Microwave-assisted synthesis of α-aminophosphonates with sterically demanding α-aryl substituents

Article abstract of DOI:10.1080/00397911.2019.1679186

A series of N-benzhydryl protected α-aminophosphonates with α-phenyl, α-(1-naphtyl), α-(9-anthryl) or α-(1-pyrenyl) substituents was synthesized by the Kabachnik–Fields condensation of diphenylmethylamine (benzhydrylamine), the corresponding aryl aldehyde and a dialkyl phosphite under MW irradiation. X-ray studies performed at low temperatures for a few of these α-aminophosphonates confirmed the presence of unusually short intramolecular C_α–H^δ+ ··· ^δ+H–C_peri contacts.

Full text of DOI:10.1080/00397911.2019.1679186

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Microwave-assisted synthesis of α-
aminophosphonates with sterically demanding α-
aryl substituents
Harry R. Hudson, Ádám Tajti, Erika Bálint, Mátyás Czugler, Konstantin
Karaghiosoff & György Keglevich
To cite this article: Harry R. Hudson, Ádám Tajti, Erika Bálint, Mátyás Czugler,
Konstantin Karaghiosoff & György Keglevich (2020): Microwave-assisted synthesis of α-
aminophosphonates with sterically demanding α-aryl substituents, Synthetic Communications, DOI:
10.1080/00397911.2019.1679186
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1679186
Microwave-assisted synthesis of a-aminophosphonates with
sterically demanding a-aryl substituents
a
b
b
b
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
, Matyas Czugler
Harry R. Hudson , Adam Tajti
, Erika Balint
,
Konstantin Karaghiosoffc , and Gyorgy Keglevich
b
€
b
aFaculty of Life Sciences and Computing, London Metropolitan University, London, UK; Department of
Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest,
c
€
€
Hungary; Department Chemie, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany
ABSTRACT
ARTICLE HISTORY
Received 11 September 2019
A
series of N-benzhydryl protected a-aminophosphonates with
a-phenyl, a-(1-naphtyl), a-(9-anthryl) or a-(1-pyrenyl) substituents was
synthesized by the Kabachnik–Fields condensation of diphenylme-
thylamine (benzhydrylamine), the corresponding aryl aldehyde and a
dialkyl phosphite under MW irradiation. X-ray studies performed at
low temperatures for a few of these a-aminophosphonates con-
firmed the presence of unusually short intramolecular Ca–Hdþ ꢀꢀꢀ
dþH–Cperi contacts.
KEYWORDS
a-Aminophosphonate;
crystal structure; C ꢁ Hdþ ꢀꢀꢀ
dþH ꢁ C bonds;
Kabachnik–fields reaction;
microwave; X-ray diffraction
GRAPHICAL ABSTRACT
Introduction
a-Aryl-a-aminophosphonates are the P-analogues of a-aryl-a-amino acids. They play an
important role as enzyme inhibitors, antibiotics, antiviral or anticancer agents.[1–4] The
synthesis of a-aryl-a-aminophosphonates can be carried out in two main routes: by the
Kabachnik–Fields condensation,[5–9] or by the Pudovik (aza-Pudovik) reaction.[10–13]
Although, the Pudovik addition, where a > P(O)H reagent, such as a dialkyl phosphite
is added to the C ¼ N double-bond of imines, is simpler and widely applied, the
Kabachnik–Fields condensation, in which an amine, an aldehyde or ketone and
a > P(O)H species react in a one-pot manner, is also of an increased interest. Both reac-
tion types were performed in the presence of a catalyst and/or a solvent.[14] Nowadays,
€
CONTACT Gyorgy Keglevich
gkeglevich@mail.bme.hu
Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, Budapest, 1521, Hungary.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License
(http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium,
provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

2
H. R. HUDSON ET AL.
greener accomplishments have come to the front, from which the catalyst- and solvent-
free microwave (MW)-assisted variations are to be mentioned.[14–18]
The benzhydryl group may be utilized as an N-protecting group in organic and pep-
tide chemistry.[19–21] The easy introduction and elimination of this moiety, as well as
the stability and the good crystallization properties of the products make this unit useful
for preparative chemists. Up to now, only three cases were reported for
the Kabachnik–Fields-type syntheses of a-aryl-a-aminophosphonates containing an
N-benzhydryl group.[22–24] In one case the condensation of benzhydrylamine,
1-naphthaldehyde and diethyl phosphite was carried out in the presence of montmoril-
lonite KSF catalyst in a kitchen MW oven.[22] A scandium tris(dodecylsulfate)-catalyzed
synthesis of a-aryl-a-aminophosphonates was also described, where triethyl phosphite
was applied as the P-component.[23] Benzhydrylamine was also reacted with formylben-
zoic acid and dimethyl phosphite, where 3-oxoisoindolin-1-ylphosphonate was synthe-
sized in a moderate yield.[24] In most cases, these derivatives were synthesized by the
Pudovik reaction of a-aryl imines with dialkyl phosphites,[25,26] also providing new
information on the peculiar proximity H atoms.[26]
In this paper, the synthesis of a-aryl-a-aminophosphonates by the solvent- and cata-
lyst-free Kabachnik–Fields condensation of benzhydrylamine, aromatic aldehydes and
dialkyl phosphites was revisited under MW irradiation. The investigation involved the
preparation of the dialkyl a-aryl-a-(diphenylmethylamino)methanephosphonates, and
the determination of the X-ray structures of a few of these products at low
temperatures.
Results and discussion
Kabachnik–fields reaction of benzhydrylamine, benzaldehyde and
dialkyl phosphites
The title phospha-Mannich condensation starting from benzhydrylamine, benzaldehyde
and dialkyl phosphites was performed under solvent-free microwave (MW)-assisted
conditions (Scheme 1). Using 1 equivalent of dimethyl phosphite (DMP), diethyl phos-
phite (DEP) or dibutyl phosphite (DBP) at 100 ꢂC for a reaction time of 1 h, conver-
sions of 87%, 89% and 63%, respectively, were obtained. In these cases, the imine
intermediate 2 could also be detected in the reaction mixtures. Complete conversion
required a 1.1 equivalents quantity of the dialkyl phosphites. After an irradiation of 1 h
Scheme 1. Kabachnik–Fields reaction of benzhydrylamine, benzaldehyde and dialkyl phosphites.

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SYNTHETIC COMMUNICATIONSV
3
at 100 ꢂC, the methyl and ethyl aminophosphonates (1a and 1b) were obtained in yields
of 88% and 90%, respectively. Efficient synthesis (91% yield) of the butyl product (1c)
required a reaction temperature of 120 ꢂC.
The products (1a–c) obtained after column chromatography were characterized by
1
31P, 13C and H NMR spectral data.
Kabachnik–fields reaction of benzhydrylamine, 1-naphthaldehyde and
dialkyl phosphites
A similar series of the phospha-Mannich reaction was carried out applying 1-
naphtylaldehyde as the oxo component (Scheme 2). The situation was somewhat more
complicated as in the previous case discussed above. With this sterically more hindered
aryl aldehyde, complete conversions required somewhat more forcing conditions. At the
same time, beside imine 3, the other possible intermediate, hydroxyphosphonate 5 could
be pointed out from the mixture by 31P NMR and LC-MS. Moreover, the corresponding
mixed ester-acid aminophosphonic derivative 6 was also present in the mixtures.
Experimental data are listed in Table 1. Using 1 equivalent of DMP at 100 ꢂC/1 h, the
proportion of components 3, 4, 5 and 6 was 15:67:15:3 (Table 1, entry 1). Increasing
the quantity of DMP to 1.2 equivalents, not much change could be observed (Table 1,
entry 2). However, the application of 1.5 equivalents of DMP led to a proportion of
82% of the desired aminophosphonate 4a (Table 1, entry 3). Repeating the experiment
marked by entry 1 of Table 1 at 120 ꢂC, the proportion of product 4 was almost
the same, but no imine 3 was present, while the relative quantity of the monoester by-
product (6) increased (Table 1, entry 4). Preparation of the ethyl derivative (4b) was
Scheme 2. Kabachnik–Fields reaction of benzhydrylamine, 1-naphthaldehyde and dialkyl phosphites.

4
H. R. HUDSON ET AL.
Table 1. The condensation of benzhydrylamine, 1-naphthaldehyde and dialkyl phosphites.
Product composition (%)a
DAP
(equiv.)
T
Yield of 4
Entry
R
(ꢂC)
3
4
5
6
(%)b
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Et
Et
Et
Et
1
100
100
100
120
100
120
120
120c
120
120
120
15
15
0
0
51
7
4
0
20
8
0
67
70
82
68
46
86
90
90
76
86
94
15
11
15
8
3
3
2
4
3
3
3
4
3
24
0
4
4
6
1
–
–
1.2
1.5
1
1
1
1.2
1.5
1
1.2
1.5
80 (4a)
–
–
–
84 (4b)
82 (4b)
–
9
10
11
Bu
Bu
Bu
3
3
–
3
90 (4c)
aBased on HPLC (222 nm).
bAfter column chromatography.
cIn the comparative thermal experiment, the conversion was 94%, and the mixture contained 85% of 4, 5% of 5 and
4% of 6.
O
NH P(OR)2
N
+
MW
T, t
O
O
8
7
a
b
c
Me ( ), Et ( ), Bu ( )
NH2
HP(OR)
+
+
2
no solvent
O
O
OR
HO
P(OR)2
NH
P
+
OH
9
10
Scheme 3. Kabachnik–Fields reaction of benzhydrylamine, 9-anthraldehyde and dialkyl phosphites.
more appropriate at 120 ꢂC (Table 1, entry 5 vs. entry 6). An increase in the quantity of
DEP to 1.5 equivalents was useful, as again a relative proportion of 90% of product 4b
could be attained, but without imine 3 (Table 1, entry 8). Butyl aminophosphonate 4c
was also synthesized best at 120 ꢂC for 1 h using 1.5 equivalents of DBP (Table 1,
entry 11). a-Aminophosphonates 4a, 4b and 4c were obtained in 80%, 84% and 90%
yields, respectively. Structure of the products was characterized as above. Identification
data of the imines (HRMS), as well as the a-hydroxyphosphonates and the a-amino-
phosphonate monoesters (31P NMR and HRMS) are listed in Tables S1, S2 and S3,
respectively.
Kabachnik–fields reaction of benzhydrylamine, 9-anthraldehyde and
dialkyl phosphites
9-Anthraldehyde proved to be a somewhat more hindered model in Kabachnik–Fields
reaction with benzhydrylamine and dialkyl phosphites, as only lower proportions of the

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SYNTHETIC COMMUNICATIONSV
5
Table 2. The condensation of benzhydrylamine, 9-anthraldehyde and dialkyl phosphites.
Product composition
(%)a
DAP
(equiv.)
T
T
(h)
Yield of 8
Entry
R
(ꢂC)
7
8
9
10
(%)b
1
2
3
4
5
6
7
8
Me
Me
Me
Et
Et
Et
1
100
100
100
100
120
120
120c
100
120
120
120
1
1
1
1
1
1.25
1
31
7
0
57
14
5
36
27
17
17
14
4
4
4
11
9
9
6
4
4
0
3
11
15
0
2
6
–
1.2
1.5
1
72
79
29
79
80
81
31
70
85
86
–
73 (8a)
–
1c
–
1.2
1.5
1
1
1.2
1.5
77 (8b)
78 (8b)
–
Et
0
Bu
Bu
Bu
Bu
1
58
19
0
9
10
11
1d
1.25
1
–
80 (8c)
82 (8c)
0
9
5
aBased on HPLC (222 nm).
bAfter column chromatography.
cIn the comparative thermal experiment the conversion was 91%, and the mixture contained 74% of 8, 8% of 9 and
9% of 10.
dNo change on further irradiation (t ¼ 1.25 h).
Table 3. The condensation of benzhydrylamine, 1-pyrenecarbaldehyde and dialkyl phosphites.
Product composition (%)a
T
Yield of 11
Entry
R
(ꢂC)
11
12
13
(%)b
1
2
3
Me
Et
Bu
100
120
120
70
84
91
6
3
2
24
13
7
68 (11a)
80 (11b)
88 (11c)
aBased on HPLC.
bAfter column chromatography.
corresponding a-aminophosphonates (8a–c) could be obtained. The same type of by-
products, a-hydroxyphosphonate 9, and monoester 10 could be found in the mixtures
(Scheme 3 and Table 2). As can be seen from the data, the conditions explored in the
previous sets of experiments were proved to be the most suitable also for the prepar-
ation of the anthryl-substituted aminophosphonates 8a–c. The methyl-, ethyl- and butyl
esters could be prepared in yields of 73%, 78% and 82%, respectively (Table 3, entries 3,
7 and 11, respectively).
Kabachnik–fields reaction of benzhydrylamine, 1-pyrenecarbaldehyde and
dialkyl phosphites
The phospha-Mannich condensations of 1-pyrenecarbaldehyde, benzhydrylamine and
dialkyl phosphites were performed at the conditions found suitable in the previous
experiments suggesting 1.5 equivalents of the dialkyl phosphite and 100–120 ꢂC
(Scheme 4, Table 3). In these cases, no unreacted imine remained in the mixture, and
the corresponding a-aminophosphonates 11a–c were obtained in yields of 68%, 80%
and 88%, respectively (Table 3, entries 1–3).
A few of the reactions were also carried out on conventional heating. Based
on our results, the MW-assisted variations reached somewhat (by <10%) higher con-
versions as compared to the control experiments (see footnote “c” of Tables 1
and 2).

6
H. R. HUDSON ET AL.
Scheme 4. Kabachnik–Fields reaction of benzhydrylamine, 1-pyrenecarbaldehyde and dia-
lkyl phosphites.
Altogether 12 a-aminophosphonates (1a–c, 4a–c, 8a–c and 11a–c) were prepared and
1
characterized by 31P, 13C and H NMR spectroscopy, as well as by HRMS data. Apart
from the four ethyl esters (1b, 4b, 8b and 11b), all derivatives are new.
X-ray diffraction study of the ethyl a-aryl-a-aminophosphonates
Results of the redetermination of the crystal structures of three ethyl a-aminophospho-
nates 4b, 8b and 11b at low temperatures (c.f. Table S4) can be summarized as leading
to the same dimensions and conclusions as from those from the earlier, mostly room-
temperature structure determinations.[24] Neither phase transitions nor any relevant
changes occur in the 173–295 K temperature range for 4b, 8b and 11b. As a measure of
the similarity of these three pairs of independent structures at two sets of temperatures
(295 K and 173 K) for 4b, 8b and 11b is provided by a least-square fit of the Caryl–Ca
–N moiety.[25] The results of the fitting can be summarized by the r.ms. deviations for
the respective models. The values are 0.002 Å for 4b, 0.005 Å for 8b, and 0.004 Å for
11b (c.f. Figs. S1, S2 and S3, respectively). These indicate that the low temperature
structures are practically the same as reported.[24] This applies for the basic packing
motifs (c.f. Table S5), too. a-Aminophosphonates 4b and 11b form N ꢁ H ꢀꢀꢀ O ¼ P
bridged dimers, while structure 8b shows a C ꢁ H ꢀꢀꢀ O ¼ P contact that links molecules
into chains (c.f. Figs. S4, S5 and S6).
As far as the important H atom positions are concerned, these are intriguing either from
the point of view of C ꢁ Hdþ ꢀꢀꢀ dþH ꢁ C bonding, or due to the hybridization state of the
N atom. In a neutral molecule, the latter depends on the nature of the distal substituent
ꢁ
atom vis a vis the Ca atom. As a result e.g. in 8b the symmetric peri-position H atom dis-
tances become similarly short: the CaꢁHꢀꢀꢀH ꢁ Cperi is dH(1)ꢀꢀꢀCꢁHdþꢀꢀꢀdþHꢁCꢀꢀꢀH(4) ¼ 1.80(2)
Å, while the N ꢁ HꢀꢀꢀHꢁ Cperi2 is dH(14)ꢀꢀꢀCꢁHdþꢀꢀꢀdþHꢁCꢀꢀꢀH(10) ¼ 2.00(2) Å.

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SYNTHETIC COMMUNICATIONSV
7
The history of short C–H ꢀꢀꢀ H–C contacts begun with experimental proofs. Extreme
short (1.754(4) Å and 1.713(3) Å) non-bonded H ꢀꢀꢀ H distances were reported by
Ermer and Mason.[27] An even shorter (1.617(3) Å) such non-bonded distance was
found using neutron diffraction, as well.[28] Theoretic and experimental results sug-
gested that such short distances may well be resulting from attractive
C ꢁ HdþꢀꢀꢀdþH ꢁ C type interactions.[29,30] The theory was increasingly used to explain
whether the experimentally observed distances are of attractive, or of repulsive
nature.[29,31–35] The H–H bonding was confirmed in nitroimidazole derivatives[31] and
in biphenyl.[35] A DFT, ab initio, QTAIM and ELF study concluded that stability of a
few branched alkanes is due to H – H bonds,[36] however, atom–atom short contacts
still remain a field of ongoing discussions.[37]
Conclusions
The MW-assisted, catalyst- and solvent-free Kabachik–Fields reaction afforded the
a-aminophosphonates bearing sterically demanding aryl groups efficiently in a one-pot
manner. The products obtained were characterized by 31P, 13C and 1H NMR spectroscopy,
as well as by HRMS data. Eight of the 12 a-aminophosphonate derivatives are new.
Redetermination of some of the crystal structures at 173 K temperatures verifies
results and conclusions based on earlier data. Thus, we conclude that no phase
change nor any structural change occur in the 295–173 K temperature range in these
crystals. The very short intramolecular C ꢁ Hdþ ꢀꢀꢀ dþH ꢁ C contacts persist and their
quality, as inferred from other studies too, is of cohesive nature. They are contribu-
ting to stabilization of the shape, conformation and dimensions of these molecules in
their crystals.
Experimental section
General procedure for the synthesis of a-aminophosphonates
The mixture of 0.17 mL (1.00 mmol) of benzhydrylamine, 1.0 mmol of aldehyde (benzal-
dehyde: 0.10 mL, 1-naphtaldehyde: 0.14 mL, 9-anthracenecarboxaldehyde: 0.20 g or
1-pyrenecarboxaldehyde: 0.23 g) and 1.0/1.2/1.5 mmol of dialkyl phosphite (dimethyl
phosphite 0.092/0.11/0.14 mL, diethyl phosphite: 0.13/0.16/0.19 mL, dibutyl phosphite:
0.20/0.23/0.29 mL) was irradiated in a sealed tube at 100–120 ꢂC for 60–75 min in a
CEM Discover Microwave reactor equipped with a pressure controller. The crude prod-
uct was purified by flash column chromatography using silica gel, and dichlorome-
thane-methanol 97:3 as the eluent. See the Supplementary Information for the
characterization data of products 1a–c, 4a–c, 8a–c and 11a–c.
Funding
This project was sponsored by the National Research, Development and Innovation Office
[K119202 and FK123961]. Support of grant BME FIKP-BIO by EMMI is kindly acknowledged.

8
H. R. HUDSON ET AL.
ORCID
ꢀ
ꢀ
Adam Tajti
http://orcid.org/0000-0003-0505-940X
http://orcid.org/0000-0002-5107-7089
http://orcid.org/0000-0001-5986-7432
ꢀ
Erika Balint
ꢀ ꢀ
Matyas Czugler
Konstantin Karaghiosoff
http://orcid.org/0000-0002-8855-730X
€
Gyorgy Keglevich
http://orcid.org/0000-0002-5366-472X
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