2
P. Kour et al. / C. R. Chimie xxx (2016) 1e6
Table 1
encapsulated nano-Fe3O4, [26] ionic liquid [Bmim]OH [27],
PEG [28], potassium phosphate [29], -cyclodextrin [30],
Optimization of catalysts and conditionsa.
b
InCl3 [31], and electrochemical approach [32] have been
used for the synthesis of 2-amino-4H-chromen-4-
ylphosphonates. Importantly, to the best of our knowl-
edge, there are only few reports on the use of common
catalysts [33e38] for the construction of both b-phospho-
nomalonates and 2-amino-4H-chromen-4-ylphosphonates
scaffolds. Recently, DMAP has evolved as an efficient cata-
lyst [39] due to its water tolerant property, accessibility at a
modest price and well documented efficacy in many
organic conversions such as BayliseHilman reaction [40],
indole synthesis [41], and lactamization [42].
Microwave technology has witnessed an extensive
popularity in the past few years due to its great efficiency in
organic transformation with the introduction of greater
molecular diversity in a short reaction time [43]. Reactions
in aqueous condition offer several benefits as water is
economical, non-toxic and shows immense selectivity [44].
Further, the combination of water as solvent and microwave
heating, widely acknowledged as aqueous microwave-
assisted chemistry has evolved into a rapid unconventional
synthetic route strictly as per the principles of green
chemistry [45].
Entry Catalyst (mol %) Solvent Temperature Time (h) Yield (%)b
1
2
3
4
5
6
7
8
DMAP (10)
DMAP (10)
DMAP (20)
DMAP (30)
no catalyst
DMAP (20)
DMAP (20)
DMAP (20)
DMAP (20)
DMAP (20)
DMAP (20)
DMAP (20)
DBU (20)
H2O
H2O
H2O
H2O
H2O
EtOH
MeOH reflux
CH2Cl2 reflux
CHCl3
DMSO reflux
r.t
20
15
10
7
28
45
88
89
trace
80
78
76
78
70
70
79
82
72
74
70
reflux
reflux
reflux
reflux
reflux
24
10
10
10
10
10
10
10
10
10
10
10
9
reflux
10
11
12
13
14
15
16
THF
neat
H2O
H2O
reflux
100 ꢀC
reflux
reflux
reflux
reflux
CSA (20)
Zn(Proline)2 (20) H2O
-proline 20 H2O
L
a
Reactions conditions: 1 mmol of each of 1a, 2a and 3a in 1 mL of
solvent.
b
Yields are for isolated products.
2. Results and discussion
Finally, related organocatalysts were screened for
In view of our curiosity in developing novel synthetic
routes using aqueous condition [46], we disclose herein a
comparative purposes for 4a and results are depicted in
Table 1 (entries 13e16). DMAP appeared to be better as
compared to other examined catalysts. It is worth
mentioning that without the catalyst, only trace amount of
the product was detected even after 24 h (Table 1, entry 5).
With all the optimal reaction conditions in hand, addi-
tional substrates were screened, the reaction worked well
with aldehydes bearing electron withdrawing and electron
donating groups. Highest yield, 90% was obtained with 4-
methoxybenzaldehyde, 4b (Table 2, entry 2) however, 4-
nitrobenzaldehyde, 4c furnished relatively less yield, 75%
(entry 3). Importantly, trimethylphosphite also coupled
efficiently under optimized conditions providing the
desired product, 4g in good yield (80%, entry 7). With ethyl
cyanoacetate as active methylene partner, a comparatively
low yield of the product, 4h was obtained (75%, entry 8).
Pertinent to mention that a trace amount of knoevenagel
new route to synthesize
b-phosphonomalonates and 2-
amino-4H-chromen-4-ylphosphonates via the domino
Knoevenagel-phospha-Michael reaction of benzaldehyde,
malononitrile and triethylphosphite. We started our
investigation by performing the model reaction of 1 mmol
of each of benzaldehyde, malononitrile and triethylphos-
phite with 10 mol % DMAP in water at room temperature
(Scheme 1).
The reaction provided the desired product, diethyl (2,2-
dicyano-1-phenylethyl)phosphonate, 4a, which was iso-
lated in 28% yield (20 h) as revealed by comparison of its
physical and spectroscopic data [17]. Then we heated the
reaction mixture under reflux to evaluate the effect of
temperature and surprisingly the yield was increased to
45% (15 h). Next, we optimized catalyst charge by varying
load of DMAP. Importantly, 20 and 30 mol % led to the
improved conversion to afford the desired product in 88%
and 89% (Table 1, entries 3 and 4), therefore, 20 mol % under
reflux was selected for solvent screening. It is clear from
Table 1 (entries 6e12) that the reaction successfully
occurred both in solvents and under neat conditions,
however with less yields. The water emerged as the best
solvent as the reactions in aqueous conditions were carried
out efficiently, thus avoiding the use of volatile and toxic
organic solvents.
product and
a-hydroxy phosphonates generated from
probable hydrophosphonation of aldehydes was also
detected in some cases, however we have purified and
isolated only a major product under the present protocol.
Fascinating with the well recognized applications of
aqueous microwave-assisted technology [45], we irradiated
the equimolar mixture of benzaldehyde, malononitrile and
triethylphosphite at 100 ꢀC in a microwave reactor (Biotage,
Model: Initiator EXP EU 355301, 012180). We were pleased
to note that the desired product, 4a was formed much faster
(12 min) with improved yield from 88 to 92% (Table 4, entry
1). Based on this observation and for comparison purposes,
we screened additional substrates and the results are
summarised in Table 2. The improvement in terms of yields
and time economy was observed in almost all the cases
compared to the conventional route, which undoubtedly
Scheme 1. Synthesis of diethyl-(2,2-dicyano-1-phenylethyl) phosphonate.
Please cite this article in press as: P. Kour, et al., Aqueous microwave-assisted DMAP catalyzed synthesis of b-phosphonomal-
onates and 2-amino-4H-chromen-4-ylphosphonates via a domino Knoevenagel-phospha-Michael reaction, Comptes Rendus
Kour, Parteek
