Study on the microwave-assisted batch and continuous flow synthesis of N-alkyl-isoindolin-1-one-3-phosphonates by a special Kabachnik–Fields condensation

Article abstract of DOI:10.3390/molecules25143307

A simple and efficient microwave (MW)-assisted method was elaborated for the catalyst-free synthesis of isoindolin-1-one-3-phosphonates by the three-component condensation of 2-formylbenzoic acid, aliphatic primary amines and various dialkyl phosphites. The batch and the continuous flow reactions were optimized in respect of the temperature, the reaction time and the molar ratio of the starting materials. To evaluate the potential of MW irradiation, comparative thermal experiments were also carried out. In order to obtain “real time” information about the condensation, the special Kabachnik–Fields reaction of 2-formylbenzoic acid, butylamine and diethyl phosphite was monitored by in situ FT-IR spectroscopy. The novel title compounds could be prepared in high yields at low temperature under a short reaction time. A suitable method could also be developed for the preparation of the isoindolin-1-one-3-phosphonates at a “few g” scale by using a continuous flow MW reactor.

Full text of DOI:10.3390/molecules25143307

molecules
Article
Study on the Microwave-Assisted Batch and
Continuous Flow Synthesis of
N-Alkyl-Isoindolin-1-One-3-Phosphonates by a
Special Kabachnik–Fields Condensation
Ádám Tajti 1 , Nóra Tóth , Bettina Rávai , István Csontos , Pál Tamás Szabó and
Erika Bálint *
1
1
1
2
1
,
1
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
521 Budapest, Hungary; tajti.adam@mail.bme.hu (Á.T.); toth.nora@mail.bme.hu (N.T.);
1
betti.ravai08@gmail.com (B.R.); icsontos@mail.bme.hu (I.C.)
2
MS Metabolomics Laboratory, Instrumentation Center, Research Centre for Natural Sciences, Hungarian
Academy of Sciences, Magyar tudósok krt. 2., H-1117 Budapest, Hungary; szabo.pal@ttk.mta.hu
Correspondence: ebalint@mail.bme.hu; Tel.: +36-1-463-3653
*
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Derek J. McPhee
Received: 30 June 2020; Accepted: 17 July 2020; Published: 21 July 2020
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: A simple and efficient microwave (MW)-assisted method was elaborated for the
catalyst-free synthesis of isoindolin-1-one-3-phosphonates by the three-component condensation of
2
-formylbenzoic acid, aliphatic primary amines and various dialkyl phosphites. The batch and the
continuous flow reactions were optimized in respect of the temperature, the reaction time and the
molar ratio of the starting materials. To evaluate the potential of MW irradiation, comparative thermal
experiments were also carried out. In order to obtain “real time” information about the condensation,
the special Kabachnik–Fields reaction of 2-formylbenzoic acid, butylamine and diethyl phosphite
was monitored by in situ FT-IR spectroscopy. The novel title compounds could be prepared in high
yields at low temperature under a short reaction time. A suitable method could also be developed for
the preparation of the isoindolin-1-one-3-phosphonates at a “few g” scale by using a continuous flow
MW reactor.
Keywords: isoindolin-1-one phosphonates;
α-aminophosphonate derivatives; three-component
condensation; Kabachnik–Fields reaction; microwave; in situ FT-IR spectroscopy; continuous flow
microwave reactor
1
. Introduction
Isoindolin-1-ones (
may be considered as an important compound family among N-heterocycles [
This moiety can be found in a number of biologically active natural compounds and synthetic
derivatives as well [ ]. As a special subgroup, isoindolin-1-ones bearing a carboxylic ester or
carboxylic amide function ( ) may show anticancer- [ ], antiarrhythmic- [ ] or sodium channel
modulator activities [ ]. It is known that phosphorus analogues of biologically active carboxylic acid
derivatives may often show important effects, e.g., -aminophosphonates and -amino acids [10].
1) and their derivatives, such as 3-acyl- and 3-alkylidene-isoindolin-1-ones,
1–4
] (Figure 1).
5–7
2
5
8
9
α
α
Isoindolin-1-one phosphonates (
growth regulators [11].
3)—the P-analogues of compound
2—have been tried out as plant
Molecules 2020, 25, 3307; doi:10.3390/molecules25143307
www.mdpi.com/journal/molecules

Molecules 2020, 25, 3307
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Figure 1. General formula of isoindolin-1-one derivatives (
isoindolin-1-one phosphonates (3).
1), isoindolin-1-one carboxylates (2) and
Only a few examples have been reported on the synthesis of isoindolin-1-one phosphonates
by the three-component condensation of 2-formylbenzoic acid, amines and dialkyl phosphites
(
Scheme 1/
reaction [18]; however, the carboxyl group of the 2-formylbenzoic acid allows a special ring closure
step, as the speciality of this transformation. Ord ñez and co-workers carried out the condensation
of 2-formylbenzoic acid, dimethyl phosphite and aromatic amines or aminoacetaldehyde dimethyl
acetal under solvent-free conditions or in methanol in a microwave (MW) reactor [12 13]. The special
A) [7,12–17]. This process is somewhat analogous to the ‘regular’ Kabachnik–Fields
ó
,
Kabachnik–Fields reaction starting from amino alcohols [14] or chiral amines was also investigated
using dimethyl phosphite as the phosphorus reagent [15]. In a few cases, the transformations were
investigated in the presence of NaH [16], T3P®
[
17] or OSU-6 [
best of our knowledge, the three-component reaction of 2-formylbenzoic acid, aliphatic amines
butyl-, cyclohexyl- or benzylamine) and dialkyl phosphites, such as diisopropyl-, dibutyl- or dibenzyl
phosphite, has not been studied comprehensively before.
7] as catalysts or additives. To the
(
Scheme 1. Synthetic routes of isoindolin-1-one phosphonates (3).
Beside the three-component condensation, a few other synthetic routes are also known for the
preparation of isoindolin-1-one phosphonates ( ), such as the ring opening of tricyclic oxanorbornenes
) (Scheme 1/ ) [19], the ring closure of -amidophosphonates ( ) (Scheme 1/ ) [20] or the reaction
of trialkyl phosphites with 3-hydroxy-isoindolin-1-ones ( ) (Scheme 1/ 22]. In these examples,
the target compounds ( ) were prepared starting from complex molecules ( ), which were usually
obtained after many reaction steps.
3
(4
B
α
5
C
6
D
) [21
,
3
4–
6
The application of the MW technique may be advantageous in several organic reactions and
organophosphorus transformations as well [23]. The reactions may proceed faster and the use of
a catalyst and/or a solvent is often evitable [24]. In case of multicomponent reactions, the MW
irradiation may also be useful, as the corresponding products can usually be obtained more selectively.

Molecules 2020, 25, 3307
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Therefore, the development of MW-assisted variations of multicomponent reactions is of growing
interest [25]. The scale-up of MW-assisted transformations is a real challenge due to the limited geometry
of the MW unit [26]. This problem can be solved by the use of continuous flow MW reactors [27].
In the last decade, various applications of the continuous flow MW technique were reported; however,
in most cases non-professional MW reactors were applied, in which the parameters cannot be measured
accurately [28]. In our previous work, we introduced a MW-assisted continuous flow synthesis of simple
α
-aryl-α-aminophosphonates by the three-component Kabachnik–Fields reaction [29], which may
mean a good starting point towards the development of special condensation-ring closure reactions in
continuous flow.
In this paper, at first, the catalyst- and solvent-free condensation of 2-formylbenzoic acid, aliphatic
primary amines and various >P(O)H reagents was studied in a batch MW reactor. Our aim was
to optimize the process and to synthesize and characterize new derivatives. The effect of the MW
irradiation was also investigated; thus, comparative thermal experiments were also carried out.
We also aimed at the monitoring of the special Kabachnik–Fields reaction by in situ FT-IR spectroscopy.
Furthermore, we wished to develop a continuous flow MW-assisted method for the three-component
reaction of 2-formylbenzoic acid, aliphatic amines and diethyl phosphite to obtain the corresponding
isoindolin-1-one-3-phosphonates at a higher productivity.
2
. Results and Discussion
2
.1. Synthesis of Isoindolin-1-one-3-phosphonates
As the initial step of our work, the special Kabachnik–Fields reaction of 2-formylbenzoic acid,
aliphatic primary amines, such as butyl-, cyclohexyl- or benzylamine, and diethyl phosphite was
studied under catalyst- and solvent-free conditions (Table 1). The condensations were optimized in
respect of the molar ratio of the starting materials, the temperature and the reaction time.
Table 1. Optimization of the condensation of 2-formylbenzoic acid, aliphatic primary amines and
diethyl phosphite in a batch microwave reactor.
Conversion a
(%)
Yield b
(%)
Mode of
Heating
Amine
(equiv)
DEP
(equiv)
T
( C)
Entry
R
t (min)
◦
1
2
3
4
5
6
7
8
9
-
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
1
1
1
1
1
1
1
1
1.1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1
1
1
1
1
25
40
60
80
60
60
60
60
60
60
60
60
60
60
60
60
60
60
180c
10
10
10
20
30
10
10
10
10
10
10
20
30
30
10
20
20
77
61
85
87
90
91
87
89
92
100
90
82
93
100
84
89
100
88
-
-
-
-
-
-
-
-
MW
MW
MW
MW
MW
MW
MW
MW
MW
-
MW
MW
MW
-
MW
MW
-
1
1.1
1.2
1
1
1
1
1
1
1
-
10
11
12
13
14
15
16
17
18
Bu
Bu
94 (7a)
-
-
-
c
c
c
c
Hex
Hex
Hex
Hex
Bn
84 (8a)
-
1
1
1
-
90 (9a)
-
Bn
Bn
a
On the basis of GC; b After column chromatography; c No change after longer reaction time.

Molecules 2020, 25, 3307
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At first, the 2-formylbenzoic acid was reacted with butylamine and diethyl phosphite in a
molar ratio of 1:1:1 at room temperature for 3 h, and the conversion was only 77% (Table 1,
◦
Entry 1). Carrying out the reaction at a higher temperature of 40 C under MW irradiation, 61%
of diethyl (2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7a) was obtained after 10 min
◦
(
Table 1, Entry 2). Repeating the condensation at 60 C for 10 min, the conversion increased
◦
to 85% (Table 1, Entry 3). Applying a higher temperature of 80 C for the same reaction time,
the conversion did not change significantly (Table 1, Entry 4). Performing the condensation at 60 C
◦
using longer reaction times (20 or 30 min), the proportion of the isoindolin-1-one-3-phosphonate
(7a) was somewhat higher (90% and 91%, respectively) as compared to the reaction carried out
for 10 min (Table 1, Entries 5 and 6 vs. Entry 3). In the next experiments, the effect of the molar
◦
ratio of the starting materials was studied at 60 C applying a reaction time of 10 min (Table 1,
Entries 7–10). Increasing the amount of diethyl phosphite to 1.1 or 1.2 equivalents had no effect on
the conversion (Table 1, Entry 3 vs. Entries 7 and 8). However, by using a small excess of butylamine
(
1.1 equivalents), an increase in the conversion was observed, and applying 1.2 equivalents of the
amine component, a complete conversion could be achieved (Table 1, Entries 9 and 10). The diethyl
2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7a) was isolated in a yield of 94% (Table 1,
(
Entry 10). To evaluate the potential of the MW irradiation, the same reaction was repeated using
conventional heating, resulting in a conversion of only 90% (Table 1, Entry 11).
Carrying out the condensation of the 2-formylbenzoic with 1.2 equivalents of
◦
cyclohexylamine and 1 equivalent of diethyl phosphite at 60 C for 10 min, 82% of diethyl
(2-cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (8a) was formed (Table 1, Entry 12).
After an irradiation of 20 min, 93% of 8a was present in the reaction mixture (Table 1, Entry 13),
while after 30 min, a complete conversion was achieved (Table 1, Entry 14). The corresponding
isoindolin-1-one-3-phosphonate (8a) could be obtained in a yield of 84% after column chromatography.
The comparative thermal experiment reached a conversion of only 84% (Table 1, Entry 15).
Applying benzylamine, a reaction time of 10 min was also not enough for a complete
conversion; however, after 20 min the proportion of the diethyl (2-benzyl-3-oxo-2,3-dihydro-
1
H-isoindol-1-yl)phosphonate (9a) was 100% (Table 1, Entries 16 and 17). Product 9a was isolated in a
yield of 90%. The thermal reaction was somewhat slower, the conversion was only 88% after 20 min
(Table 1, Entry 18).
Based on the results obtained, all the three aliphatic amines allowed fast transformation towards
the desired isoindolin-1-one phosphonates (7a–9a). The butylamine was the most reactive amine, as the
special Kabachnik–Fields reaction was already complete after 10 min, and the cyclohexylamine was
the less reactive, possibly due to the steric hindrance of the bulky cyclohexyl group. The conversions
in the comparative thermal experiments were by 10–16% lower, which clearly indicates the efficiency
of the MW technique.
In the next series of experiments, the three-component condensation of 2-formylbenzoic acid,
primary amines and various dialkyl phosphites was studied using the optimized conditions
◦
(
60 C, 10–30 min) (Scheme 2). The reactions were complete in all cases. Carrying out the
condensation of 2-formylbenzoic acid and butylamine with dimethyl phosphite, the dimethyl
2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7b) was obtained in a yield of 85% after
(
column chromatography. Changing for diisopropyl- or dibutyl phosphite, the corresponding
isoindolin-1-one-3-phosphonates (7c and 7d) were synthesized in yields of 89% and 91%, respectively.
Dibenzyl phosphite was also tried out as the P-reagent. In this case, the corresponding
isoindolin-1-one phosphonate (7d) could be prepared in a slightly lower yield (81%). Performing the
experiments starting from cyclohexylamine, the condensations were slower (30 min), and the desired
isoindolin-1-one-3-phosphonates (8b–e) were isolated in yields of 71–80%. The condensation was also
extended for benzylamine, obtaining isoindolin-1-one phosphonates 9b–e in high yields (80–85%).

Molecules 2020, 25, 3307
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Scheme 2. Microwave (MW)-assisted condensation of 2-formylbenzoic acid, primary amines and
dialkyl phosphites. a Isolated yield.
Finally, the reaction of 2-formylbenzoic acid and butylamine was also carried out using ethyl
◦
phenyl-H-phosphinate as the P-reagent at 60 C, for an irradiation of 10 min (Scheme 3). After column
chromatography, product 10 was isolated in a yield of 78%. Due to the chiral center on the phosphorus
atom, the isoindolin-1-one phosphinate (10) was obtained as a mixture of diastereomers in a ratio of
4
7:53 based on 31P NMR spectroscopy.
Scheme 3.
Microwave-assisted condensation of 2-formylbenzoic acid, butylamine and
ethyl phenyl-H-phosphinate.
Altogether 16 isoindolin-1-one-3-phosphonate derivatives were synthesized in high yields at
low temperature for a short reaction time, and characterized by 31P, H and C NMR spectroscopy,
1
13

Molecules 2020, 25, 3307
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1
as well as by HRMS. Except products 9a and 9b, all derivatives are new compounds. (Copies of 31P, H,
and 13C NMR spectra for all compounds synthesized are presented in the Supplementary Materials.)
2
.2. Study on the Condensation of 2-Formylbenzoic Acid, Butylamine and Diethyl Phosphite by In Situ
FT-IR Spectroscopy
The condensation of 2-formylbenzoic acid, butylamine and diethyl phosphite was followed
by in situ Fourier transform (FT)-IR spectroscopy (Scheme 4). The reaction was carried out under
◦
conventional heating at 60 C in ethanol as the solvent.
O
Δ
COOH
EtO
EtO
O
H
6
0 °C, 2 h
N
Bu
+
Bu NH2
1.2 equiv)
+
P
ethanol
CHO
OEt
(
P
O
OEt
7a
Scheme 4. Condensation of 2-formylbenzoic acid, butylamine and diethyl phosphite in ethanol.
The first step was to register the IR spectra of the reaction components in ethanol solution
−
1
(
Figure 2). 2-Formylbenzoic acid (FBA) has a strong absorption band at 1756 cm corresponding
to the C=O. The single absorption suggests that FBA is present in its lactone tautomer form
in ethanol [30
ν
ν
C=O
−1
,
31]. At the same time, diethyl phosphite (DEP) has strong signals at 964 cm and
−1
1
254 cm assigned to the
ν
and the
ν
vibrations, respectively. Butylamine (BA) may be
(1605 cm ) absorptions. In the spectrum of diethyl
P-O-C
P=O
−
1
−1
identified based on the
δ
C-H
(1381 cm ) and
δ
N-H
(
2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7a), a strong characteristic
ν
signal can
C=O
−1
be observed at 1690 cm .
Figure 2. IR spectra of the reaction components in ethanol (absorptions of the solvent were subtracted
for clarity).
In the in situ FT-IR investigation, the starting materials were mixed in ten-minute intervals in
◦
the following order: 1. FBA, 2. DEP, 3. BA. Then, the mixture was heated to 60 C in an oil bath and
was reacted until completion. A segment of the time-dependent IR spectrum (3D diagram) can be
seen in Figure 3. The reaction components (FBA, DEP, BA and 7a) could be easily identified by their
characteristic absorptions (Figure 2).

Molecules 2020, 25, 3307
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Figure 3. A segment of the time-dependent IR spectrum of the condensation of 2-formylbenzoic
acid (FBA), butylamine (BA) and diethyl phosphite (DEP) in ethanol.
The result of our study is the diagram showing the concentration profile of the starting components
(
FBA
the basis of the decrease/increase of the different absorptions on the time scale. This calculation
MCR-ALS, multivariate curve resolution-alternating least squares) gives the concentration profiles
of the components and the spectra of pure components. It can be seen—also in the 3D diagram
Figure 3)—that the signal of FBA immediately decreased after adding BA; however, no new significant
, DEP and BA) and the product (7a) (Figure 4). This was constructed by deconvolution on
(
(
absorptions could be observed, which would indicate the formation of an intermediate, such as an
imine [32]. Decreasing of the signals is possibly due to the change of IR properties of FBA in the
presence of BA. During the reaction, the relative concentrations of the starting materials were constantly
decreasing, while the signal of product 7a was constantly increasing. The condensation was complete
at ca. 2 h.
Figure 4. Concentration profiles of the reaction components in the condensation of 2-formylbenzoic
acid (FBA), butylamine (BA) and diethyl phosphite (DEP) in ethanol.
Finally, the IR spectra of the reaction components (FBA, DEP, BA and 7a) were extracted from the
calculation (Figure 5). As compared to the spectra obtained in ethanol solution (Figure 2), the agreement
is rather good.

Molecules 2020, 25, 3307
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Figure 5. IR spectra of the reaction components obtained after deconvolution.
2
.3. Condensation of 2-Formylbenzoic Acid, Aliphatic Primary Amines and Diethyl Phosphite in a Continuous
Flow Microwave Reactor
In order to increase the productivity of the MW-assisted synthesis developed, the reaction of
2
-formylbenzoic acid, aliphatic primary amines and diethyl phosphite was studied using a dual pump
®
continuous flow system containing a CEM (Matthews, NC, USA) MW reactor equipped with a
commercially available CEM continuous flow cell (Figures S1 and S2) (Scheme 5, Table 2).
®
COOH
Cooler
CHO
O
Pump A
Pump B
flow cell
N R
OEt
OEt
Back pressure
regulator
P
O
H
OEt
OEt
O
c
P
+
R NH
2
n
R = Bu (7a), Hex (8a), Bn (9a)
Scheme 5. Condensation of 2-formylbenzoic acid, aliphatic primary amines and diethyl phosphite in a
continuous flow microwave reactor.
The 2-formylbenzoic acid in ethanol (solution A) and the mixture of the corresponding amine
and diethyl phosphite in ethanol (solution B) were fed separately into the mixer. The mixture reached
the reactor at a summa flow rate of 0.15–0.70 mL/min (corresponding to residence times of 45–10 min,
respectively). The temperature was monitored and controlled by the IR sensor of the MW device.
◦
The mixture leaving the reactor was cooled down to 25 C using a spiral-like cooler and was passed
through a back pressure regulator operating at 250 psi (17 bar). Consecutive fractions of the leaving
mixture were analyzed by GC measurements to determine the composition and to identify the
stationary operation.
◦
Performing the condensation using 1.2 equivalents of the butylamine at 60 C at a flow rate
of 0.7 mL/min (corresponding to a residence time of 10 min), the conversion was 43% (Table 2,
Entry 1). Increasing the residence time to 20 min (by decreasing the flow rate to 0.35 mL/min),
the proportion of the isoindolin-1-one-3-phosphonate (7a) was somewhat higher (52%) (Table 2, Entry
2). The condensation was also carried out at a residence time of 30 min (at a flow rate of 0.25 mL/min);
however, the conversion increased by only 4% (Table 2, Entry 3). In the next series of experiments,
the effect of the molar ratio of the starting materials was investigated. Applying 1.5 equivalents of the
butylamine at a residence time of 20 min, the conversion already increased to 70% (Table 2, Entry 4).

Molecules 2020, 25, 3307
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At a higher excess of butylamine (2 equivalents), the outcome did not change significantly (Table 2,
Entry 5). Carrying out the condensation with 1.2 or 1.5 equivalents of diethyl phosphite, the ratio of the
isoindolin-1-one-3-phosphonate (7a) was 81% and 95%, respectively (Table 2, Entries 6 and 7). Using
1
.5 equivalents of both of the butylamine and the diethyl phosphite, the reaction was complete under a
residence time of 30 min, and the diethyl (2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate
(7a) was isolated in a yield of 95% (Table 2, Entry 8).
Performing the continuous flow three-component reaction with cyclohexylamine at the same
◦
temperature (60 C), the condensation was somewhat slower, as it was complete applying a
residence time of 45 min (at a flow rate of 0.15 mL/min) (Table 2, Entry 9). The corresponding
isoindolin-1-one-3-phosphonate (8a) was obtained in a yield of 86% after column chromatography.
◦
In case of benzylamine, a flow rate of 0.18 mL/min (a residence time of 40 min) at 60 C
were the optimal parameters (Table 2, Entry 10). The diethyl (2-benzyl-3-oxo-2,3-dihydro-
1
H-isoindol-1-yl)phosphonate (9a) could be isolated in a yield of 91%.
In the flow approaches, the productivity was 2.3 g/h for product 7a, 1.4 g/h for product 8a
,
and 1.8 g/h in case of compound 9a, which are higher than the batch results (1.8 g/h, 0.6 g/h and 1.0 g/h,
respectively). However, it should be noted that the batch productivity was calculated based on the
net reaction time of several (six, two and three, respectively) consecutive reactions - apart from the
necessary preparations of the experiments.
Table 2. Optimization of the condensation of 2-formylbenzoic acid, aliphatic primary amines and
diethyl phosphite in a continuous flow MW reactor.
flow MW
60 °C,
O
COOH
CHO
EtO
EtO
O
H
N R
OEt
+
R
NH2
+
P
ethanol
P
O
OEt
n
c
R = Bu (7a), Hex (8a), Bn (9a)
Yield b
(%)
Amine
DEP
(equiv)
Flow Rate
(mL/min)
Conversion a
Entry
R
τ (min)
(equiv)
(%)
1
2
3
4
5
6
7
8
9
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Hex
Bn
1.2
1.2
1.2
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1
1
1
1
1
1.2
1.5
1.5
1.5
1.5
0.70
0.35
0.25
0.35
0.35
0.35
0.35
0.25
0.15
0.18
10
20
30
20
20
20
20
30
45
40
43
52
56
70
73
81
95
100
100
100
-
-
-
-
-
-
-
95% (7a)
86% (8a)
91% (9a)
c
1
0
a
On the basis of GC; b Isolated yield.
3
. Materials and Methods
3
.1. General
The reactions were carried out in a 300 W CEM Discover focused microwave reactor (CEM
Microwave Technology Ltd., Buckingham, UK) equipped with a pressure controller using 5–20 W
irradiation under isothermal conditions.
The continuous flow reactions were performed in a self-developed continuous flow system
comprising a 300 W CEM Discover (CEM Microwave Technology Ltd., Buckingham, UK) focused
microwave reactor equipped with a CEM 10 mL Flow Cell Accessory continuous flow unit (irradiated
volume 7 mL) [29,33,34], a Gilson 332 dual HPLC pump (Gilson U.K., Bedfordshire, UK), an HPLC
backpressure regulator with a 250 Psi (17.2 bar) cartridge (CEM Microwave Technology Ltd.,

Molecules 2020, 25, 3307
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®
Buckingham, UK) and a cooler. Teflon PFA tubes (DuPont, Wilmington, DE, USA) with outside
diameter 0.125” (3.175 mm) and inside diameter 0.064” (1.575 mm) were used. The exact lengths and
volumes of each tube parts are shown in Figure S1. All of the tubes, nuts and ferrules applied were
fully compatible with a regular HPLC system.
GC measurements were performed on an Agilent® 6890 GC-FID chromatograph (Agilent, Santa
Clara, CA, USA), using a 15 m
×
0.18 mm Restek, Rtx-5 column with a film layer of 0.20
µ
m.
◦
The temperature of the column was initially held at 40 C for 1 min, followed by programming at
◦
◦
◦
2
5 C/min up to 300 C and a final period at 300 C (isothermal) for 10 min. The temperature of the
◦
◦
injector was 290 C and of the FID detector 300 C. The carrier gas was N .
2
The 31P, H, C, NMR spectra were taken in CDCl solution on a Bruker AV-300 spectrometer
1
13
3
(
Bruker Scientific LLC, Billerica, MA, USA) operating at 121.5, 300 and 75.5 MHz, respectively. Chemical
shifts are downfield relative to 85% H PO and TMS. Couplings are given in Hz. Non-equivalence
3
1
4
1
13
effects were observed in H and C{ H} NMR spectra. Corresponding pairs of resonances were
marked with (I) and (II), respectively.
High resolution mass spectrometric measurements were performed using a Sciex 5600+ Q-TOF
mass spectrometer (AB Sciex UK Limited, Warrington, UK) in positive electrospray mode.
In situ FT IR measurements were conducted using ReactIR 1000 equipment (Mettler-Toledo Inc.,
Columbus, OH, USA). An attenuated total reflectance (ATR) diamond probe was placed in a 100 mL
four-necked flask equipped with a dropping funnel, a condenser, a thermometer and a magnetic stirrer.
The temperature was maintained by using an appropriately adjusted oil bath.
3
.2. General Procedure for the Synthesis of Isoindolin-1-One-3-Phosphonates (7–9) and
Isoindolin-1-One-3-Phosphinate (10)
A mixture of 1.0 mmol (0.15 g) 2-formylbenzoic acid, 1.0 mmol (0.10 mL), 1.1 mmol (0.11 mL)
or 1.2 mmol (0,12 mL) butylamine, 1.2 mmol (0.14 mL) cyclohexylamine or 1.2 mmol (0.13 mL)
benzylamine and >P(O)H derivative (1.0 mmol (diethyl phosphite (0.13 mL), dimethyl phosphite
(
0.09 mL), diisopropyl phosphite (0.17 mL), dibutyl phosphite (0.20 mL), dibenzyl phosphite (0.22 mL),
ethyl phenyl-H-phosphinate (0.15 mL) or 1.1 mmol (0.14 mL) or 1.2 mmol (0.16 mL) diethyl phosphite
◦
was irradiated in a sealed tube at 40–60 C for 10–30 min in a CEM Microwave reactor equipped with a
pressure controller. The volatile components were removed in vacuum, and the residue was analysed by
gas chromatography. The isoindolin-1-one-3-phosphonates and isoindolin-1-one-3-phosphinate were
obtained by column chromatography using silica gel as the absorbent and dichloromethane:methanol
(97:3) as the eluent. The following products were thus prepared:
3
.2.1. Diethyl (2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7a)
Yield: 94% (0.31 g), colourless oil; 31P (CDCl )
δ
18.3; H NMR (CDCl )
1
δ
0.94 (t, J
= 7.4, 3H,
HH
3
3
I
II
CH (CH ) N), 1.12 (t, J
= 7.1, 3H, CH CH O ), 1.27 (t, J
= 7.1, 3H, CH CH O ), 1.29–1.38 (m, 2H,
3
2 3
HH
3
2
HH
3
2
CH (CH ) N), 1.56–1.65 (m, 1H, CH , CH CH N), 1.65–1.75 (m, 1H, CH , CH CH N), 3.53–3.60 (m, 1H,
2
2 2
A
2
2
B
2
I
2
I
CH , CH N), 3.76–3.85 (m, 1H, CH , CH O ), 3.91–4.00 (m, 1H, CH , CH O ), 4.08–4.18 (m, 3H, CH ,
A
2
A
2
B
2
B
II
CH N, CH O ), 4.89 (d, J = 13.6, 1H, C H), 7.51 (t, J
= 7.5, 1H, C H), 7.58 (t, J
= 8.0, 1H, C H),
2
2
HP
1
HH
5
HH
6
1
3
7
1
4
1
1
.78 (d, J
= 7.6, 1H, C H), 7.87 (d, J
= 7.5, 1H, C H); C NMR (CDCl3)
δ
13.8 (CH (CH ) N),
HH
7
HH
4
3
2 3
3
I
3
II
6.2 (d, J = 5.6, CH CH O ), 16.4 (d, J = 5.6,CH CH O ), 20.0 (CH (CH ) N), 30.0 (CH CH N),
1.5 (CH N), 57.2 (d, J = 155.0, C ), 63.2 (d, J = 7.3, CH O ), 63.5 (d, J = 7.1, CH O ),
23.8 (d, J = 1.6, C ), 124.5 (d, J = 2.6, C ), 128.9 (d, J = 2.2, C ), 131.5 (d, J = 2.5, C6),
CP 4 CP 7 CP 5 CP
32.5 (d, J = 4.3, C ), 138.5 (d, J = 5.8, C ), 168.8 (d, J = 3.5, C ); [M + H]
CP
3
2
CP
3
2
2
2 2
2
2
1
2
I
2
II
2
CP
1
CP
2
CP
2
3
3
2
3
+
= 326.1509,
CP
3a
CP
7a
CP
3
found
C H NO P requires 326.1521.
16
25
4
3
.2.2. Dimethyl (2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7b)
Yield: 85% (0.25 g), white crystals; Mp: 77–78 C; 31P (CDCl3)
◦
δ
18.5; H NMR (CDCl )
3
1
δ
0.94 (t, JHH = 7.3, 3H, CH (CH ) N), 1.22–1.45 (m, 2H, CH (CH ) N), 1.49–1.81 (m, 2H, CH CH N),
3
2 3
2
2 2
2
2

Molecules 2020, 25, 3307
11 of 17
I
3
3
7
.42–3.64 [3.56 (d, JHH = 10.9, CH O ) overlapped by the multiplet of CH , CH N total int. 4H],
3 A 2
II
.75 (d, JHH = 10.9, 3H, CH O ), 4.03–4.24 (m, 1H, CH , CH N), 4.91 (d, J
= 13.4, 1H, C H),
1
3
B
2
HP
.52 (t, JHH = 6.9, 1H, C H), 7.59 (t, J
= 6.4, 1H, C H), 7.77 (d, J
= 7.5, 1H, C H), 7.88 (d, J
= 7.4,
HH
5
HH
6
HH
7
13
1
H, C H); C NMR (CDCl )
δ
13.7 (CH (CH ) N), 19.9 (CH (CH ) N), 29.9 (CH CH N), 41.5 (CH N),
4
3
3
2 3
2
2 2
1
2
2
2
2
I
2
II
5
3.6 (d, J = 7.3, CH O ), 53.7 (d, J = 7.1, CH O ), 56.7 (d, J = 155.4, C ), 123.8 (d, J = 1.6,
CP
3
CP
3
CP
1
CP
3
3
C ), 124.3 (d, J = 2.7, C ), 128.9 (d, J = 2.2, C ), 131.5 (d, J = 2.5, C ), 132.3 (d, J = 4.1,
C ), 138.2 (d, J = 5.9, C ), 168.6 (d, J = 3.4, C ); [M + H]
4
CP
7
CP
3
5
CP
+
6
CP
2
= 298.1196, C H NO P
14 21 4
3a
CP
7a
CP
3
found
requires 298.1208.
3
.2.3. Diisopropyl (2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7c)
Yield: 89% (0.32 g), colourless oil; 31P (CDCl )
δ
16.6; H NMR (CDCl )
1
δ
0.92 (t, J
= 7.3, 3H,
HH
3
3
I
II
CH (CH ) N), 0.95 (d, J
= 7.3, 3H, CH CH ), 1.19–1.41 [1.24 (d, J
= 6.1, CH CH ) overlapped by the multiplet of CH (CH ) N total int. 11H],
= 6.2, CH CH ), 1.25 (d, J
= 6.2,
HH
3
2 3
III
HH
3
IV
HH
3
CH CH ), 1.28 (d, J
3
HH
3
2
2 2
1
4
.52–1.79 (m, 2H, CH CH N), 3.51–3.65 (m, 1H, CH , CH N), 4.06–4.20 (m, 1H, CH , CH N),
2
I
2
A
2
B
2
II
.32–4.49 (m, 1H, CHO ), 4.66–4.80 (m, 1H, CHO ), 4.84 (d, J = 13.8, 1H, C H), 7.50 (t, J = 7.3, 1H,
HH
HP
1
1
3
C H), 7.56 (t, J
= 6.8, 1H, C H), 7.79 (d, J
= 7.5, 1H, C H), 7.86 (d, J
= 7.2, 1H, C H); C NMR
HH 4
5
HH
6
HH
7
3
I
3
(CDCl3)
δ
13.8 (CH (CH ) N), 20.0 (CH (CH ) N), 23.3 (d, J = 5.3, CH CH ), 23.9 (d, J = 5.0,
3
3
2 3
2
2 2
CP
3
CP
II
III
3
IV
CH CH ), 24.06 (d, J = 6.6, CH CH ), 24.10 (d, J = 6.1, CH CH ), 30.0 (CH CH N), 41.5 (CH N),
5
C ), 124.4 (d, J = 2.6, C ), 128.8 (d, J = 2.2, C ), 131.4 (d, J = 2.5, C ), 132.4 (d, J = 4.3,
C ), 138.4 (d, J = 5.8, C ), 168.7 (d, J = 3.5, C ); [M + H]
3
CP
3
CP
I
3
2
2
II
2
2
1
2
7.1 (d, J = 155.0, C ), 63.1 (d, J = 7.3, CHO ), 63.4 (d, J = 7.1, CHO ), 123.7 (d, J = 1.6,
CP
1
CP
CP
CP
3
3
4
CP
7
CP
3
5
CP
+
6
CP
2
= 354.1826, C H NO P
18 29 4
3
a
CP
7a
CP
3
found
requires 354.1828.
3
.2.4. Dibutyl (2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7d)
Yield: 91% (0.35 g), colourless oil; 31P (CDCl3)
δ
18.3; H NMR (CDCl )
1
δ
0.82 (t, JHH = 7.3,
3
I
II
3
H, CH (CH ) O ), 0.89 (t, J
= 7.2, 3H, CH (CH ) O ), 0.94 (t, J
= 7.3, 3H, CH (CH ) N),
HH 3 2 3
3
2 3
HH
3
2 3
I
II
1
3
3
7
(
(
.13–1.49 (m, 8H, CH (CH ) N, CH (CH ) O, CH CH O ), 1.49–1.79 (m, 4H, CH CH N, CH CH O ),
2 2 2 2 2 2 2 2 2 2 2 2
I
I
.46–3.62 (m, 1H, CH , CH N), 3.63–3.78 (m, 1H, CH , CH O ), 3.81–3.95 (m, 1H, CH , CH O ),
A
2
A
2
B
2
II
.96–4.24 (m, 3H, CH , CH N, CH O ), 4.89 (d, J = 13.6, 1H, C H), 7.51 (t, J
= 7.4, 1H, C H),
5
B
2
2
HP
1
HH
13
.57 (t, JHH = 7.4, 1H, C H), 7.78 (d, J
= 7.5, 1H, C H), 7.86 (d, J
13.41 (CH (CH ) O ), 13.43 (CH (CH ) O ), 13.7 (CH (CH ) N), 18.5 (CH (CH ) O ), 18.6
= 7.3, 1H, C H); C NMR
6
HH
7
HH
4
I
II
I
CDCl3)
δ
3
2 3
3
2 3
3
2 3
2
2 2
3
II
3
I
CH (CH ) O ), 20.0 (CH (CH ) N), 30.0 (CH CH N), 32.3 (d, J = 5.6, CH CH O ), 32.4 (d, J = 5.9,
2
2 2
II
2
2 2
2
2
CP
2
2
CP
1
2
I
2
CH CH O ), 41.5 (CH N), 57.1 (d, J = 155.0, C ), 66.7 (d, J = 7.5, CH O ), 67.1 (d, J = 7.2,
2
2
2
CP
1
CP
2
CP
II
3
CH O ), 123.7 (d, J = 1.4, C ), 124.4 (d, J = 2.7, C ), 128.8 (d, J = 2.2, C ), 131.4 (d, J = 2.4, C6),
2
CP
4
CP
7
CP
5
CP
3
2
3
+
1
32.5 (d, J = 4.3, C ), 138.5 (d, J = 5.8, C ), 168.6 (d, J = 3.3, C ); [M + H]
= 382.2131,
found
CP
3a
CP
7a
CP
3
C H NO P requires 382.2147.
20
33
4
3
.2.5. Dibenzyl (2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7e)
Yield: 81% (0.36 g), white crystals; Mp: 103–104 C; 31P (CDCl3)
◦
δ
19.2; H NMR (CDCl )
3
1
δ
0.85 (t, JHH = 7.3, 3H, CH (CH ) N), 1.13–1.30 (m, 2H, CH (CH ) N), 1.41–1.65 (m, 2H, CH CH N),
3
2 3
2
2 2
2
2
3
.37–3.56 (m, 1H, CH , CH N), 3.96–4.14 (m, 1H, CH , CH N), 4.61–4.76 (m, 1H, C H), 4.76–4.90 (m, 2H,
A
2
B
2
1
I
II
CH O ), 4.90–5.06 (m, 2H, CH O ), 7.10–7.24 (m, 4H, C
C H, C H), 7.73 (d, J
0
H), 7.24–7.57 (m, 6H, C
0
H), 7.43–7.57 (m, 2H,
2
2
2
3,4
13
= 7.2, 1H, C H), 7.81 (d, J
= 7.0, 1H, C H); C NMR (CDCl ) δ 13.7
HH 4 3
5
6
HH
7
1
(CH (CH ) N), 19.9 (CH (CH ) N), 29.9 (CH CH N), 41.5 (CH N), 57.4 (d, J
= 154.9, C ),
3
2 3
2
2 2
2
2
2
CP
1
2
I
2
II
3
6
8.6 (d, J = 7.3, CH O ), 68.8 (d, J = 7.0, CH O ), 123.8 (d, J = 1.6, C ), 124.4 (d, J = 2.7,
CP
2
CP
I
2
CP
4
CP
I
II
II
I
II
C ), 128.1 (C3
0
), 128.2 (C3
0
), 128.66 (C2
0
), 128.67 (C2
0
), 128.87 (C4
0
), 128.90 (C4
0
), 128.9 (d, J = 2.4,
7
CP
3
3
I
3
C ), 131.4 (d, J = 2.5, C ), 132.5 (d, J = 4.2, C ), 135.43 (d, J = 5.5, C1
C1
0
), 135.44 (d, J = 5.7,
5
CP
6
CP
3a
CP
CP
II
2
3
+
0
), 138.2 (d, J = 6.0, C ), 168.6 (d, J = 3.5, C ); [M + H]
= 450.1822, C H NO P
found 26 29 4
CP
7a
CP
3
requires 450.1828.

Molecules 2020, 25, 3307
12 of 17
3
.2.6. Diethyl (2-Cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (8a)
Yield: 84% (0.30 g), colourless oil; 31P (CDCl3)
δ
II
18.7; H NMR (CDCl )
1
δ
1.14 (t, J = 7.1, 3H,
3
HP
I
c
(
6
CH CH O ), 1.28–1.45 [1.25 (t, J
= 7.1, CH CH O ) overlapped by the multiplet of HexH total int.
H], 1.57–2.03 (m, 5H, HexH), 2.13–2.31 (m, 1H, HexH), 2.36–2.55 (m, 1H, HexH), 3.69–3.88 (m, 2H,
3
2
HH
3
2
c
c
c
I
II
CH O ), 3.88–4.02 (m, 1H, C
0
H), 4.02–4.19 (m, 2H, CH O ), 4.85 (d, 1H, J = 13.2, C H), 7.49 (t, 1H,
2
1
2
HP
1
J
= 7.6, C H), 7.55 (t, 1H, J
= 7.2, C H), 7.74 (d, J
= 7.6, 1H, C H), 7.82 (d, J
= 7.3, 1H, C H);
HH
3
5
HH
3
6
HH
7
HH
II
4
1
I
3
C NMR (CDCl )
δ
16.2 (d, J = 4.6, CH CH O ), 16.3 (d, J = 5.5, CH CH O ), 25.3 (C
0
), 26.1
3
CP
3
2
0
CP
3
2
4
I
II
I
II
1
2
I
(
C3
0
), 26.3 (C3
0
), 29.3 (C2
0
), 29.7 (C2
0
), 56.7 (C1
), 58.6 (d, J = 155.4, C ), 63.2 (d, J = 7.5, CH O ),
CP
1
CP
2
3.4 (d, 2J = 7.0, CH O ), 123.4 (d, J = 1.3, C ), 124.4 (d, J = 2.7, C ), 128.7 (d, J = 2.3, C5),
II
3
6
1
[
CP 2 CP 4 CP 7 CP
3
2
3
31.2 (d, J = 2.6, C ), 133.6 (d, J = 4.0, C ), 138.8 (d, J = 5.7, C ), 169.0 (d, J = 3.4, C3);
CP 6 CP 3a CP 7a CP
M+H]+
= 352.1672, C H NO P requires 352.1672.
found 18 27 4
3
.2.7. Dimethyl (2-Cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (8b)
Yield: 71% (0.23 g), colourless oil; 31P (CDCl )
δ
20.9; H NMR (CDCl ) 1.18–1.45 (m, 3H, HexH),
1
c
3
3
c
c
c
c
1
3
.60–1.72 (m, 1H, HexH), 1.72–2.02 (m, 4H, HexH), 2.10–2.30 (m, 1H, HexH), 2.31–2.50 (m, 1H, HexH),
I
II
.59 (d, JHP = 10.7, 3H, CH O ), 3.76–3.86 [3.72 (d, J = 10.9, CH O ) overlapped by the multiplet of
3 HP 3
C1
0
H total int. 4H], 4.88 (d, JHP = 13.1, 1H, C H), 7.44–7.61 (m, 2H, C H, C H), 7.71 (d, J
= 7.5, 1H,
1
5
6
HH
II
13
I
I
C H), 7.83 (d, J
= 7.2, 1H, C H); C NMR (CDCl )
δ
25.2 (C4
0
), 26.0 (C3
0
), 26.3 (C3
0
), 29.4 (C2
0
),
7
HH
4
3
II
2
I
2
II
1
2
9.7 (C2
0
), 53.7 (d, J = 7.2, CH O ), 53.8 (d, J = 7.2, CH O ), 56.6 (C
0
), 59.2 (d, J = 156.4,
CP
3
CP
3
1
CP
3
C ), 123.5 (d, J = 1.6, C ), 124.3 (d, J = 2.6, C ), 128.8 (d, J = 2.2, C ), 131.3 (d, J = 2.5, C6),
1
CP
4
CP
7
CP
5
CP
3
2
3
+
1
33.4 (d, J = 4.1, C ), 138.5 (d, J = 6.0, C ), 169.0 (d, J = 3.5, C ); [M + H]
= 324.1364,
found
CP
3a
CP
7a
CP
3
C H NO P requires 324.1359.
16
23
4
3
.2.8. Diisopropyl (2-Cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (8c)
Yield: 78% (0.30 g), white crystals; Mp: 112–113 C; 31P (CDCl3)
◦
δ
17.1; H NMR (CDCl )
1
3
I
II
δ
0.96 (d, J
= 6.2, 3H, CH CH ), 1.15–1.44 (1.23 [d, J
CH CH , CH CH ) overlapped by the multiplet of HexH total int. 12H], 1.57–2.03 (m, 5H, HexH),
.16–2.36 (m, 1H, HexH), 2.38–2.59 (m, 1H, HexH), 3.68–3.88 (m, 1H, C
.64–4.85 [4.79 (d, JHP = 13.5, C H) overlapped by the multiplet of CHO total int. 2H], 7.42–7.58
= 6.2, CH CH ), 1.26 (d, J
= 6.1,
HH
3
HH
3
HH
c
III
IV
c
3
3
c
c
I
2
4
0
H), 4.30–4.49(m, 1H, CHO ),
1
II
1
[
7.47 (t, JHH = 7.4, C H) overlapped by the multiplet of C H total int. 2H], 7.75 (d, J
= 7.6, 1H,
5
6
HH
13
3
I
3
C H), 7.81 (d, J
= 7.2, 1H, C H); C NMR (CDCl )
δ
23.4 (d, J = 5.3, CH CH ), 23.9 (d, J = 5.3,
7
HH
4
3
CP
IV
3
CP
II
3
III
3
I
II
CH CH ), 24.0 (d, J = 3.5, CH CH ), 24.1 (d, J = 3.4, CH CH ), 25.2 (C
2
CHO ), 123.2 (d, J = 1.7, C ), 124.5 (d, J = 2.6, C ), 128.6 (d, J = 2.2, C ), 131.1 (d, J = 2.6, C6),
1
0
), 26.1 (C3
0
), 26.3 (C3
0
),
3
CP
II
3
CP
3
4
I
1
2
I
2
9.2 (C
0
), 29.6 (C2
0
), 56.7 (C1
0
), 59.2 (d, J = 156.3, C ), 72.0 (d, J = 7.7, CHO ), 72.4 (d, J = 7.3,
2
CP
1
CP
CP
II
3
CP
4
CP
7
CP
5
CP
3
2
3
+
33.8 (d, J = 4.1, C ), 139.0 (d, J = 5.6, C ), 169.0 (d, J = 3.7, C ); [M + H]
= 380.1990,
found
CP
3a
CP
7a
CP
3
C H NO P requires 380.1985.
20
31
4
3
.2.9. Dibutyl (2-Cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (8d)
Yield: 80% (0.33 g), colourless oil; 31P (CDCl3)
δ
20.6; H NMR (CDCl )
1
δ
0.85 (t, J
= 7.3,
3
HH
I
II
c
3
H, CH (CH ) O ), 0.86 (t, J
= 7.3, 3H, CH (CH ) O ), 1.17–1.36 (m, 6H, CH (CH ) O, HexH),
.39–1.49 (m, 2H, CH CH O ), 1.49–1.60 (m, 2H, CH CH O ), 1.62–1.98 (m, 6H, HexH), 2.15–2.33 (m, 1H,
HexH), 2.35–2.54 (m, 1H, HexH), 3.64–3.82 (m, 2H, CH , CH O , C H), 3.82–3.95 (m, 1H, CHB,
3
2 3
HH
3
2 3
2
2 2
I
II
c
1
2 2 2 2
c
c
I
0
A
2
1
I
II
CH O ), 3.95–4.12 (m, 2H, CH O ), 4.85 (d, J
= 13.2, 1H, C H), 7.43–7.58 (m, 2H, C H, C H),
1 5 6
= 7.2, 1H, C H); C NMR (CDCl )
2
2
HP
1
3
I
7
.73 (d, JHH = 7.5, 1H, C H), 7.82 (d, J
δ
13.4 (CH (CH ) O ),
7
HH
4
3
3
2 3
II
I
II
I
II
1
2
5
3.5 (CH (CH ) O ), 18.5 (CH (CH ) O ), 18.6 (CH (CH ) O ), 25.3 (C
0
), 26.1 (C3
0
), 26.3 (C3
0
),
),
3
2 3
2
2 2
2
2 2
4
I
II
3
I
3
II
9.3 (C2
0
), 29.6 (C2
0
), 32.36 (d, J = 5.6, CH CH O ), 32.40 (d, J = 6.0, CH CH O ), 56.7 (C
0
CP
2
2
I
CP
2
2
1
1
2
2
II
8.6 (d, J = 155.6, C ), 66.9 (d, J = 7.6, CH O ), 67.1 (d, J = 7.3, CH O ), 123.3 (d, J = 1.4,
CP
1
CP
2
CP
2
CP
3
3
C ), 124.4 (d, J = 2.6, C ), 128.7 (d, J = 2.2, C ), 131.1 (d, J = 2.6, C ), 133.6 (d, J = 4.0,
4
CP
7
CP
5
CP
6
CP

Molecules 2020, 25, 3307
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C ), 138.9 (d, J = 5.8, C ), 169.0 (d, J = 3.6, C ); [M + H]+
2
3
= 408.2298, C H NO P
3a
CP
7a
CP
3
found
22 35
4
requires 408.2298.
3
.2.10. Dibenzyl (2-Cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (8e)
Yield: 70% (0.33 g), white crystals; Mp: 97–98 C; 31P (CDCl3)
◦
δ
c
19.5; H NMR (CDCl )
3
1
c
c
δ
c
1.06–1.31 (m, 3H, HexH), 1.51–1.62 (m, 1H, HexH), 1.66–1.92 (m, 4H, HexH), 2.10–2.23 (m, 1H,
HexH), 2.30–2.42 (m, 1H, HexH), 3.67–3.77 (m, 1H, C H), 4.64–4.73 (m, 1H, CH , CH O ), 4.79–4.87
4.84 (d, J = 12.7, C H) overlapped by the multiplet of CH , CH O total int. 2H], 4.87–5.02 (m, 2H,
c
I
0
1
A 2
I
[
HP
1
B
2
II
CH O ), 7.14–7.21 (m, 4H, C
0
H), 7.27–7.33 (m, 6H, C
0
H), 7.45 (t, J
= 7.5, 1H, C H); C NMR (CDCl )
= 7.4, 1H, C H), 7.50 (t, J
= 7.5,
HH
2
2 ’
3,4 ’
HH
5
1
3
1
H, C H), 7.69 (d, J
= 8.3, 1H, C H), 7.76 (d, J
δ
25.1 (C4
0
), 25.9
6
HH
7
HH
4
3
2
I
II
I
II
1
I
(
C3
0
), 26.1 (C3
0
), 29.3 (C2
0
), 29.6 (C2
0
), 56.5 (C1
0
), 58.8 (d, J = 155.4, C ), 68.7 (d, J = 7.5, CH O ),
CP
3
1
CP
2
II
I
0
II
6
1
8.8 (d, 2JCP = 6.9, CH O ), 123.4 (d, J = 1.4, C ), 124.3 (d, J = 2.4, C ), 128.0 (C
), 128.2 (C
0
),
2
CP
4
CP
7
3 ’
3 ’
I
II
I
II
28.58 (C2 ’
0
), 128.61 (C
0
), 128.62 (C
0
), 128.66 (C
0
), 128.74 (d, J = 2.4, C ), 131.2 (d, J = 2.5,
), 135.5 (d, J = 5.6, C
= 476.1997, C H NO P requires 476.1985.
28 31 4
2 ’
4 ’
4 ’
CP 5 CP
3
3
I
3
II
2
C ), 133.5 (d, J = 4.3, C ), 135.4 (d, J = 6.3, C
C ), 168.9 (d, J = 3.9, C ); [M + H]
0
0
), 138.5 (d, J = 6.0,
6
CP
3a
CP
1 ’
CP
1 ’
CP
3
+
7
a
CP
3
found
3
.2.11. Diethyl (2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (9a)
Yield: 90% (0.32 g), colourless oil; 31P (CDCl3) 18.3; 31P (CDCl3), [17] 17.7; [M + H]+
60.1360, C H NO P requires 360.1359.
δ
δ
=
found
3
3
19
23
4
.2.12. Dimethyl (2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (9b)
Yield: 80% (0.27 g), light yellow crystals; Mp: 130–131 C; Mp [13]: 130–132 C; 31P (CDCl3)
◦
◦
δ
21.8;
δ[13] 21.6; [M + H]+
= 332.1050, C H NO P requires 332.1046.
found
17 19
4
3
.2.13. Diisopropyl (2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (9c)
Yield: 83% (0.32 g), colourless oil; 31P (CDCl )
δ
16.6; H NMR (CDCl )
1
δ
0.85 (d, JHH = 6.2, 3H,
= 6.2, 3H,
3
3
III
I
II
CH CH ), 1.16 (d, J
= 6.2, 3H, CH CH ), 1.19 (d, J
= 6.1, 3H, CH CH ), 1.23 (d, J
CH CH ), 4.28–4.44 (m, 1H, CHO ), 4.50–4.74 [4.56 (d, J = 15.0, CH , CH N), 4.57 (d, J = 12.5, C H)
3
HH
3
HH
3
HH
IV
I
3
HP
A
2
HP
1
II
overlapped by the multiplet of CHO total int. 3H], 5.48 (d, J = 14.9, 1H, CH , CH N), 7.12–7.29 (m, 5H,
HP
B
2
C -
0
H), 7.39–7.55 (m, 2H, C H, C H), 7.64 (d, J
= 7.1, 1H, C H), 7.84 (d, J
= 6.8, 1H, C H);
2
4
5
3
6
HH
7
HH
4
13
I
3
II
3
C NMR (CDCl )
δ
23.3 (d, J = 5.4, CH CH ), 23.9 (d, J = 5.1, CH CH ), 24.06 (d, J = 5.8,
3
CP
3
CP
3
CP
III
3
IV
1
2
CH CH ), 24.11 (d, J = 5.4, CH CH ), 44.9 (CH N), 56.9 (d, J = 156.5, C ), 72.3 (d, J = 7.4,
CHO ), 72.6 (d, J = 7.2, CHO ), 123.9 (d, J = 1.6, C ), 124.5 (d, J = 2.5, C ), 127.6 (C
3
CP
3
2
CP
3
1
CP
I
2
II
0
), 128.4
CP
CP
4
CP
7
4
3
(
(
C3
C1
0
), 128.68 (C2 ), 128.70 (d, JCP = 2.6, C ), 131.6 (d, J = 2.6, C ), 132.2 (d, J = 4.3, C ), 136.9
0
5 CP 6 CP 3a
), 139.0 (d, J = 5.8, C ), 168.9 (d, J = 3.7, C ); [M + H]
2
3
+
0
= 388.1667, C H NO P
21 27 4
CP
7a
CP
3
found
requires 388.1672.
3
.2.14. Dibutyl (2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (9d)
Yield: 85% (0.35 g), colourless oil; 31P (CDCl )
δ
18.3; H NMR (CDCl )
1
δ
0.83 (t, JHH = 7.4, 3H,
3
II
3
I
(
CH CH ) O ), 0.89 (t, J
= 7.4, 3H, CH (CH ) O ), 1.15–1.36 (m, 4H, CH (CH ) O), 1.36–1.50 (m, 2H,
HH 3 2 3 2 2 2
CH CH O ), 1.52–1.64 (m, 2H, CH CH O ), 3.67–3.79 (m, 1H, CH , CH O ), 3.84–3.79 (m, 1H, CH ,
CH O ), 3.98–4.10 (m, 2H, CH O ), 4.6 (d, J = 14.9, 1H, CH , CH N), 4.68 (d, J = 13.3, 1H,
3
2 3
I
II
I
2
2
2
II
2
A
2
B
I
2
2
HP
A
2
HP
C H), 5.57 (d, J = 14.8, 1H, CH , CH N), 7.21–7.34 (m, 5H, C -
0
H), 7.47–7.60 (m, 2H, C H, C H),
1
HP
B
2
2 4
5
6
13
I
7
.70 (d, JHH = 7.0, 1H, C H), 7.92 (d, J
= 6.7, 1H, C H); C NMR (CDCl ) 13.4 (CH (CH ) O ),
4 3 3 2 3
3.5 (CH (CH ) O ), 18.5 (CH (CH ) O ), 18.6 (CH (CH ) O ), 32.3 (d, J = 5.6, CH CH O ),
7
HH
I
II
II
3
I
1
3
6
3
2 3
2
2 2
2
2 2
CP
2
2
3
II
1
2
I
2.5 (d, J = 5.6, CH CH O ), 45.0 (CH N), 56.4 (d, J = 155.5, C ), 66.9 (d, J = 7.4, CH O ),
CP
2
2
II
2
CP
1
CP
2
2
3
7.1 (d, J = 7.3, CH O ), 124.0 (d, J = 1.7, C ), 124.5 (d, J = 2.6, C ), 127.6 (C
0
), 128.3
CP
2
CP
4
CP
7
4
3
(C3
0
), 128.7 (C2 ), 128.8 (d, JCP = 2.4, C ), 131.6 (d, J = 2.5, C ), 132.0 (d, J = 4.3, C ), 136.8
0
5 CP 6 CP 3a

Molecules 2020, 25, 3307
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), 138.8 (d, 2JCP = 5.7, C ), 168.8 (d, J = 3.6, C ); [M + H]+
3
= 416.1979, C H NO P
(C1
0
7a
CP
3
found
23 31
4
requires 416.1985.
3
.2.15. Dibenzyl (2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (9e)
Yield: 84% (0.33 g), colourless oil; 31P (CDCl3)
δ
19.2; H NMR (CDCl )
1
δ
4.49 (d, JHP = 14.9, 1H,
3
I
CH , CH N), 4.61–4.74 [4.65 (d, J = 13.0, C H) overlapped by the multiplet of CH , CH O total
int. 2H], 4.79–4.86 (m, 1H, CH , CH O ), 4.92–5.02 (m, 2H, CH O ), 5.48 (d, J = 14.9, 1H, CHB,
A
2
HP
1
A
2
I
II
B
2
2
HP
CH N), 7.10–7.18 (m, 4H, ArH), 7.18–7.25 (m, 5H, ArH), 7.27–7.31 (m, 3H, ArH), 7.31–7.39 (m, 3H,
2
1
3
ArH), 7.45–7.55 (m, 2H, C H, C H), 7.64 (d, J
NMR (CDCl ) 45.0 (CH N), 56.6 (d, J = 155.5, C ), 68.6 (d, J = 7.3, CH O ), 68.9 (d, J = 6.9,
= 6.9, 1H, C H), 7.87 (d, J
= 5.8, 1H, C H);
C
5
6
HH
7
2
HH
4
1
I
2
3
2
CP
1
CP
2
CP
II
II
3
I
CH O ), 124.1 (d, J = 1.7, C ), 124.4 (d, J = 2.6, C ), 127.6 (C
0
), 128.1 (C
0
), 128.3 (C
0
), 128.4
), 128.9 (d, J = 2.3, C ),
2
CP
4
0
CP
7
4
3 ’
3 ’
I
II
I
II
(
1
1
C3
0
), 128.65 (C
0
), 128.66 (C2
), 128.67 (C
0
), 128.71 (C
0
), 128.8 (C
0
2 ’
2 ’
4 ’
4 ’
CP
5
II
3
3
I
3
31.7 (d, JCP = 2.6, C ), 132.0 (d, J = 4.1, C ), 135.36 (d, J = 5.1, C
36.7 (C1
0
), 135.40 (d, J = 5.5, C
0
),
6
2
CP
3a
CP
1 ’
CP
1 ’
3
+
0
), 138.4 (d, J = 5.8, C ), 168.7 (d, J = 3.7, C ); [M + H]
= 484.1679, C H NO P
found 29 27 4
CP
7a
CP
3
requires 484.1672.
3
.2.16. Ethyl (2-Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)(phenyl)phosphinate (10)
Yield: 78% (0.28 g), colourless oil; [M + H]+
= 358.1558, C H NO P requires 358.1566;
found
20 25
3
31
Product 10 formed as a mixture of two isomers (
The two series of signals could be separated in the NMR spectra: Isomer A
NMR (CDCl3) 0.94 (t, JHH = 7.4, 3H, CH (CH ) N), 1.23–1.38 (m, 2H, CH (CH ) N), 1.43 (t, J
A
and
B
) in a proportion of 47:53 based on P NMR.
31
1
:
P (CDCl3)
δ
35.4; H
δ
= 7.0,
3
2 3
2
2 2
HH
3
H, CH CH O), 1.54–1.80 (m, 2H, CH CH N), 3.66–3.78 (m, 1H, CH , CH N), 4.19–4.39 (m, 3H, CH ,
3 2 2 2 A 2 B
CH N, CH O), 5.05 (d, J = 16.7, 1H, C H), 7.12–7.67 (m, 8H, ArH, C5–7H), 7.75 (d, JHH = 7.8, 1H,
2
2
HP
1
13
3
C H); C NMR (CDCl3) δ 13.7 (CH (CH ) N), 16.50 (d, J = 6.1, CH CH O), 20.0 (CH (CH ) N),
3 2 3 CP 3 2 2 2 2
0.02 (CH CH N), 41.5 (CH N), 60.1 (d, J = 107.9, C ), 61.9 (d, J = 6.7, CH O), 123.4 (d, J = 1.6,
C ), 123.7 (d, J = 1.7, C ), 124.45 (d, J = 23.1, C3
), 128.67 (d, J = 2.0, C ), 131.1 (d, J = 2.3, C ), 132.1 (d, J = 9.4, C4
C ), 138.7 (d, J = 4.1, C ), 168.3 (d, J = 2.6, C3); Isomer B
4
1
2
3
2 2 2 CP 1 CP 2 CP
3
3
1
2
0
), 125.5 (d, J = 127.3, C1
0
), 128.21 (d, J = 12.7,
4
CP
7
CP
CP
CP
3
C2
0
0
), 133.04 (d, J = 3.0,
CP
5
CP
6
CP
CP
2
3
31P (CDCl3)
1
:
δ
39.2; H NMR
3a
CP
7a
CP
(
CDCl3)
δ
0.95 (t, JHH = 7.4, 3H, CH (CH ) N), 1.23–1.38 (m, 2H, CH (CH ) N), 1.45 (t, J
= 7.0, 3H,
HH
3
2 3
2
2 2
CH CH O), 1.54–1.80 (m, 2H, CH CH N), 3.51–3.66 (m, 1H, CH , CH N), 3.98–4.19 (m, 3H, CH ,
3
2
2
2
A
2
B
CH N, CH O), 5.05 (d, J = 16.7, 1H, C H), 7.12–7.67 (m, 8H, ArH, C5–7H), 7.86 (d, JHH = 7.7, 1H,
2
2
HP
1
13
3
C H); C NMR (CDCl3) δ 13.7 (CH (CH ) N), 16.54 (d, J = 6.1, CH CH O), 20.0 (CH (CH ) N),
3 2 3 CP 3 2 2 2 2
9.98 (CH CH N), 41.4 (CH N), 59.4 (d, J = 104.5, C ), 62.2 (d, J = 7.1, CH O), 123.4 (d, J = 1.6,
C ), 123.7 (d, J = 1.7, C ), 124.42 (d, J = 22.8, C3
), 128.60 (d, J = 2.5, C ), 131.3 (d, J = 2.6, C ), 131.9 (d, J = 9.3, C4
38.1 (d, J = 1.8, C ), 168.7 (d, J = 2.1, C3).
CP 7a CP
4
1
2
2
2 2 2 CP 1 CP 2 CP
3
3
1
2
0
), 125.1 (d, J = 128.4, C1
0
), 128.25 (d, J = 12.8,
4
CP
7
CP
CP
CP
3
C2
0
0
), 132.98 (d, J = 3.3, C3a),
CP
5
CP
6
CP
CP
2
3
1
3
.3. Procedure for the Real Time Monitoring of the Condensation of 2-Formylbenzoic Acid, Butylamine and
Diethyl Phosphite by In Situ FT-IR Spectroscopy
◦
To 30 mL of ethanol, the starting materials were mixed at room temperature (25 C) in ten-minute
intervals in the following order: 30 mmol (4.5 g) of 2-formylbenzoic acid, 30 mmol (3.9 mL) of diethyl
phosphite and 36 mmol (3.6 mL) of butylamine. After the additions, the mixture was heated gradually
◦
◦
from 25 C to 60 C in an oil bath. Then the temperature was held for an additional 2.5 h.
3
.4. Procedure for the Continuous Flow Synthesis of Diethyl
(
2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7a)
Before each experiment, two solutions (A and B) were prepared. For solution A, 41.8 mmol
3
of 2-formylbenzoic acid was dissolved in ethanol in a 50 cm volumetric flask, resulting in the
aldehyde concentration of 0.84 M. For solution B, amines (50.2 mmol of butylamine (5.0 mL)
or 62.7 mmol of butylamine (6.2 mL), 62.7 mmol of cyclohexylamine (7.2 mL) or 62.7 mmol of

Molecules 2020, 25, 3307
15 of 17
benzylamine (6.8 mL)) and 41.8 mmol of diethyl phosphite (5.4 mL) or 62.7 mmol of diethyl phosphite
3
(
8.1 mL) were dissolved in ethanol in a 50 cm volumetric flask, resulting in the amine concentration
of 1.01 M or 1.26 M and the dialkyl phosphite concentration of 0.84 M or 1.26 M, respectively.
The two solutions (A and B) were pumped separately. The system was flushed with 15 mL of
◦
solution A and 15 mL of solution B with a summa flow rate of 10 mL/min (A:B = 1:1) at 25 C
and 17 bar. Next, under the same pressure, the flow rate was set to the desired value (can be
seen in Table 2) and the vessel was irradiated with a power of 10–15 W for 2–3 min, until the
temperature reached the desired value, then the power was controlled automatically by the software
of the MW reactor. The operation was regarded steady state on the basis of the results of the GC
measurements. The desired diethyl (2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7a),
diethyl (2-cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (8a) or diethyl (2-benzyl-3-oxo-
2,3-dihydro-1H-isoindol-1-yl)phosphonate (9a) were obtained by column chromatography using silica
gel as the absorbent and dichloromethane:methanol (97:3) as the eluent. Yields were calculated on
the basis of the weights obtained after separation and evaporation taking into consideration the
quantity of the limiting starting materials fed in during a given time. After a 3 h flow operation
in steady state, 6.9 g of diethyl (2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (7a), 4.1 g
of diethyl (2-cyclohexyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (8a) or 5.3 g of diethyl
(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)phosphonate (9a) were obtained.
4
. Conclusions
In conclusion, we have developed a facile, efficient, catalyst-free method for the batch and
continuous flow preparation of isoindolin-1-one-3-phosphonates containing alkyl substituents on the
nitrogen atom. The novel batch approach enabled the solvent-free synthesis of the target compounds in
◦
high yields (70–94%) at low temperature (60 C) under short reaction times (10–30 min). By the in situ
FT-IR study on the condensation of 2-formylbenzoic acid, butylamine and diethyl phosphite, the reaction
was followed in “real time” and the time-dependent concentration profiles of the reaction components
were determined. The continuous flow MW-assisted method developed for the condensation of
2
-formylbenzoic acid, aliphatic primary amines and diethyl phosphite are suitable for the synthesis of
the corresponding isoindolin-1-one-3-phosphonates in a “few g” scale. Altogether 16 derivatives were
isolated and characterized. Except two, all of them are new compounds.
Supplementary Materials: Supplementary materials are available online.
Author Contributions: E.B. and
I.C. contributed to the Fourier transform FT-IR reaction monitoring, P.T.S. performed the high resolution mass
spectrometric measurements, E.B., .T. and N.T. wrote the paper. All authors have read and agreed to the
published version of the manuscript.
Á.T. planned the experiments, N.T. and. B.R. carried out the experiments,
Á
Funding: The above project was supported by the Hungarian Research Development and Innovation Office
FK123961), by the National Research, Development and Innovation Fund of Hungary in the frame of
(
FIEK_16-1-2016-0007 (Higher Education and Industrial Cooperation Center) project. N.T. was supported
by the Servier-Beregi PhD Research Fellowship. E.B. was supported by the János Bolyai Research Scholarship of
the Hungarian Academy of Sciences (BO/00278/17/7).
Conflicts of Interest: The authors declare no conflict of interest.
References
1
.
Bhatia, R.K. Isoindole derivatives: Propitious anticancer structural motifs. Curr. Top. Med. Chem. 2017
7, 189–207. [CrossRef] [PubMed]
Palillero-Cisneros, A.; Bedolla-Medrano, M.; Ord
,
1
2
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ó
ñez, M. Efficient PhB(OH) -catalyzed one-pot synthesis of
2
3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones under solvent free conditions. Tetrahedron
2
018, 74, 4174–4181. [CrossRef]

Molecules 2020, 25, 3307
16 of 17
3.
4.
5.
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Sample Availability: Samples of the compounds 7–10 are available from the authors.
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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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