Microwave-assisted cyclizations promoted by polyphosphoric acid esters: A general method for 1-aryl-2-iminoazacycloalkanes

Article abstract of DOI:10.3762/bjoc.12.190

The first general procedure for the synthesis of 5 to 7-membered 1-aryl-2-iminoazacycloalkanes is presented, by microwave-assisted ring closure of ω-arylaminonitriles promoted by polyphosphoric acid (PPA) esters. 1-Aryl-2-iminopyrrolidines were easily pre

Full text of DOI:10.3762/bjoc.12.190

Microwave-assisted cyclizations promoted by
polyphosphoric acid esters: a general method for
1-aryl-2-iminoazacycloalkanes
Jimena E. Díaz, María C. Mollo and Liliana R. Orelli*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2026–2031.
Universidad de Buenos Aires. CONICET. Departamento de Química
Orgánica. Facultad de Farmacia y Bioquímica. Junín 956, (1113)
Buenos Aires, Argentina
doi:10.3762/bjoc.12.190
Received: 27 May 2016
Accepted: 30 August 2016
Published: 14 September 2016
Email:
Liliana R. Orelli* - lorelli@ffyb.uba.ar
Associate Editor: B. Stoltz
* Corresponding author
© 2016 Díaz et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cyclic amidines; medium size heterocycles; microwaves; PPE; PPSE
Abstract
The first general procedure for the synthesis of 5 to 7-membered 1-aryl-2-iminoazacycloalkanes is presented, by microwave-
assisted ring closure of ω-arylaminonitriles promoted by polyphosphoric acid (PPA) esters. 1-Aryl-2-iminopyrrolidines were easily
prepared from the acyclic precursors employing a chloroformic solution of ethyl polyphosphate (PPE). The use of trimethylsilyl
polyphosphate (PPSE) in solvent-free conditions allowed for the synthesis of 1-aryl-2-iminopiperidines and hitherto unreported
1-aryl-2-iminoazepanes. The cyclization reaction involves good to high yields and short reaction times, and represents a novel ap-
plication of PPA esters in heterocyclic synthesis.
Introduction
The synthesis of new nitrogen heterocycles has a great interest A few methods have been described for the synthesis of
in medicinal chemistry since they are part of many drugs and 2-iminoazacycloalkanes from acyclic precursors. One strategy
represent structures with a wide therapeutic potential [1,2]. involves the cyclization of ω-aminonitriles, which requires the
2-Iminoazacycloalkanes are cyclic amidines where the formally presence of protic acids [9,10]. It has also been described the
sp2 nitrogen is exocyclic. These compounds have been de- reaction between halonitriles and primary or secondary amines,
scribed as selective inhibitors of the inducible form of human where the ω-aminonitrile is formed in situ [8,11-14]. This
nitric oxide synthase (iNOS), which catalyzes the reaction to heterocyclic core has also been prepared by cyclization of
form nitric oxide via the oxidation of L-arginine to L-citrulline azidonitriles [15]. These methods usually require drastic
[3-6]. Some urea and thiourea derivatives have been studied as reaction conditions and are generally limited to 2-iminopyrro-
CNS agents [7] and anthelmintic drugs [8]. This heterocyclic lidines and/or to N-unsubstituted or N-alkyl derivatives. Other
core therefore represents the foundation for potential bioactive methods involve cyclic precursors such as lactams [4,6,7,16],
agents.
thiolactams [3,6] or 2-aminopyridines [6].
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Beilstein J. Org. Chem. 2016, 12, 2026–2031.
Literature examples on the corresponding N-unsubstituted or reaction 1) [41-43]. In this case, PPA esters activate the amidic
N-alkyl seven membered heterocycles, i.e. 2-iminoazepanes oxygen and, at the same time, react chemically with water.
[3,7,9,10], are very scarce, and no general method has been de-
scribed for their synthesis. To our knowledge, N-aryl deriva- We hypothesized that applying similar reaction conditions to
tives have not been hitherto reported. The lack of synthetic ω-arylaminonitriles could lead to 1-aryl-2-imino-1-azacy-
methods can be attributed to the intrinsic difficulty of cycliza- cloalkanes (Scheme 1, reaction 2), providing a novel synthetic
tions leading to seven membered heterocycles. This is a conse- method for these heterocycles. In this case no dehydration
quence of the high activation energies involved in these would be involved and PPA esters, due to their Lewis acid
reactions, which are also hindered by entropic factors [17-22]. nature, would solely increase the electrophilicity of the cyano
In addition to this, due to the considerably lower nucleophilici- group towards an intramolecular nucleophilic attack. This ap-
ty of the arylamino group, procedures for N-alkyl or N-unsubsti- proach would avoid the use of strong protic acids, which may
tuted 2-iminoazacycloalkanes are usually not suitable for the be disadvantageous for sensitive substrates.
synthesis of N-aryl derivatives.
Results and Discussion
Ethyl polyphosphate (PPE) and trimethylsilyl polyphosphate The ω-arylaminonitrile precursors were obtained by reaction of
(PPSE) are mild irreversible dehydrating agents of the Lewis the corresponding ω-halonitrile and arylamines, as previously
acid type. They have been widely used for several synthetically reported by our group [44].
useful transformations like dehydration of amides leading to
nitriles [23,24] or the Beckmann rearrangement [23,25]. They We examined first the cyclization of 4-(p-tolylamino)butyroni-
have also been employed in the synthesis of heterocycles such trile (1a) with PPE under microwave irradiation in a closed
as benzimidazoles, benzothiazoles, benzoxazoles [23,26-28], vessel reactor. The reaction was completed after 5 minutes at
indoles and 3,4-dihydroisoquinolines [23,29]. Microwave- 100 °C and 1-(p-tolyl)-2-iminopyrrolidine (2a) was obtained in
assisted organic reactions proceed in general faster, with higher 86% yield (Table 1, entry 1). No reaction occurred in the
yields and more efficiently than those performed under conven- absence of PPE, while the use of classical Lewis acids (ZnCl2,
tional heating [30-38]. This technology has found interesting AlCl3, BF3) as cyclization agents led to very low yields of the
applications in heterocyclic synthesis, specially in cycloconden- desired product 2a (Table 1, entries 2–5).
sation reactions [39,40]. In particular, it has enabled the synthe-
sis of the more challenging medium size (7–9 membered) Employing the optimized experimental conditions, 1-aryl-2-
heterocycles by overcoming limitations such as low reactivity iminopyrrolidines 2b–h were prepared in high yields (Table 1,
and yields, harsh reaction conditions and side reactions typical entries 6–12).
of conventional heating [17].
In order to extend the scope of the method, we investigated next
In previous work, we reported the microwave-assisted synthe- the synthesis of 1-aryl-2-iminopiperidines 4. The conversion of
sis of 5 to 8 membered cyclic amidines by cyclodehydration of 5-(p-tolylamino)valeronitrile (3a) to 1-(p-tolyl)-2-iminopiperi-
N-aryl-N´-acyl-1,n-alkanediamines (n = 2–5) promoted by dine (4a) was chosen for the optimization of the reaction condi-
polyphosphoric acid (PPA) esters PPE and PPSE (Scheme 1, tions (Table 2). In the conditions used for the lower homo-
Scheme 1: Our previous and present work.
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Beilstein J. Org. Chem. 2016, 12, 2026–2031.
obtained exclusively (Table 2, entries 4–6), while working
under solvent-free conditions further improved the yield
(Table 2, entry 7).
Table 1: Synthesis of 1-aryl-2-iminopyrrolidines 2a–h.
Employing the optimized reaction conditions (neat PPSE,
30 min at 150 °C), 1-aryl-2-iminopiperidines 4 were synthe-
sized in high yields (Table 3). Compound 4g required a higher
reaction temperature (200 °C) due to steric hindrance of the
N-aryl moiety.
Entry
Compound 2
Ar
Yield (%)
1
2a
3b
4c
5d
6
a
a
a
a
a
b
c
d
e
f
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
C6H5
86
0
traces
11
The encouraging results obtained up to this point, together with
the absence of methods for the synthesis of the higher homo-
logues 1-aryl-2-iminoazepanes 7 prompted us to attempt the
microwave-assisted cyclization of 6-arylaminohexanenitriles 6
promoted by PPA esters. We examined first the cyclization of
compound 6a under different reaction conditions (Table 4). No
conversion was observed using PPE/CHCl3 at 100 °C for
5 minutes (Table 4, entry 1). When longer reaction times and/or
higher temperatures were used, 1-(p-tolyl)-2-ethylimi-
noazepane (8a) was obtained as the only product (Table 4,
entries 2 and 3). The use of PPSE in DCM solution afforded
traces of the desired product 7a (Table 4, entry 4). Performing
the reaction under solvent-free conditions at 150 °C, compound
7a was obtained in modest yield (Table 4, entry 5). Significant-
17
85
7
4-FC6H4
74
8
4-ClC6H4
82
9
4-BrC6H4
2-CH3C6H4
2-ClC6H4
77
10
11
12e
77
g
h
80
2-OCH3C6H4
85
aThe reaction was run in the absence of reagents (background
reaction). bThe reaction was run using stoichiometric amount of ZnCl2.
cThe reaction was run using stoichiometric amount of AlCl3. dThe
reaction was run using stoichiometric amount of BF3. eThe reaction
time was 20 minutes.
logues 2 (PPE/CHCl3, 100 °C), no reaction occurred after ly better results were achieved by increasing the temperature to
5 minutes (Table 2, entry 1). Increasing the reaction time and/or 200 °C (Table 4, entry 6).
temperature resulted in higher conversion, but the N-ethyl de-
rivative 5a was obtained along with the desired product Employing the optimized reaction conditions, we synthesized
(Table 2, entries 2 and 3). This side reaction was quite unex- some novel 1-aryl-2-iminoazepanes 7 in good to high yields
pected, although some examples in the literature show that PPE (Table 5). A clear steric effect on the reactivity was observed in
can act as an ethylating agent under certain conditions [45,46]. the case of compound 7g (Table 5, entry 7), which resulted in
Using a dichloromethane solution of PPSE, compound 4a was low conversion of the substrate.
Table 2: Reaction conditions screening for 1-(p-tolyl)-2-iminopiperidine (4a).
Entry
Cyclization agent
Solvent
Temp. (°C)
Time (min.)
4a (%)
5a (%)
1
2
3
4
5
6
7
PPE
PPE
CHCl3
CHCl3
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
none
100
100
150
130
150
150
150
5
0
traces
32
0
30
30
15
15
30
30
traces
PPE
32
0
PPSE
PPSE
PPSE
PPSE
34
62
0
71
0
74
0
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Beilstein J. Org. Chem. 2016, 12, 2026–2031.
Table 3: Synthesis of 1-aryl-2-iminopiperidines 4.
Entry
Compound 4
Ar
Yield (%)
1
2
a
b
c
d
e
f
4-CH3C6H4
C6H5
74
79
72
74
82
73
86
3
4-ClC6H4
4a
5
2-CH3C6H4
2-FC6H4
6a
7b
2-ClC6H4
g
2,6-(CH3)2C6H4
aThe reaction time was 40 minutes. bThis reaction was carried out at 200 °C.
Table 4: Reaction conditions screening for 1-(p-tolyl)-2-iminoazepane (7a).
Entry
Cyclization agent
Solvent
Temp. (°C)
Time (min)
7a (%)
8a (%)
1
2
3
4
5
6
PPE
PPE
CHCl3
CHCl3
CHCl3
CH2Cl2
none
100
100
150
150
150
200
5
0
0
0
10
77
0
30
30
30
30
30
PPE
0
PPSE
PPSE
PPSE
traces
45
0
none
73
0
Table 5: Synthesis of 1-aryl-2-iminoazepanes 7.
Entry
Compound 7
Ar
Yield (%)
1
2
3
4
5
6
7
a
b
c
d
e
f
4-CH3C6H4
C6H5
73
62
62
75
55
68
28
4-FC6H4
4-BrC6H4
2-CH3C6H4
2-FC6H4
g
2,6-(CH3)2C6H4
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Conclusion
In summary, we have developed a straightforward and efficient
protocol for the microwave-assisted synthesis of
1-aryl-2-iminoazacycloalkanes, by ring closure of
ω-arylaminonitriles promoted by PPA esters. This reaction
constitutes a novel application of such reagents in heterocyclic
synthesis. The procedure involves easily available starting ma-
terials and requires remarkably short reaction times. It affords
the desired compounds in good to high yields and avoids the
use of protic acids. Noteworthly, classical Lewis acids failed to
efficiently promote this transformation. To our knowledge, this
is the first method which allows the synthesis of the hitherto
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Supporting Information File 1
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