to N-acylated inter-
mediates has been a desirable strategy in various
synthetic sequences. N-Arylacetamides and N-arylform-
amides have been widely used as intermediates for the
synthesis of biologically active compounds such as
As a part of our continuing research toward the synthe-
8
sis of heterocyclic natural products, we have reported
various methods for azide group reduction. Recently
2
3
9
we have also reported the preparation of N-arylforma-
mides from the corresponding azides employing a
microwave-assisted Zn–ammonium formate system.
In continuation of these efforts, we herein report the
preparation of N-arylformamides/N-arylacetamides
employing NaI in the presence of formic acid and acetic
acid, respectively. Additionally, we also report an azide
reductive-cyclization process for the synthesis of 1,4-
benzodiazepine-2,5-diones and fused [2,1-b]quinazoli-
nones using NaI in acetic acid. This reagent system
4
chemotherapeutic and antibacterial agents and in the
synthesis of isocyanides and allylated carbonyl com-
pounds. Several methods have been reported for the
synthesis of these compounds from the amine precursors
5
6
7
while very few methods are available in the literature
1
0
for the direct conversion of azides in to N-acylamines.
The majority of these methods have shortcomings in
relation to their general applicability, selectivity, longer
reaction times, and ease of handling. In view of these
has been recently reported for the ring opening of
cyclopropanes.
2. N-Acylation of azides
Keywords: Sodium iodide; Acetic acid; Formic acid; Azides; N-Aryl-
formamides; N-Arylacetamides; Reductive cyclization; 1,4-Benzodiaze-
pine-2,5-diones; Fused [2,1-b]quinazolinones; Pyrrolo[2,1-c][1,4]ben-
zodiazepine-5,11-diones.
N-Acylamines have been synthesized from azides using
1
1
12
RuCl –thioacetic acid or AlI –acetic anhydride.
3
3
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189;
e-mail addresses: ahmedkamal@ins.iictnet.com; ahmedkamal@iict.
res.in
In the former case the use of thioacetic acid is often
found to be inconvenient due to its noxious smell and
RuCl3 is very expensive. The latter reagent system
0
040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.09.046

8188
A. Kamal et al. / Tetrahedron Letters 45 (2004) 8187–8190
H
N
quinazolinones, especially vasicinone and its analogues
have also been reported to possess various pharmacologi-
N3
R1
R
NaI
1
5a
15b
O
cal properties such as bronchodilation, antitumor,
1
R2
RCOOH, reflux
R2
R1
5c
and antimycobacterial.
Moreover, azido reductive-
1
a-j
R = H, 2a-j
16
cyclization especially the aza-Wittig approach has
been an important strategy for the synthesis of these
N-containing heterocycles.
R = CH , 3a-j
3
Scheme 1.
As a part of our efforts for the synthesis of N-containing
heterocycles, we have developed novel and versatile
methods through the azide reductive route. In this
connection we have earlier reported the synthesis of pyr-
rolo[2,1-c][1,4]benzodiazepines (PBD) and fused [2,1-b]-
Table 1. Synthesis of N-arylformamides 2 and N-arylacetamides 3
employing NaI in formic acid and acetic acid, respectively
a,b
Yield (%)
Product
Substrate
R
Time (h)
1
R
2
R
8
a
8b
quinazolinones employing TMSCl–NaI,
8
HMDST,
NaI, HI, and bakerÕs yeast. Continuing our efforts
in this direction, we have employed NaI/AcOH for the
synthesis of 1,4-benzodiazepine-2,5-diones and fused
FeSO4,
FeCl3–
c
8d
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
H
Cl
Br
F
H
3.5
5
90
80
90
80
85
80
85
75
74
70
85
70
88
75
80
70
78
75
73
70
FeCl –N,N-dimethylhydrazine,
3
8
e
13
8f,g
H
H
H
H
3
H
CH
3
H
4
H
OCH
OH
H
3
H
4
[
2,1-b]quinazolinone systems. Precursors N-(2-azi-
H
H
3.5
4
dobenzoyl)-amino acid methyl esters 6, 10, and N-(2-azi-
dobenzoyl) lactams 14 readily cyclized to the
corresponding 1,4-benzodiazepinediones 7 (Table 2),
g
h
i
Cl
CH
H
3
H
H
3.5
5
COCH
COPh
H
3
H
H
1
4
1 (Table 3), and fused [2,1-b]quinazolinone 15 (Table
), respectively, as shown in Schemes 2–4. Further, the
j
H
Cl
H
4.5
3
a
b
c
d
e
f
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
H
Br
F
4.5
3
products 7b–i exhibited significant optical rotations
and chiral HPLC analysis of these diones indicated no
notable racemization.
H
H
CH
3
3.5
3
H
OCH
OH
H
3
H
Cl
3
This method is an efficient and convenient alternative to
the aza-Wittig approach employing triphenylphosphine
or tributylphosphine as it does not require anhydrous
conditions and further, the reagent system is inexpen-
sive. Additionally, 1,4-benzodiazepine-2,5-diones were
obtained directly unlike in the former case, which
g
h
i
4
CH
3
H
3.5
5
COCH
COPh
3
H
j
H
4
a
Isolated yields.
b
1
Compounds characterized by H NMR, EIMS, and by comparison
with authentic samples.
Table 2. Synthesis of 1,4-benzodiazepine-2,5-diones 7 by employing
NaI in acetic acid
employs moisture sensitive AlI . In view of these disad-
3
vantages, we herein report the reductive acylation of
azides employing NaI in acetic acid and NaI in formic
acid to obtain N-arylacetamides and N-arylformamides,
respectively, as shown in Scheme 1.
a,b
26
Product
R
Yield (%) ½aꢀD (c 0.5, MeOH)
7a
7b
7c
7d
7e
H
CH
81
75
70
80
75
76
78
78
78
—
3
+421
+92
+221
+60
+175
—
CH(CH
3 2
)
CH CH(CH
2
3
)
2
The azide precursors 1a–j have been found to undergo
acetylation/formylation under reflux for 3-4h in 70–
CH(CH
3
)CH
CH
2 3
7f
CH Ph
2
9
0% yield as shown in Table 1. Selectivity toward N-acyl-
7g
7h
(±)Ph
(+)Ph
ation against O-acylation was clearly evident as seen in
the entries 2f and 3f. These reductive acylations could
have been initiated by the in situ generation of HI, as
+67
ꢁ66
7
i
(ꢁ)Ph
a
Isolated yields.
Compounds characterized by H NMR, EIMS.
1
3
b
1
mentioned in our previous report. It is interesting to
note that azides 3a–e have been reduced to the corre-
sponding amines by employing this reagent system at
room temperature.
Table 3. Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones 11
employing NaI in acetic acid
3
. Synthesis of 1,4-benzodiazepinediones and fused
2,1-b]quinazolinones
a,b
Yield (%)
Product
1a
11b
1c
Isolated yields.
X
[
1
H
96
92
90
Benzodiazepines are an important class of compounds
with biological activities ranging from CNS depressant
to anti-cancer,
Another important class of compounds, fused [2,1-b]-
5-CH
4-Cl
3
1
1
4a
14b
14c
a
anti-HIV,
and anti-Alzheimer.
b
1
Compounds characterized by H NMR, EIMS.

A. Kamal et al. / Tetrahedron Letters 45 (2004) 8187–8190
8189
Table 4. Synthesis of fused [2,1-b]quinazolinones 15 employing NaI
in acetic acid
In conclusion, we have demonstrated an efficient,
cost-effective, and ecofriendly protocol for the synthesis
of N-arylacetamides and N-arylformamides. Further,
this method has been successfully applied to the
synthesis of pharmacologically important N-containing
heterocycles namely 1,4-benzodiazepine-2,5-diones,
pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones, and fused
[2,1-b]quinazolinones.
1
R
2
R
a,b
Yield (%)
Product
n
1
1
1
1
1
1
1
1
1
5a
5b
5c
5d
5e
5f
H
H
H
Cl
H
H
Cl
H
H
Cl
1
1
1
2
2
2
3
3
3
95
95
94
90
88
87
90
93
95
CH
H
3
3
3
H
CH
H
5g
5h
5i
H
CH
H
4. Typical procedure
a
Isolated yields.
Compounds characterized by H NMR, EIMS.
Compound 7i: To a solution of 6i (1mmol) in acetic acid
10mL) was added sodium iodide (10mmol). The result-
b
1
(
ing mixture was stirred at reflux for 12h. The solvent
was then removed under reduced pressure and the resi-
due was dissolved in ethyl acetate. The organic layer
was washed with aq NaHCO solution and aq Na S O
3
afforded imino-ether derivatives in 16–84h. These were
further converted to the 1,4-benzodiazepine-2,5-diones
in TFA–H O–THF in 1:1:12.5 for 7h at room tempera-
2
3
2
2
ture. Further it was an interesting observation that the
precursor 6a–i did not cyclize with methods previously
reported by us.
followed by brine. The ethyl acetate fraction was dried
over anhydrous Na SO and then concentrated under
reduced pressure. The residue thus obtained was purified
2
4
8
over silica gel using ethyl acetate–hexane (1:1) to afford
1
This method has also been extended for the synthesis of
the pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione ring
system (PBD dilactams). These molecules are known
to be noncovalent interactive minor groove binders.
These are also the intermediates for the synthesis of
structurally modified PBD imines via oxidation of sec-
pure 7i. H NMR (200MHz, DMSO-d ): d 5.00–5.10 (d,
6
1H, J = 6Hz), 6.90–7.50 (m, 8H), 7.71 (d, 1H,
J = 6.5Hz), 8.95 (d, 1H, J = 7.7Hz), 10.6 (s, 1H); EIMS
+
m/z 252 (M ).
Compound 15a: This compound was obtained following
the above procedure using compound 14a but refluxing
1
7a
ondary amines or by reduction of N-protected dilac-
1
7b
1
tams.
Further, they exhibit different types of
for 3h. H NMR (200MHz, CDCl ): d 2.3 (dd, 2H,
3
biological properties such as antiphase activity, analge-
sic antagonist, anti-inflammatory, psychomotor depres-
sant activity, and herbicidal properties.
J = 7.5 and 8.0Hz), 3.2 (t, 2H, J = 8.0Hz), 4.2 (t, 2H,
J = 7.5Hz), 7.5 (t, 1H, J = 7.4Hz), 7.6–7.8 (m, 2H),
1
8
+
8.3 (d, 1H, J = 8.0Hz); EIMS m/z 186 (M ).
R
H
N
O
N3
ClH.H N
COOMe
a-i
N3
O
2
H
5
NaI/acetic acid
reflux, 12 h
H
N
R
Et N/THF, r. t.
COOMe
3
NH
COCl
R
O
4
a
6a-i
7a-i
Scheme 2.
Scheme 3.
Scheme 4.
H
N
O
COOCH3
H.HCl
Et N/THF, r. t.
COOCH3
N3
N
N3
9
NaI/acetic acid
reflux, 2 h
H
N
3
X
COCl
X
X
N
O
O
4
a-c
10a-c
11a-c
n
R1
R1
R1
N3
O
N
O
N3
O
O
N
H
NaI/acetic acid
reflux, 3 h
1
3
n
N
N
R2
R2
COCl
Et N/THF, r. t.
3
R2
n
1
2
14a-i
15a-i

8190
A. Kamal et al. / Tetrahedron Letters 45 (2004) 8187–8190
Acknowledgements
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9
The authors A.V.R., K.S.R., K.V.R., A.H.B., and
B.R.P. thank CSIR (New Delhi) for the award of
research fellowships.
1
1
9
2. Bez, G. Synth. Commun. 2002, 32, 3625–3628.
085.
1
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