Microwave-assisted synthesis of (aminomethylene)bisphosphine oxides and (aminomethylene)bisphosphonates by a three-component condensation

Article abstract of DOI:10.3762/bjoc.12.146

A practical method was elaborated for the synthesis of (aminomethylene)bisphosphine oxides comprising the catalyst- and solventfree microwave-assisted three-component condensation of primary amines, triethyl orthoformate and two equivalents of diphenylpho

Full text of DOI:10.3762/bjoc.12.146

Microwave-assisted synthesis of (aminomethylene)bisphos-
phine oxides and (aminomethylene)bisphosphonates by a
three-component condensation
Erika Bálint*1, Ádám Tajti2, Anna Dzielak2, Gerhard Hägele3 and György Keglevich*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1493–1502.
1MTA-BME Research Group for Organic Chemical Technology, 1521
Budapest, Hungary, 2Department of Organic Chemistry and
Technology, Budapest University of Technology and Economics,
1521 Budapest, Hungary and 3Institute of Inorganic Chemistry,
Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
doi:10.3762/bjoc.12.146
Received: 29 April 2016
Accepted: 17 June 2016
Published: 19 July 2016
Email:
Associate Editor: L. Vaccaro
Erika Bálint* - ebalint@mail.bme.hu; György Keglevich* -
gkeglevich@mail.bme.hu
© 2016 Bálint et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
(aminomethylene)bisphosphine oxides;
(aminomethylene)bisphosphonates; microwave; three-component
condensation
Abstract
A practical method was elaborated for the synthesis of (aminomethylene)bisphosphine oxides comprising the catalyst- and solvent-
free microwave-assisted three-component condensation of primary amines, triethyl orthoformate and two equivalents of
diphenylphosphine oxide. The method is also suitable for the preparation of (aminomethylene)bisphosphonates using
(MeO)2P(O)H/(MeO)3CH or (EtO)2P(O)H/(EtO)3CH reactant pairs and even secondary amines. Several intermediates referring to
the reaction mechanism together with a few by-products could also be identified.
Introduction
Substituted (hydroxymethylene)bisphosphonic acid derivatives diseases, besides they display antibacterial, antiparasitic, anti-
form an important group of drugs used in the treatment of cancer and herbicidal activities [5].
osteoporosis and related bone diseases [1-3]. In the last decades,
at least three generations of dronic acid derivatives appeared (Aminomethylene)bisphosphonates may be prepared in
[4].
different ways [5]. One of the most convenient and widespread
methods is the three-component condensation involving an
(Aminomethylene)bisphosphonic acid derivatives are analo- amine, an orthoformate and a dialkyl phosphite. Usually,
gous species, that also have potential bioactivity in bone primary or secondary amines were reacted with an equivalent,
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Beilstein J. Org. Chem. 2016, 12, 1493–1502.
or a small excess of triethyl orthoformate and 2–7 equivalents orthoformate, in which imine-type intermediates I or II may be
of diethyl phosphite [6-21]. In most cases, the corresponding formed. The next step is the nucleophilic addition of diethyl
acids were the target molecules that were obtained by hydroly- phosphite to the C=N bond of the imines resulting in phos-
sis of the esters [15-21]. The use of crown ethers with an NH phonates III or IV, respectively. Then, the elimination of an
unit, or thienopyrimidine amines as starting materials was also amine or ethanol and the addition of another unit of diethyl
reported [22,23]. The catalyst- and solvent-free methods re- phosphite may lead to (aminomethylene)bisphosphonates (VI).
quired long reaction times and/or a high temperature [6-14,21- If the amine is in predominance over the phosphite in the
23]. Ionic liquids and a few catalysts were also tried out [24- reaction, the pathway A is more likely, but if the phosphite is
27], and the synthesis was also described under microwave used in excess, the pathway B comes to the fore.
(MW) irradiation [28-32]. However, most of the MW-assisted
syntheses were performed in kitchen ovens [28-30], hence these There are other possibilities to synthesize (aminomethylene)bis-
results cannot be reproduced.
phosphonates, such as by the reaction of dimethylformamide
diethyl acetal with diethyl phosphite (Scheme 2a) [33], by the
The mechanism of the three-component condensation has been condensation of formamides and diethyl phosphite using 2,6-di-
investigated by the research group of Krutikov and Kafarski tert-butyl-4-methylpyridine (DTBMP) as the base, and
[6,7]. A detailed proposal is shown in Scheme 1 [7]. The first trifluoromethanesulfonic anhydride (Tf2O) as the catalyst
step of the condensation is the reaction of the amine with the (Scheme 2b) [34], or by the reaction of isonitriles with triethyl
phosphite (Scheme 2c) [35,36]. (Aminomethylene)bisphospho-
nates can also be obtained starting from amides, triethyl phos-
phite and phosphorus oxychloride (Scheme 3a) [37], or in the
reaction of amines with diazophosphonate in the presence of a
rhodium catalyst (Scheme 3b) [38].
Scheme 2: Synthetic methods for (aminomethylene)bisphosphonates
I.
(Aminomethylene)bisphosphine oxides are analogous to
(aminomethylene)bisphosphonates, but they are much less
studied. Only a few publications were found, which focus on
their synthesis [33,39-42], however, a three-component conden-
sation has not been described. They can also be prepared
starting from dimethylformamide dimethyl acetal, as in the syn-
thesis of (aminomethylene)bisphosphonates, but in the latter
Scheme 1: Proposed routes for the three-component condensation
[7].
case a secondary phosphine oxide is the P-reagent [33,39]. In
addition, (aminomethylene)bisphosphine oxides can be synthe-
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Beilstein J. Org. Chem. 2016, 12, 1493–1502.
Scheme 3: Synthetic methods for (aminomethylene)bisphosphonates II.
sized by the reaction of two molecules of (dialkylamino)(di- phine oxide, and we aimed at the preparation of new deriva-
phenylphosphinoyl)chloromethane (Scheme 4a) [40,41], or by tives.
the addition of diphenylphosphine oxide to an isonitrile
Results and Discussion
(Scheme 4b) [36,42].
Synthesis of alkylamino- and (phenylamino-
methylene)bisphosphine oxides
In the first series of experiments, the condensation of primary
amines, such as butyl-, cyclohexyl- and benzylamine or aniline
with triethyl orthoformate, and 2 equivalents of diphenylphos-
phine oxide at 150 °C for 1 h under MW conditions was studied
(Scheme 5). To avoid the formation of by-products, benzyl-
amine was reacted at a lower temperature of 125 °C (Table 1,
entry 3). The reactions were carried out without any catalyst
and solvent. After column chromatography, the new amino-
methylenebisphosphine oxides 1a–d were obtained in yields of
72–82% (Table 1, entries 1–4).
Table 1: Synthesis of alkylamino- and (phenylaminomethylene)bispho-
sphine oxides 1a–d.
Scheme 4: Synthetic methods for (aminomethylene)bisphosphine
oxides.
Entry
Y
T (°C)
Yield (%)a
1
2
3
4
Bu
c-Hex
Bn
150
150
82 (1a)
79 (1b)
72 (1c)
80 (1d)
In this paper, we wish to report the results of our investigations
on the synthetic protocol utilizing the three-component conden-
sations of primary or secondary amines, orthoformates and
>P(O)H species, such as dialkyl phosphites or diphenylphos-
125b
150
Ph
aIsolated yield. bAt 150 °C by-products were formed.
Scheme 5: Synthesis of alkylamino- and (phenylaminomethylene)bisphosphine oxides.
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Beilstein J. Org. Chem. 2016, 12, 1493–1502.
The condensation of simple secondary amines (diethyl-, tion of butylamine, triethyl orthoformate with 2 equivalents of
dibutyl-, N-butylmethyl-, N-cyclohexylmethyl-, N-benzyl- diethyl phosphite was studied at 125 °C. After a 2 h’s reaction
methylamine, N-methylaniline and morpholine) was also inves- time, the conversion was 91%, and beside the expected (amino-
tigated with triethyl orthoformate, and 2 equivalents of methylene)bisphosphonate 3a formed in 81%, the N-ethylated
diphenylphosphine oxide (Scheme 6, Table 2). The by-product 4a was formed in 19% (Table 3, entry 1). Increas-
MW-assisted reactions were performed at 150 °C for 1 h under ing the temperature to 150 °C, the reaction was
solvent- and catalyst-free conditions, and the (dialkyl-amino- completed after 30 min, but the proportion of the main product
methylene)bisphosphine oxides 2a–g were obtained in yields of 3a was somewhat lower (78%), and another by-product 5a also
60–85% after column chromatography (Table 2, entries 1–7). appeared in 7% (Table 3, entry 2). The target compound 3a
Except for compound 2g, all (aminomethylene)bisphosphine could be obtained in a yield of 61%. Using 3.5 equivalents of
oxides (2a–f) prepared are new compounds. According to the diethyl phosphite at 125 °C for 1 h, the conversion was only
literature method [41], 2g was synthesized by the reaction of 75%, but the expected product 3a was formed exclusively
two molecules of (diphenylphosphinoyl)morpholino- (Table 3, entry 3). After a longer reaction time of 1.5 h,
chloromethane in the presence of chloroform at 5 °C for 18 h in by-product 4a also appeared in 22% (Table 3, entry 4). In the
a yield of 41% (Scheme 4a). Using the MW-assisted three- reaction with cyclohexylamine, the same tendency was ob-
component condensation method, this compound (2g) can be served (Table 3, entries 5–8), and the corresponding (cyclo-
synthesized without any catalyst and solvent in a short time hexylaminomethylene)bisphosphonate 3b was obtained in a
(1 h), and in a yield of 85% (Table 2, entry 7).
yield of 68% after column chromatography (Table 3, entry 6).
Finally, the three-component condensation of aniline, triethyl
orthoformate and diethyl phosphite was studied (Table 3,
entries 9–11). Applying 2 equivalents of phosphite, the reaction
was not complete, neither at 125 °C, nor at 150 °C (Table 3,
entries 9 and 10). Two types of imine intermediates (6a and 6b)
could be observed in the reaction mixture beside the expected
product 3c. These intermediates refer to the mechanism of the
condensation (see compounds I and V in Scheme 1, pathway
A). Previously, iminephosphonate 6b was only an assumed
intermediate [7], but now we could prove it by 31P NMR and
HRMS (Table 4). Increasing the amount of diethyl phosphite to
3 equivalents, the reaction was complete at 125 °C after 1 h, and
only 3c was formed with a yield of 82% (Table 3, entry 11). In
the cases discussed, no ethylated or formylated by-products (4
and 5, respectively) were formed. (Aminomethylene)bisphos-
phonates 3b and 3c were synthesized earlier in unoptimized ex-
Table 2: Synthesis of (dialkylaminomethylene)bisphosphine oxides
2a–g.
Entry
Y1
Y2
Yield (%)a
1
2
3
4
5
6
7
Et
Bu
Et
82 (2a)
73 (2b)
69 (2c)
66 (2d)
64 (2e)
60 (2f)
85 (2g)
Bu
Me
Me
Me
Me
Bu
c-Hex
Bn
Ph
-(CH2)2-O-(CH2)2-
aIsolated yield.
Synthesis of alkylamino- and (phenylamino-
methylene)bisphosphonates
In the next stage, our method was extended to the synthesis of periments to provide compounds 3b and 3c in yields of 36% [9]
alkyl- and (phenylaminomethylene)bisphosphonates by reacting and 53% [8], respectively. The former compound 3b was
butyl- and cyclohexylamine or aniline, and triethyl orthofor- characterized only by 1H NMR [9]. Compound 3c was also syn-
mate with diethyl phosphite under MW irradiation in the thesized under MW irradiation in a yield of 75% [31]. It can be
absence of catalyst and solvent (Table 3). First, the condensa- seen, that the refined MW-assisted method elaborated by us
Scheme 6: Synthesis of (dialkylaminomethylene)bisphosphine oxides.
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Beilstein J. Org. Chem. 2016, 12, 1493–1502.
Table 3: The reactions of primary amines with triethyl orthoformate and diethyl phosphite.
Entry
Y
DEP
(equiv)
T (°C)
t (h)
Conversion
(%)a
Product composition (%)a
Yield of 3
(%)c
3
by-productsb
4
5
1
2
Bu
Bu
2
2
125
150
125
125
125
150
125
125
125
150
125
2
0.5
1
91
100
75
81
78
19
15
0
0
7
0
0
0
2
0
0
0
0
0
–
61 (3a)
3
Bu
3.5
3.5
2
100
78
–
4
Bu
1.5
2
90
22
17
10
0
–
–
5
c-Hex
c-Hex
c-Hex
c-Hex
Ph
76
83
6
2
0.5
1
100
63
88
68 (3b)
–
7
3.5
3.5
2
100
86
8
1.5
2
83
14
0
–
9
68
56d
70d
100
36 (3c)
52 (3c)
82 (3c)
10
11
Ph
2
1
90
0
Ph
3
1
100
0
aOn the basis of GC (entries 1–8) or on the basis of HPLC (entries 9–11). bThe by-products identified:
cIsolated yield. dThe following intermediates were also formed based on LC–MS:
Table 4: Spectral characterization of N-ethyl- (4) and N-formyl- (5) (aminomethylene)bisphosphonates and imine-type intermediates 6a and 6b.
Compounds
δP in CDCl3
δP [lit.]
[M + H]+found
[M + H]+requires
4a
4b
19.98
20.63
–
–
388.2020
414.2162
388.2012
414.2169
16.08 and 16.16
(E and Z isomers)
15.69 and 15.98a
(E and Z isomers) [43]
5a
5b
388.1659
414.1797
388.1649
414.1805
16.00 and 16.06
(E and Z isomers)
–
6a
6b
–
–
–
197.1075
242.0936
197.1073
242.0941
17.67
aIn CCl4.
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Beilstein J. Org. Chem. 2016, 12, 1493–1502.
may give the (aminomethylene)bisphosphonates 3b and 3c in
Table 5: Synthesis of (dialkylaminomethylene)bisphosphonates 8a–g.
yields of 68% and 82%, respectively.
Entry
Y1
Y2
Yield (%)a
Next, the condensation of aniline with trimethyl orthoformate
and dimethyl phosphite was also performed (Scheme 7). In this
case, the reaction was complete after a 1 h heating at 110 °C
using 3.5 equivalents of dimethyl phosphite. After column chro-
matography, the corresponding product 7a was isolated in a
yield of 63%. At higher temperatures, decomposition was ob-
served.
1
2
Et
Bu
Et
86 (8a)
68 (8b)
79 (8c)
72 (8d)
70 (8e)b
65 (8f)
Bu
Me
Me
Me
Me
3
Bu
4
c-Hex
Bn
5
6c
7
Ph
-(CH2)2-O-(CH2)2-
81 (8g)d
aIsolated yield. bIt was synthesized in a yield of 61% [10]. c4.5 equiva-
lents of diethyl phosphonate was used.dIt was synthesized in a yield of
46% [4].
In the next stage, the MW-assisted reaction of secondary amines
was studied with triethyl orthoformate and diethyl phosphite
(Scheme 8). The condensations were carried out applying
3.5 equivalents of diethyl phosphite at 125 °C for 1 h in the
absence of a catalyst and a solvent. In case of N-methylaniline, (aminomethylene)bisphosphonates (9–11 and 3c) were also
4.5 equivalents of the P-reagent was necessary to attain formed beside the expected (phenylaminomethylene)bisphos-
complete conversion (Table 5, entry 6). The corresponding phonates 7a or 7b (Table 6,entries 1 and 6, 7). The transesteri-
(dialkylaminomethylene)bisphosphonates (8a–g) were obtained fied by-products (9-11 and 3c) were indentified by GC–MS
in yields of 65–86% after purification by chromatography (Figure 2) or LC–MS, and were proved by HRMS (Table 7).
(Table 5, entries 1–7).
The composition of the reaction mixture for the experiment
marked by Table 6, entry 6 was analyzed by 31P NMR (see
Finally, the three-component condensation of aniline, triethyl Figure 3). It was observed that increasing the quantity of dialkyl
orthoformate and dimethyl or dibutyl phosphite was studied phosphite, the proportion of the by-products was decreased, and
(Table 6, Figure 1). Using dimethyl phosphite, the reactions the condensations became more selective for the desired
were performed at 110 °C for 1 h, but in case of dibutyl phos- product (7a or 7b) (Table 6, Figure 1). In the reaction with
phite, the conditions applied were the same as those in the con- dimethyl phosphite, the best result was achieved using
densations with diethyl phosphite (125–150 °C, 1 h). Using 20 equivalents of the P-reagent, but in case of dibutyl phosphite,
2 equivalents of dialkyl phosphite, more or less transesterified a 15-fold excess was sufficient (Table 6, entries 5 and 10).
Scheme 7: Synthesis of tetramethyl (phenylaminomethylene)bisphosphonate.
Scheme 8: Synthesis of (dialkylaminomethylene)bisphosphonates.
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Beilstein J. Org. Chem. 2016, 12, 1493–1502.
Table 6: Condensation of aniline, triethyl orthoformate and dimethyl or dibutyl phosphite.
Entry
R
Dialkyl phosphite (equiv)
T (°C)
Product composition (%)a
7
9
10
11
3c
1
2
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bu
2
6
110
110
110
110
110
150
125
125
125
125
14
54
77
87
91
19
54
82
93
95
36
37
18
13
9
36
9
11
0
3
0
0
0
0
3
0
0
0
0
3
10
15
20b
2
5
0
4
0
0
5
0
0
6
23
33
16
7
29
10
2
26
3
7
2
8
6
0
9
10
15b
0
0
10
5
0
0
aOn the basis of GC (entries 1–5) or on the basis of HPLC (entries 6–9). bThe product composition has not changed using a larger excess of dialkyl
phosphite.
Figure 1: Effect of the quantity of dimethyl phosphite (DMP) on the product composition (from Table 6, entries 1–5.)
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Beilstein J. Org. Chem. 2016, 12, 1493–1502.
Figure 2: GC–MS chromatogram for the condensation of aniline, triethyl orthoformate and 2 equivalents of dimethyl phosphite (from the exp. marked
by Table 6, entry 1).
Figure 3: 31P NMR spectrum for the condensation of aniline, triethyl orthoformate and 2 equivalents of dibutyl phosphite (from the exp. marked by
Table 6, entry 6).
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Beilstein J. Org. Chem. 2016, 12, 1493–1502.
Table 7: Mass spectral characterization of (aminomethylene)bisphosphonates.
R = Me (b)
R = Bu (c)
[M + H]+found
[M + H]+requires
[M + H]+found
[M + H]+requires
7
324.0760
338.0921
352.1072
366.1231
380.1382
324.0760
338.0917
352.1073
366.1230
380.1386
492.2648
464.2329
436.2011
408.1711
380.1382
492.2638
464.2325
436.2012
408.1699
380.1386
9
10
11
3c
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Keglevich, G. Mini-Rev. Med. Chem. 2012, 12, 313–325.
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Conclusion
In summary, we have developed a facile, solvent- and catalyst-
free MW-assisted method for the synthesis of (amino-
methylene)bisphosphine oxides (AMBPOs) and (amino-
methylene)bisphosphonates by the condensation of a primary or
secondary amine, an orthoformate, and diphenylphosphine
oxide or a dialkyl phosphite. This method is a novel approach
for the preparation of AMBPOs and an optimized process for
the synthesis of (aminomethylene)bisphosphonates. Twenty-
two derivatives were isolated and characterized, except two, all
of them are new compounds. Furthermore, a few intermediates
supporting the mechanism of the condensation, and several
by-products were also identified.
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Supporting Information
Experimental procedures, characterization data, details of
the NMR structural determination of all products and
copies of 31P, 1H, and 13C NMR spectra for all compounds
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Acknowledgements
The above project was supported by the Hungarian Scientific
Research Fund (PD111895) and the Hungarian Research
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