The formation of dimethyl amino(pyrene-1-yl)methylphosphonates in the Kabachnik-Fields reaction with dibenzyl phosphite, pyrene-1-carboxaldehyde and a non-aromatic amine in methanol

Article abstract of DOI:10.1080/10426507.2017.1308932

The Kabachnik-Fields reaction of pyrene-1-carboxaldehyde with dibenzyl phosphite and aliphatic amines in methanol led to the formation of dimethyl amino(pyren-1-yl)methyl-phosphonates, in some cases accompanied by dimethyl hydroxy(pyren-1-yl)methyl-phosphonate. These results are exclusive for the above compounds, in all other studied cases (aromatic aldehydes, aromatic amines) the mixtures of several aminophosphonates were obtained.

Full text of DOI:10.1080/10426507.2017.1308932

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
The formation of dimethyl amino(pyrene-1-
yl)methylphosphonates in the Kabachnik-Fields
reaction with dibenzyl phosphite, pyrene-1-
carboxaldehyde and a non-aromatic amine in
methanol
Jarosław Lewkowski & Maria Rodriguez Moya
To cite this article: Jarosław Lewkowski & Maria Rodriguez Moya (2017): The formation of
dimethyl amino(pyrene-1-yl)methylphosphonates in the Kabachnik-Fields reaction with dibenzyl
phosphite, pyrene-1-carboxaldehyde and a non-aromatic amine in methanol, Phosphorus, Sulfur,
and Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1308932
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1308932
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Mar 2017.
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Date: 26 March 2017, At: 07:26

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Transesterification of Dibenzyl Phosphite in Methanol
The formation of dimethyl amino(pyrene-1-yl)methylphosphonates in the
Kabachnik-Fields reaction with dibenzyl phosphite, pyrene-1-carboxaldehyde and
a non-aromatic amine in methanol.
Jarosław Lewkowski* and Maria Rodriguez Moya
Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12,
91-403 Łódź, Poland.
E-mail: jlewkow@uni.lodz.pl
In memoriam of Professor Harry R. Hudson
ABSTRACT
The Kabachnik-Fields reaction of pyrene-1-carboxaldehyde with dibenzyl phosphite and
aliphatic amines in methanol led to the formation of dimethyl amino(pyren-1-yl)methyl-
phosphonates, in some cases accompanied by dimethyl hydroxy(pyren-1-yl)methyl-
phosphonate. These results are exclusive for the above compounds, in all other studied
cases (aromatic aldehydes, aromatic amines) the mixtures of several
aminophosphonates were obtained.
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Keywords
Transesterification, pyrene-1-carboxaldehyde, Kabachnik-Fields reaction, dibenzyl
phosphite
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INTRODUCTION
The study of aminophosphonic acids is one of the most explored branches of organic
chemistry. In the late 40’s, Chavanne1 synthesized the first phosphonic analog of
glycine, which gave rise to the beginning for aminophosphonic derivatives but the great
boom for these compounds started after the discovery of herbicidal properties of
glyphosate.2 Scientists used to synthesize newer and newer phosphonic analogs of
known amino acids in hope to find the one having herbicidal properties similar to or
even better than glyphosate.3
The classical methodology for their synthesis, elaborated by Kabachnik4 and Fields5
known as the Kabachnik-Fields reaction, has been improved and discussed a thousand
of times.6-13 Simultaneously, the alternative method has been worked out14,15 and its
inventor’s name was immortalized too – the method is called today the aza-Pudovik
reaction.
Despite the enormous number of scientific papers describing the synthesis of
aminophosphonic acids and their esters, there is still a lot of unknown, which waits to be
discovered.
It is commonly known that for any reaction of phosphonic acid ester that is carried out in
alcohol, one should use the alcohol with alkyl group the same as in ester. Otherwise,
such a modus operandi could lead to the mixture of at least three possible
phosphonates as products of the partial transesterification. Such a problem is
encountered also in a case of aminophosphonic acid esters, that is why chemists, e.g.
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Gancarz16 stressed that the synthesis of diethyl aminophosphonates should be carried
out in ethanol.
Accidental transesterification of phosphoric acid derivatives was reported once to our
knowledge – it was described 60 years ago by Li and Eakin.17. The reaction occurred by
accident during the attempts to convert N-dibenzylphosphoryl amino acid esters into
their corresponding amides with ammonia in methanol. Instead of the desired product,
the authors obtained N-dimethylphosphoryl amino acid amides, where ammonia played
a double role, the amidation reagent and the basic catalyst of transesterification. Much
more recent examples of the phosphonic group transesterification have been described
by Keglevich et al.18,19 They reported18 the Kabachnik-Fields reaction of aniline, ethyl
orthoformate and dimethyl (or dibutyl) phosphite, which led to the mixture of ethyl-
methyl (or ethyl-butyl) bis-phosphonates. The same team published several examples
of the alcoholysis of dialkyl phosphites under microwave conditions, which resulted in
the formation of mixed derivatives as well as products of full transesterification.19
RESULTS AND DISCUSSION
Undoubtedly, curiosity is the driving force for many discoveries. Being motivated by
curiosity, we wanted to know, what would happen, if the Kabachnik-Fields reaction of
1-propylamine, dibenzyl phosphite and pyrene-1-carboxaldehyde was carried out in
methanol. Do we obtain dibenzyl N-(1-propyl)amino(pyren-1-yl)methylphosphonate or
the mixture of dimethyl, dibenzyl and monomethyl or monobenzyl phosphonates? Or
maybe, O-benzyl, O-methyl mixed phosphonic acid ester?
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To our surprise, the reaction provided exclusively one product: dimethyl
N-(1-propyl)amino(pyren-1-yl)methylphosphonate (1Aa), so the transesterification
occurred practically in 100%. (Scheme 1, Figure 1, Figure S 1 in Supplemental
Materials) The isolated product was compared to an authentic sample prepared
previously.20 To exclude artifactual nature of our finding, we repeated the reaction three
time obtaining the same results.
1
On the Figure 1, spectra of the pyrene-derived aminophosphonate 1Aa with H NMR
13
signals assigned to corresponding protons of a pyrene ring are presented. Scans of C
NMR spectra of 1Aa are presented at Figure S 1 in Supplemental Materials The full
spectral analysis of the selected pyrene-derived aminophosphonates is the subject of a
separate paper.21 Similar analysis was reported by Hägele22 for diethyl
N-(benzhydryl)amino(pyren-1-yl)methylphosphonate.
In order to have a closer look at the phenomenon, we investigated the above reaction
using a variety of amines. The mixture of dibenzyl phosphite and 1-pyrene-
carboxaldehyde in methanol with t-butylamine converted exclusively into dimethyl
N-t-butylamino(pyren-1-yl)methylphosphonate (1Ac), so we observed the same
tendency as in a case of n-propylamine. (Table 1) (see spectra at Figure S 2 in
Supplemental Materials)
However, when the same reaction was carried out with 1-butylamine, it led to the
formation of a mixture of dimethyl N-1-butylamino(pyren-1-yl)methylphosphonate (1Ab)
and dimethyl hydroxy(pyren-1-yl)methylphosphonate (2A) in a 100:88 ratio,
respectively. (Table 1) (Figure S 3 in Supplemental Materials) We investigated also the
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reaction with two other aliphatic amines: cyclohexylamine and benzylamine. In both
cases, we identified exclusively two corresponding products: the dimethyl
aminophosphonate and the dimethyl hydroxyphosphonate. In the case of
cyclohexylamine, dimethyl N-cyclohexylamino(pyren-1-yl)methylphosphonate (1Ad) and
dimethyl hydroxy(pyren-1-yl)methylphosphonate (2A) formed in a 100:30 ratio, while in
a second case, the ratio of dimethyl N-benzylamino-(pyren-1-yl)methylphosphonate
(1Ae) and dimethyl hydroxy(pyren-1-yl)methyl-phosphonate (2A) was 100:10. (Table 1)
(Figure S 4-S 5 in Supplemental Materials) Dibenzyl aminophosphonate was not
detected in the post-reaction mixture. As previously, isolated products 1Ab-e and 2A
were identified by comparison to samples prepared previously.20
The phenomenon of hydroxyphosphonate formation as a byproduct of the Kabachnik-
Fields reaction of pyrene-1-carboxaldehyde was described and discussed in the
previous paper.20
The reaction with m-toluidine led to the mixture consisting of four aminophosphonic
products: dimethyl N-(3-methylphenyl)-amino(pyren-1-yl)methylphosphonate (1Af),
monobenzyl (4Af) and monomethyl N-(3-methylphenyl)-amino(pyren-1-yl)methyl-
phosphonate
(5Af)
and
dibenzyl
N-(3-methylphenyl)amino(pyren-1-
yl)methylphosphonate (3Af) in a 9:39:29:100 ratio respectively, as shown by
multinuclear NMR experiments. So, the presence of aromatic amine forced the different
course of the reaction. (Scheme 2, Figure S 6 in Supplemental Materials)
The above results tend us to the statement, that the Kabachnik-Fields reaction of
pyrene-1-carboxaldehyde and dibenzyl phosphite with aliphatic amine in methanol leads
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either exclusively to dimethyl aminophosphonate, or to its mixture with dimethyl
hydroxyphosphonate; the formation of dibenzyl aminophosphonate was not observed.
In order to verify, if such tendency is of a more general nature, we investigated the
reactions of dibenzyl phosphite and 1-propylamine with various aromatic and
heteroaromatic aldehydes in methanol. Propylamine was chosen, since it provided the
most spectacular results with pyrene-1-carboxaldehyde.
The reaction with furfural gave a 100:100:15:15 ratio of four phosphonic products.
Dimethyl
N-1-propylamino(2-furyl)methylphosphonate
(1Ba)
and
dibenzyl
N-1-propylamino(2-furyl)methylphosphonate (3Ba) were identified by the NMR
spectroscopy. Two other products remained unidentified but, most probably they are
monobenzyl and monomethyl aminophosphonates 4Ba and 5Ba. (Scheme 2, Figure S
7 in Supplemental Materials)
The reaction with thiophene-2-carboxaldehyde gave four aminophosphonic products (in
a 1:1:2:1 ratio), but only dimethyl N-1-propylamino(2-thienyl)methylphosphonate (1Ca)
was identified using the NMR spectroscopy. (Scheme 2, Figure S 8 in Supplemental
Materials)
More complex mixture was formed in a course of the reaction with p-anisaldehyde.
From among seven unidentified products, dimethyl N-1-propylamino(4-methoxyphenyl)-
methylphosphonate (1Da) was identified by NMR spectroscopy. (Figure S 9 in
Supplemental Materials)
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The reaction with benzaldehyde led to the formation of an unresolved mixture of five
products in a 7:100:50:48:22 ratio. We were not able to separate the products and,
therefore they remained unidentified. (Figure S 10 in Supplemental Materials)
So, the above-described phenomenon seems to be characteristic only for the
Kabachnik-Fields reaction with pyrene-1-carboxaldehyde.
The question arises, why the aliphatic amine is indispensable for the reaction with
pyrene-1-carboxaldehyde to obtain exclusively dimethyl phosphonic ester moieties? In
order to answer the question, one should consider the mechanism of the reaction. We
assumed that first, the dibenzyl phosphite molecule undergoes the reaction with
methanol, catalyzed by an amine, then the formed dimethyl phosphite enters the
Kabachnik-Fields reaction. Transesterification of a dibenzylphosphoryl moiety in
methanol and catalyzed by ammonia was described by Li and Eakin,17 which we
discuss in the introductory part.
The possibility that this reaction resulted from the transesterification of the formed
dibenzyl α-aminomethylphosphonates was excluded; heating of dibenzyl N-(4-
methylphenyl)amino(pyren-2-yl)methylphosphonate in methanol for 1 hour did not show
any slight evidence of the reaction– the substrate remained untouched. (Figure S 13 in
Supplemental Materials)
In order to confirm the hypothesis, we launched two simple experiments. In the first, the
stochiometric amount of dibenzyl phosphite (6) was mixed with methanol and
1
propylamine and the mixture was heated. After 2 min, H and 31P NMR spectra of the
mixture were recorded. Spectra showed that it contained dimethyl phosphite (7) (P =
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10.58 ppm, 29.1%), methyl phosphite (8) (P = 9.17 ppm, 34.0%), dibenzyl phosphite (6)
(P = 7.72 ppm, 11.4%), benzyl phosphite (9) (P = 6.42 ppm, 25.5%). The compounds
31
mentioned above were identified by comparison to literature data of P NMR for methyl
phosphite (P = 9.4-9.1 ppm23 or P = 8.79 ppm24) and benzyl phosphite (P = 6.91
31
ppm25). Dimethyl and dibenzyl phosphites were identified easily by comparison with P
NMR of commercial samples (Aldrich): dimethyl phosphite P = 10.48 ppm and dibenzyl
phosphite P = 7.68 ppm. (Scheme 3, Figure 2)
In the second experiment, the stochiometric amount of dibenzyl phosphite was mixed
with methanol and m-toluidine and the mixture was worked up and analyzed identically.
Spectra showed that the reaction did not occur, as the post-reaction mixture contained
exclusively dibenzyl phosphite (6) (P = 7.80 ppm). (Scheme 3, Figure 2)
1
31
After 20 min, H and P NMR spectra of the reaction with propylamine were recorded.
Spectra showed that it contained dimethyl phosphite (7) (P = 10.58 ppm, 52.8%),
methyl phosphite (8) (P = 9.17 ppm, 20%), dibenzyl phosphite (6) (P = 7.72 ppm,
3.6%), benzyl phosphite (9) (P = 6.62 ppm, 18%) and phosphorous acid (P = 4.58
ppm, 4.2%, lit.P = 4.37 ppm26). Four unidentified products constituted the rest 1.4%
(Figure S 11 in Supplemental Materials).
After 20 min of the reaction with m-toluidine, the spectra demonstrated the similar; the
post-reaction mixture contained dimethyl phosphite (7) (P = 10.75 ppm, 51.4%), methyl
phosphite (8) (P = 9.29 ppm, 21,4%), dibenzyl phosphite (6) (P = 7.80 ppm, 1.9%),
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benzyl phosphite (9) (P = 6.78 ppm, 20,3%) and phosphorous acid (P = 4.70 ppm,
5%). (Figure S 12 in Supplemental Materials).
The described above results prompted us to excogitate the following hypothetical
mechanism. During the first 2 min of the Kabachnik-Fields reaction of an aldehyde,
1-propylamine and dibenzyl phosphite, the latter reacts first with methanol giving four
detected phosphites 6-9. Furfural (B), thiophene-2-carboxaldehyde (C), benzaldehyde
(D) and anisaldehyde (E) react with all present phosphites with more or less similar
probability. Thus, the Kabachnik-Fields reaction with these aldehydes leads to the
formation of a variety of products. Pyrene-1-carboxaldehyde (A) seems to be not a
strong nucleophile and that is why it reacts with a strongly nucleophilic dimethyl
phosphite more easily than with dibenzyl phosphite, which is a weaker nucleophile.
Sterical reasons cannot be excluded either. Likely, the weaker electrophilicity and bulky
hydrocarbon moiety of pyrene-1-carboxaldehyde is the reason for its smaller affinity to
dibenzyl phosphite in the reaction.
The consumption of dimethyl phosphite, causes the further conversion of dibenzyl one
to give the dimethyl phosphite. In such a way, only dimethyl amino- and (if appropriate)
hydroxyphosphonates are formed.
During first two min of the Kabachnik-Fields reaction with pyrene-1-carboxaldehyde,
dibenzyl phosphite and m-toluidine, dibenzyl phosphite does not react with methanol,
therefore the reaction leads first to dibenzyl N-(3-methylphenyl)amino(pyren-1-
yl)methylphosphonate (3Af). In the measure of time, the reaction of dibenzyl phosphite
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with methanol occurs, which results in the formation of other observed
aminophosphonates 1Af, 4Af and 5Af.
CONCLUSIONS
In summary, we have found, that the Kabachnik-Fields reaction of pyrene-1-
carboxaldehyde with dibenzyl phosphite and an aliphatic amine in methanol, led to the
exclusive formation of dimethyl amino(pyren-1-yl)methylphosphonate, in several cases
accompanied by dimethyl hydroxy(pyren-1-yl)methylphosphonate with no trace of
phosphonic acid benzyl ester. Similar reactions with aromatic amines gave mixtures of
several phosphonic products. The reaction is characteristic for pyren-1-yl derivative, as
1-propylamine reacting in the same conditions with a variety of aromatic aldehydes
(furfural, thiophene-2-carboxaldehyde, benzaldehyde, anisaldehyde) resulted in the
mixture of several aminophosphonates and/or hydroxyphosphonates. Further studies
relating to the chemistry of amino(pyren-1-yl)methylphosphonic derivatives will be
reported in due course.
EXPERIMENTAL
Methanol was routinely distilled and dried prior to use. Aldehydes, amines and dibenzyl
phosphite (Aldrich, Poland, Poznań) were used as received. NMR spectra were
recorded on a Bruker Avance III 600 MHz apparatus (Billerica, MA, USA) operating at
600 MHz (1HNMR), 150 MHz (13C NMR) and 243 MHz (31P NMR).
General procedure for the Kabachnik-Fields reaction: 1 mmol of aldehyde (A: 0.230 g,
B: 0.096 g, C: 0.112 g, D: 0.106 g, E: 0.136 g), 1 mmol of amine (a: 0.059 g, b: 0.073 g,
c: 0.073 g, d: 0.099 g, e: 0.107 g, f: 0.107 g) and dibenzyl phosphite (1mmol, 0.262 g)
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were dissolved in a small amount of dry methanol (0,5 ml). The mixture was stirred and
heated at 60°C for 24h (1Aa, 1Ad-f) or 48h (1Ab-c, 1Ba-Ea) and then, the solvent was
removed under reduced pressure to obtain a yellow solid or yellow oil. Products were
then separated by column chromatography on silica gel with chloroform as eluent.
Compounds 1Aa-e and 2A were isolated and compared to previously prepared and
published authentic samples.20 All spectral data of compounds 1Aa-e are collected in
our previous paper. 20
Dimethyl N-(1-propyl)amino(pyren-1-yl)methylphosphonate (1Aa)20
1H NMR (CDCl3, 600 MHz):  8.42-8.41 (m, Hpyr, 1H); 8.36 (dd, 3JHH = 8.0 and 4JHH = 2.0
Hz, Hpyr, 1H); 8.25 (d, 3JHH = 8.0 Hz, Hpyr, 2H); 8.20 (d, 3JHH = 7.6 Hz, Hpyr, 2H); 8.15 (d,
3JHH = 8.1 Hz, Hpyr, 1H); 8.10-8.06 (m, Hpyr, 2H); 8.02 (t, 3JHH = 7.6 Hz, Hpyr, 1H); 5.28 (d,
3
3
2JPH = (-)20.8 Hz, CHP, 1H); 3.77 (d, JPH = 10.6 Hz, POCH3, 3H); 3.36 (d, JPH = 10.4
3
Hz, POCH3, 3H); 2.52-2.48 (m, N-CH2, 2H); 1.51-1.49 (m, CH2, 2H); 0.85 (t, JHH = 7.4
Hz, CH3, 3H). 13C NMR (150 MHz, CDCl3):  131.6 (Cpyr); 131.1 (d, 4JCP = 3.1 Hz, Cpyr);
130.9 (Cpyr); 130.0 (Cpyr); 129.9 (Cpyr); 128.1 (Cpyr); 127.8 (Cpyr); 127.7 (d, 3JPC = 1.5 Hz,
4
Cpyr); 126.2 (Cpyr); 125.9 (Cpyr); 125.6 (Cpyr); 125.4 (d, JPC = 3.0 Hz, Cpyr); 125.3 (Cpyr);
4
2
125.1 (d, JPC = 1.7 Hz, Cpyr); 125.0 (Cpyr); 122.7 (Cpyr); 53.9 (d, JPC = 7.4 Hz, POC);
53.6 (d, 2JPC = 6.7 Hz, POC); 52.2 (d, 3JPC = 16.0 Hz, PCNC); 23.2 (Caliph); 11.8 (Caliph).
31P NMR (243 MHz, CDCl3):  25.90.
Experiments on transesterification: Dibenzyl phosphite (1 mmol) and propylamine or m-
toluidine (1 mmol) were dissolved in methanol and the mixture was heated. Samples
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were taken after 2 and 20 min, solvent evaporated, the residue dissolved in chloroform-
d1 and the 31P NMR spectra were recorded.
ACKNOWLEDGEMENT
We thank the Polish National Centre of Science (NCN) for funding part of the work in
the framework of the grant no. 2014/13/B/NZ9/02418.
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Table 1. Results of the Kabachnik-Fields reaction with pyrene-1-carboxaldehyde, aliphatic
amine and dibenzyl phosphite in methanol
R1
H
R2
R3
1A[%]
2A[%]
a
b
c
d
e
H
CH2CH3
100
0
H
H
CH2CH2CH3 53
47
0
CH3
H
CH3 CH3
100
77
H
H
c-Hex
23
9
H
CH2Ph
91
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Figure 1. NMR spectra of the product of the reaction between 1-propylamine, dibenzyl
phosphite and pyrene-1-carboxaldehyde in methanol – dimethyl N-(1-propyl)amino(pyren-1-yl)-
methylphosphonate (1Aa). a), b), c) – 1H NMR, d) 31P NMR
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Figure 2. 31P NMR spectra of the reaction between dibenzyl phosphite and methanol after 2 min
catalyzed by a) 1-propylamine, b) m-toluidine.
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OMe
OMe
O
OMe
OMe
O
P
P
CHO
R1
R2
R3
OH
N
H
O
P
R2 R3
R1
MeOH
OBn
OBn
+
+
NH2
H
+
1Aa-e
2A
a: R1 = R2 = H, R3 = CH2CH3; b: R1 = R2 = H, R3 = CH2CH2CH3; c: R1 = R2 = R3 = CH3; d: R1 = R2 = H, R3 = c-Hex;
e: R1 = R2 = H, R3 = CH2Ph
Scheme 1.
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O
P
OBn
OBn
R2 NH2
R1 CHO
+
+
H
A-E
a or f
MeOH
O
O
P
O
O
OMe
OMe
OBn
OBn
OBn
OH
OMe
OH
P
P
P
R1
R1
R1
R1
NHR2
NHR2
NHR2
NHR2
1
3
4
5
A: R1 = 1-pyrenyl; B: R1 = furfuryl; C: R1 = 2-thienyl; D: R1 = phenyl; E: R1 = p-methoxyphenyl
a: R2 = n-propyl; f: R2 = 3-methylphenyl
Scheme 2
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OBn
O P H
OBn
OMe
OH OH
O P H + O P H
MeOH
+
O P H
NH2
2 min
OMe
OMe
OBn
7
8
9
OBn
O P H
OBn
MeOH
no reaction
m-toluidine
2 min
OBn
O P H
OBn
OMe
OH
O P H
OMe
OH
O P H
OBn
OH
O P H
OH
MeOH
+
+
O P H
+
NH2
or
m-toluidine
OMe
7
8
9
20 min
Scheme 3
22
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