Inorganic base catalyzed synthesis of (2-amino-3-cyano-4H-chromene-4-yl) phosphonate derivatives via multi-component reaction under mild and efficient conditions

Article abstract of DOI:10.1039/c4ra09359c

Various (2-amino-3-cyano-4H-chromene-4-yl) phosphonate derivatives were synthesized in good to excellent yields by condensation of diverse substituted salicylaldehyde, malononitrile and diethyl phosphite or diphenyl phosphite using anhydrous lithium hydro

Full text of DOI:10.1039/c4ra09359c

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Inorganic base catalyzed synthesis of (2-amino-3-
cyano-4H-chromene-4-yl) phosphonate
derivatives via multi-component reaction under
mild and efficient conditions†
Cite this: RSC Adv., 2014, 4, 63420
a
a
a
a
b
a
Peng Dai, Gaofeng Zha, Xiaoyan Lai, Wei Liu, Qianwen Gan and Yongcun Shen*
Received 27th August 2014
Accepted 4th November 2014
Various (2-amino-3-cyano-4H-chromene-4-yl) phosphonate derivatives were synthesized in good to
excellent yields by condensation of diverse substituted salicylaldehyde, malononitrile and diethyl
phosphite or diphenyl phosphite using anhydrous lithium hydroxide as a catalyst under mild conditions.
DOI: 10.1039/c4ra09359c
www.rsc.org/advances
Phosphorus-containing compounds have been the focus of natural products and so on, it has aroused widespread concern
research in organic chemistry. Many synthetic drugs and natural by chemist. Meanwhile it has become one of the frontiers in the
16
products extracted from the phosphorus atom-containing drugs eld of organic chemistry today.
and benzopyran phosphonate derivatives play important roles in An extensive survey of the literature has revealed that a
1
the phosphorus-containing compounds. Currently they have number of methods have been reported for the synthesis of (2-
also been the focus of intensive studies due to their power use as amino-3-cyano-4H-chromene-4-yl) phosphonates, some of
enzyme inhibitors, metabolic probes, peptide mimetics, antibi- which involve phospha-Michael addition catalyzed by
2
–6
17
18
19
otics, pharmacologic agents etc. Owing to such a wide range of diethylamine, ethyl-enediamine diacetate, K PO , PEG,
3
4
4
applications, development of efficient protocols for the synthesis b-cyclodextrin, InCl3 (ref. 20), silica-bonded 2-hydroxy-
of phosphonates, phosphonic acids and related compounds via ethylammonium acetate (HEAA) and tetramethyl guanidine
C–P bond formation is enjoying growing interest. It is worth (TMG). But there are rarely reports about phospha-Michael
2
1
7–9
22
10
mentioning that, apart from the Kabaschnik–Field, Michaelis– addition of lower active diphenyl phosphate to 2-imino-2H-
11
10
Beke and Michaelis–Arbuzov reaction, nucleophilic addition chromene-3-carbonitrile. These methods show varying
of phosphite across carbon–carbon double bond (phospha- degrees of success as well as limitations, such as prolonged
12
Michael reaction ) is an ever green and widely used method in reaction time, low yields, requirement of excess reagent and
C–P bond formation. catalyst, use of toxic solvent, and laborious work-up proce-
Using relatively simple and readily available starting mate- dures. Hence, an economical protocol with an easy availability
rials, MCR (i.e., “one pot”) means three or more substrates are and low pollution basic catalyst operable at ambient temper-
added to a pot without isolation of intermediates and complex ature for synthesis of (2-amino-3-cyano-4H-chromene-4-yl)
structure molecules can be directly obtained. MCR with simple phosphonate derivatives are highly desired.
13
operation, high resource utilization, high atom economy, high
In the asymmetric reaction study, analytic conditions of
aggregation, high energy exploration and other features, can raceme must be rst set up. As a part of our research about
minimize chemical contamination, closer to the concept of asymmetric phospha-Michael addition, we would like to report
1
4
ideal synthesis. Since multi-component synthesis reaction can
a
mild, cost-effective procedure for the one-pot multi-
15
quickly form compounds
of structural diversity and component synthesis of (2-amino-3-cyano-4H-chromene-4-yl)
complexity, easily establishing a large library of appropriate phosphonic acid diethyl ester and diphenyl ester (4a, 7a) by
compounds, together with the characteristic that MCR in many the condensation of salicylaldehyde (1), malononitrile (2) and
research areas now have been widely used in organic chemistry, triethyl phosphate (3a) or triphenyl phosphate (6a) adopting
such as new drug development, total synthesis of high active appropriate catalyst at ambient temperature in ethanol medium
(Scheme 1).
a
As phosphate ion has denite pollution on environment, we
Department of Pharmacy, The College of Chemical Engineering, Wuhan University of
Technology, Wuhan 430070, China
b
surmise if other inorganic base could be used as catalyst in this
Pharmaceutical Engineering, Chemical and Pharmaceutical Institute, Wuhan reaction. To verify this hypothesis, initially, a model reaction
Institute of Technology, Wuhan 430070, China. E-mail: sycmichael@163.com; Fax:
using 1a (1 mmol), 2 (1 mmol) and 3a (1 mmol) was examined in
the presence of inorganic bases catalysts in ethanol at ambient
temperature (Table 1). With 20 mol% NaOH or KOH, the
+
†
1
86 027 87859019
Electronic supplementary information (ESI) available. See DOI:
0.1039/c4ra09359c
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a
Table 2 Effect of temperature on the yield of product 4a
Scheme
1 Multi-component synthesis of (2-amino-3-cyano-4H-
chromene-4-yl) phosphonate derivatives.
ꢀ
b
Entry
Temperature ( C)
Catalyst (mol%)
Yield (%)
b
1
2
3
4
5
6
7
0
10
20
30
35
40
50
20
20
20
20
20
20
20
12
a
Table 1 Effect of different catalysts on the yield of product 4a
b
17
b
38
b
95
b
88
b
85
b
73
a
Reaction conditions: 1a (1 mmol), 2 (1 mmol) with 3a (1 mmol) in
b
ethanol using LiOH (20%mol) at different temperature. Diethyl 2-
amino-3-cyano-4H-chromene-4-yl phosphonate (4a), isolated yield.
b,c
Entry
Inorganic bases
Catalyst (mol%)
Yield (%)
c
1
2
3
4
5
6
7
NaOH
KOH
LiOH
20
20
20
20
20
20
20
76
85
96
c
b
With the optimal reaction condition in hand, we began to
investigate the scope of this reaction with respect to various
substituted salicylaldehydes 1, 2 and 3a or 6a (Tables 3 and 4).
The results demonstrated that it's of good generality for
salicylaldehydes with different substitutes. The reaction of
b
K
2
CO
3
63
b
Cs CO
2
3
87
C
K
S
F
—
b
3
PO
4
85
a
Reaction conditions: 1a (1 mmol), 2 (1 mmol) with 3a (1 mmol) in malononitrile and triethyl phosphate or diethyl phosphite with
ethanol using different catalysts (20 mol%) at ambient temperature.
b
salicylaldehydes substituted with electron-donating and
electron-withdrawing groups proceeded well to give the desired
products in 86–97% yields (Table 3, entries 2–8). The catalyst
was compatible to functional groups such as –Cl, –Br, –OMe,
Intermediate 2-imino-2H-chromene-3-carbonitrile (5), isolated
c
yield.
Diethyl
2-amino-3-cyano-4H-chromene-4-yl
–
OEt and –NO . No competitive nucleophilic methyl/ethyl ether
2
cleavage was observed for the substrates with possessed aryl–O–Me
or aryl–O–Et groups (Table 3, entries 2 and 3), despite of the
strong nucleophilicity of phosphites.
phosphonate (4a), isolated yield.
Despite nucleophilicity of triphenyl phosphate is weaker
than that of triethyl phosphate, salicylaldehydes with different
substituents reacted with malononitrile and triphenyl phos-
reaction did not proceed smoothly, only intermediate 2-imino- phate in the presence of anhydrous lithium hydroxide to
H-chromene-3-carbonitrile was obtained (Table 1, entries 1 produce the corresponding products in good to excellent yields
2
and 2), but using of anhydrous lithium hydroxide could catalyze for longer reaction time (Table 4, entries 1–7). It is noteworthy
the reaction and provide the target product in excellent yield that no product was obtained when 5-nitro-salicylaldehyde was
(
(
96%) (Table 1, entry 3). We examined several alternatives used as substrate (Table 4, entry 8).
Table 1, entries 4–7), Cs CO and K PO showed similar cata-
In order to insight into the mechanism of this reaction,
HNMR spectra of different reaction time were recorded as
2
3
3
4
1
lytic activity on reaction, the yield is respectively 87% and 85%
under same conditions, while K CO provided lower yield and follows. The HNMR spectrum showed that characteristic
1
2
3
no reaction occurred with CsF.
hydrogen protons of three starting materials existed when they
Effect of temperature on reaction was tested (Table 2). When were mixed (Fig. 1). Aer 5 minutes, peak of characteristic
ꢀ
temperature was below 30 C, reaction was slower, aer 5 h the hydrogen protons of three starting materials became weak and
reaction did not nish (Table 2, entries 1–3). When the peak of characteristic hydrogen proton of compound 5 at 4-
ꢀ
temperature was above 30 C, inferior results were obtained position appeared at d 8.49 (Fig. 2). Aer reaction completed,
(
Table 2, entries 5–7). A survey of solvents resulted in conditions peak of characteristic hydrogen proton of compound 5 at 4-
that provided excellent yield: the optimal result was obtained position completely disappeared and peak of characteristic
ꢀ
when the reaction was performed in ethanol at 30 C for 20 hydrogen proton of compound at 4-position appeared at d 4.2–
minute (Table 2, entry 4).
4.5 (Fig. 3).
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a
Table 3 One-pot synthesis of the diethyl (2-amino-3-cyano-4H-chromene-4-yl) phosphonate compounds catalyzed by LiOH
c
b
Entry
Salicylaldehyde
R
1
R
2
Malononitrile
Phosphate
Time (min)
Product
Yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
—
—
—
Me
Cl
Br
Br
NO
—
2
3a or 3b
25
20
20
20
30
30
30
40
4a
4b
4c
4d
4e
4f
94
96
96
97
90
91
89
86
OEt
OMe
—
—
—
1g
1h
Br
—
4g
4h
2
a
b
Reaction conditions: 1(a–h) (1 mmol), 2 (1 mmol) with 3a or 3b (1 mmol) in ethanol using LiOH (20 mol%) at ambient temperature. Isolated
c
yield. 3a – Triethylphosphite, 3b – diethylphosphite.
a
Table 4 One-pot synthesis of the diphenyl (2-amino-3-cyano-4H-chromene-4-yl) phosphonate compounds catalyzed by LiOH
c
b
Entry
Salicylaldehyde
R
1
R
2
Malononitrile
Phosphate
Time (min)
Product
Yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
—
—
—
Me
Cl
Br
Br
NO
—
2
6a
25
20
20
20
30
30
30
40
7a
7b
7c
7d
7e
7f
91
92
92
93
90
89
85
OEt
OMe
—
—
—
1g
1h
Br
—
7g
—
d
2
—
a
b
c
Reaction conditions: 1(a–h) (1 mmol), 2 (1 mmol) with 6a (1 mmol) in ethanol using LiOH (20%mol) at ambient temperature. Isolated yield. 6a
Diphenylphosphite. The product is 2-imino-2H-chromene-3-carbonitrile (5).
d
–
The process represents a typical tandem reaction in which salicylaldehyde, malononitrile and triethyl phosphite or tri-
initial condensation of salicylaldehyde and malononitrile phenyl phosphite using lithium hydroxide as an inexpensive
occurred to form the Knoevenagel product. The spontaneous catalyst at ambient temperature. It compares favorably and
cyclization as a result of nucleophilic attack of the hydroxyl represents a valid alternative to the existing methods.
group on the cyano group led to 2-imino-2H-chromene-3- High yields along with simple reaction conditions, wide
carbonitrile which underwent nucleophilic attack by trialkyl substrate scope as well as easy work-up procedure auger well
phosphites or triaryl phosphites to produce the desired product for the application of the strategy for the synthesis of
4
a and 7a. This mechanism is similar to that reported by (2-amino-3-cyano-4H-chromene-4-yl)
phosphonic
acid
20
Perumal.
diethyl ester or diphenyl diester. Further effort will be
In summary, we have developed a new, mild and highly directed at the study of asymmetric domino reaction of sali-
efficient, one-pot reaction, which offers a simple method for cylaldehyde, malononitrile and triethyl phosphate or tri-
the synthesis of new (2-amino-3-cyano-4H-chromene-4-yl) phenyl phosphate and the results of these studies will be
phosphonic acid diethyl ester or diphenyl diester from reported in due course.
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Fig. 1 H-NMR spectra of the reaction solution (sampled immediately after feeding).
1
Fig. 2 H-NMR spectra of the reaction solution (5 minutes after feeding).
1
Fig. 3 H-NMR spectra of reaction solution (20 minutes after feeding).
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63424 | RSC Adv., 2014, 4, 63420–63424
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