ZnCl2-Mediated Double Addition of Dialkylphosphite to Nitriles for the Synthesis of 1-Aminobisphosphonates

Article abstract of DOI:10.1021/acs.joc.9b02298

In this study, the double addition of dialkylphosphite to nitriles in a ZnCl₂/Et₃N system is described. The reaction was conveniently and directly used for the synthesis of biologically important 1-aminobisphosphonates (ABPs) from ni

Full text of DOI:10.1021/acs.joc.9b02298

Subscriber access provided by DALHOUSIE UNIV
Note
ZnCl2-Mediated Double Addition of Dialkylphosphite to
Nitriles for the Synthesis of 1-Aminobisphosphonates (ABPs)
Babak Kaboudin, Hesam Esfandiari, Atieh Moradi, Foad Kazemi, and Hiroshi Aoyama
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02298 • Publication Date (Web): 15 Oct 2019
Downloaded from pubs.acs.org on October 19, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ZnCl2-Mediated Double Addition of Dialkylphosphite to
Nitriles for the Synthesis of 1-Aminobisphosphonates
(ABPs)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Babak Kaboudin,*a Hesam Esfandiari,a Atieh Moradi,a Foad Kazemi,a and Hiroshi Aoyamab
a*Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS),
Gava Zang, Zanjan 45137-66731, Iran
bSchool of Pharmacy, Tokyo University of Pharmacy and Life Sciences,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: kaboudin@gmail.com, Tel: +98 24 33153220, Fax: +98 24 33153232
Novel Synthesis of 1-Aminobisphosphonates
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 20
Graphical Abstract
1
2
3
4
5
6
7
8
ZnCl2 (1 equiv)
Et3N (2 equiv)
O R
(R'O)2P
O
NH2
R
CN +
2H P(OR')2
CH2Cl2, reflux, 12 h
P(OR')2
O
23 examples up to 75%
isolated yield
Easy to handle
Air and moisture insensetive
Readily available substrates and raegents
Practical
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Abstract:
In this study, the double addition of dialkylphosphite to nitriles in a ZnCl2/Et3N system is described.
The reaction was conveniently and directly used for the synthesis of biologically important 1-
aminobisphosphonates (ABPs) from nitriles. One-pot synthesis of 1-aminobisphosphonates from
aldehydes via in situ generation of nitriles is also described.
Nitriles; 1-Aminobisphosphonates; Dialkylphosphite; Phosphonylation; Aldehydes
Pyrophosphates with P-O-P anhydride bonds are well-known compounds for their strong coordination
affinity with metal ions that are widely present in living organisms, such as bone tissues.1-8
Bisphosphonic acids (BPs) with a geminal phosphonate group are structural stable analogues of
pyrophosphate that replacement of P-O bond with P-C bond increases their chemical and enzymatic
stability.9 BPs are well-known bone disease drug candidates due to their high tendency to
hydroxyapatite, the bone mineral compounds.10 So far, there are eight clinical BPs drugs have been
introduced for bone diseases such as paget’s, osteoporosis and bone tumors (Scheme 1).11-14
ACS Paragon Plus Environment
2

Page 3 of 20
The Journal of Organic Chemistry
O
P
OH
O
P
OH
1
2
3
4
5
6
7
OH
OH
OH
HO
OH
OH
OH
HO
N
P
N
H2N
P
O
O
Alendronate
anti-osteoprosis
Zoledronate
bone-metastasis
8
9
O
P
ONa
O
P
OH
OH
ONa
H
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
N
OH
OH
OH
HO
N
P
O
P
O
incadronate
anti-osteoporosis
Risedronate
anti-Paget's and
anti-osteoprosis
SCHEME 1: Structures of BPs drugs
In addition, BPs is widely used as a carrier for delivering of drug molecules to bone tissues for
increasing their pharmaceutical activity.15 For example, conjugate of BPs with methotrexate has five
times greater antineoplastic activity compared with methotrexate alone.16 Among the various BPs, 1-
aminobisphosphonates are of interest as effective in medicinal and industrial chemistry.17 For example,
incadronate, a sodium salt of 1-aminobisphosphonic acid, is widely used as anti-osteoporosis.
Furthermore, some of ABPs are used for their metal chelating ability to remove radioactive metal toxins
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2+
such as uranyl (UO2 ) from the water or blood.17e
1-Aminobisphosphonates are prepared by several methods including: a prolonged heating of a
mixture of nitriles with phosphorus trichloride in the presence of excess phosphoric acid,18 acid-
catalyzed Beckman rearrangement of oximes in the presence of phosphites,19 condensation reaction of
amines with phosphites in the presence of ethylorthoformate,20 phosphonylation of nitriles in the
presence of SnCl2/HCl21a or by double radical transfer mediated by titanocene/propylene oxide,21b and
rhodium-catalyzed N-H insertion reaction of amines with diphosphonodiazomethane carbene.22
Recently, Wang and Huang reported bisphosphorylation of amides in the presence of Tf2O for the
preparation of 1-amino bisphosphonates.23 Onys’ko’s reported double hydrophosphonylation of
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 20
activated polyfluorinated or polychlorinated acetonitrile with diethyl phosphite in the presence of
triethylamine to yield the corresponding 1-aminobisphosphosphonate.24 The syntheses of 1-
aminobisphosphonates that are based on the reaction between the un-reactive nitrile substrates and
phosphorous species require harsh conditions. Therefore, the development of an efficient and general
method for the double hydrophosphonylation of un-reacted nitriles is thus highly desirable.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Lewis-acid mediated addition of nucleophiles to the nitriles has attracted much attention.25 To the best
our knowledge, there is only a few report on the double phosphonylation reaction of nitriles with
phosphines and phosphites by a special air sensitive Lantanum complex and BEt3/Ni catalyst.26 The
method, using Lantanum complex,26a has no selectivity for the synthesis of 1-aminobisphosphinates (A)
and the rearrangement side products (B) have also been reported as a major product (SCHEME 2).
Furthermore, the reactions requires harsh reaction conditions (140 °C) with low selectivity.26b
O R
(Ph)2P
+
O R
(Ph)2P
O
La(Dmba)3
NH
P(Ph)2
O
NH2
R CN +
2H P(Ph)2
H
P(Ph)2
O
B
A
SCHEME 2: Double hydrophosphonylation of nitriles26
In continuation of our efforts in developing new synthetic methods for the preparation of
organophosphorous compounds, herein we report an efficient, practical, and high yielding method for
the synthesis of 1-aminobisphosphonates via double hydophosphonylation of nitriles using a ZnCl2/Et3N
system.
Initially, the bisphosphonylation of 4-chlorobenzonitrile (1a) with diethylphosphite (2a) was chosen
as the model reaction and initial screening results of various Lewis acids and base additives listed in
Table 1. As shown in Table 1, no reaction was observed when FeCl3 and AlCl3 were used as a Lewis
acid mediator (entries 1 and 2). Upon using BiCl3 compound 3a was obtained in a low yield (5%) after
12 hrs (entry 3). No activities were observed with Sc(OTf)3 and ZnO (entries 4 and 5). Upon using
Zn(OAc)2 compound 3a was obtained in 7% yield after 12 hrs (entry 6).
ACS Paragon Plus Environment
4

Page 5 of 20
The Journal of Organic Chemistry
Table 1. Screening of various reaction condition of double hydrophosphonylation of 4-
1
2
3
chlorobenzonitrile
4
5
6
7
8
O
Lewis acid
O
P(OEt)2
NH2
P(OEt)2
(1 equiv)
Cl
+
CN
Cl
2H P(OEt)2
base
(2 equiv)
O
9
3a
2a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1a
Entry
1
Catalyst
AlCl3
Solvent
base
Yield(%)a
b
b
b
b
b
b
b
b
b
b
CH2Cl2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Pyridine
K2CO3
NaOH
Et3N
Et3N
Et3N
Et3N
Et3N
-
NRc
NRc
5
2
FeCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
BiCl3
4
Sc(OTf)3
ZnO
NRc
NRc
7
5
6
Zn(OAc)2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
7
74
8
25
9
NRc
NRc
36d
51d
70e
NRc
20
10
11
12
13
14
15
16
17
18
19
Dioxane
DMF
DMSO
MeOHb
Toluenef
CH2Cl2
NRc
45g
NRh
NR
CH2Cl2
Et3N
Et3N
Et3N
CH2Cl2
CH2Cl2/Et2O (3:1)
a Yields refers to the isolated pure products after short column chromatography. b Reactions carried out
at reflux for 12 hrs. C No reaction, dReaction carried out at 70 °C for 2 hrs (more than 2 hrs the reaction
yield decreased and gave side products). eReaction carried out at 70 °C for 6 hrs (more than 6 hrs the
yield decreased and gave side products). Reaction carried out at reflux for 12 hrs. gZnCl2(0.6 equiv),
f
hZnCl2 (0.3 equiv)
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 20
In an effort to find good systems, we are interested in using ZnCl2, which is a convenient Lewis acid
that has been reported for many organic transformations.25 Interestingly, when the reaction was
conducted with ZnCl2 (1 equiv) in CH2Cl2 for 12 hrs, the compound 3a was obtained in 74% yield
(entry 7).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The results for the reactions conducted in various bases showed that there was no reaction when
K2CO3 and NaOH was used as a base (entries 9 and 10), while using pyridine as a base, the compound
3a was obtained in 25% yield (entry 8). The results for the reactions conducted in various solvents
showed that there was no reaction when methanol was used as a polar protic solvent (entry 14), while
using dioxane, DMF and toluene as a solvent, the compound 3a was obtained in modest yields (entries
11, 12, and 15).
It is worthy to note that the double hydrophosphonylation proceeds to give the compound 3a in good
yield, when the reaction was conducted in DMSO at 70 °C for 6 hrs (entry 13). No reaction was
observed when ZnCl2 was used in the absence of Et3N (entry 16). Further optimization on the amount of
ZnCl2, Et3N and diethyl phosphite showed that treatment of nitrile 1a with 2.2 equiv of diethyl
phosphite in the presence of 2 equiv of Et3N and 1 equiv of ZnCl2 in CH2Cl2 for 12 hrs produced 1-
amino bisphosphonate 3a in 74% yield (entries 7, 17 and 18). As shown in Table 1, no reaction was
observed when Et2O was added to a mixture of ZnCl2/CH2Cl2 (entry 19).
Under the optimized conditions, wide array nitriles were employed in the double
hydrophosphonylation reaction for the synthesis of 1-aminobisphosphonates in good to modest yields.
The obtained results are summarized in Table 2. Double hydrophosphonylation of different para and
meta substituted benzonitriles gave corresponding 1-aminobisphosphonates in good to modest yields
(entries 1-7). Sterically hindered 2,4-dichlorobenzonitrile failed to give the corresponding 1-
aminobisphosphonate (entry 8). It is also possible to carry out this double hydrophosphonylation for
aliphatic nitriles. The double hydrophosphonylation of different aliphatic nitriles with diethylphosphite
gave corresponding 1-aminobisphosphonate in moderate to good yields (entries 9-12).
ACS Paragon Plus Environment
6

Page 7 of 20
The Journal of Organic Chemistry
Table 2 Bisphosphonylation of nitriles in the presence of ZnCl2/Et3N
1
2
3
4
5
6
7
8
ZnCl2 (1 equiv),
Et3N (2 equiv)
2 CH2Cl2, reflux, 12 h
O R1
O
(R2O)2P
NH2
P(OR2)2
O
R1 CN
2
+
2H P(OR )
1
3
2
9
Entry
1
R1
R2
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
Et
Et
Et
Et
Et
Product
Yield(%)a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
p-ClC6H4
Ph
3a
3b
3c
3d
3e
3f
3g
-
74
45
46
75
52
70
63
b
2
3
p-BrC6H4
4
p-NO2C6H4
p-MeSC6H4
m-ClC6H4
5
6
7
m-NO2C6H4
2,4-Cl2C6H3
p-ClC6H4CH2
8
9
3h
3i
3j
3k
3l
3m
-
56
40
35
47
70
60
b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
p-MeOC6H4CH2
m-MeOC6H4CH2
PhCH2CH2
PhCH=CH-
2-Naphthyl
Ph2CH
Cyclohexyl
p-NO2C6H4
PhCH=CH-
Indolyl
-
b
3n
3o
3p
3q
-
54
51
43
74
c
p-CNC6H4
NCCH2NHCH2
p-OHC6H4
-
b
p- NH2C6H4
-
d
a Yields refers to the isolated pure products after short column chromatography. b No desired product
detected. CA mixture of unknown products. dProduct is not stable for further purification.
57
58
59
60
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 20
1
2
3
4
5
6
7
8
9
This method was also applied to double hydrophosphonylation of -unsaturated and 2-naphthyl
nitriles (entries 13 and 14). The double hydrophosphonylation of sterically hindered diphenyl
acteonitrile and cyclohexyl nitrile failed to give desired 1-aminobisphosphonate (entries 15 and 16).
This method was also applied to double hydrophosphonylation of nitriles with di-isopropylphosphite
(entries 17 and 18). The reaction of 3-indolyl actonitrile, as a heterocylic nitrile, in the presence of
ZnCl2/Et3N gave 3p in 43% yield (entry 19). Double hydrophosphonylation of 1,4-dicyanobenzene
(terephthalonitrile), as an aromatic dinitrile, gave corresponding 1-aminobisphosphonate 3q in 74%
yield (entry 20). This result showed that the hydrophosphonylation occurred only on the one nitrile
group (similar result was obtained with increasing of reagents and ZnCl2). The double
hydrophosphonylation of diimioactonitrile [HN(CH2CN)2] gave a mixture of unknown products (entry
21).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
p-Hydroxybenzonitrile failed to give the corresponding 1-aminobisphosphonate (entry 22). Finally,
the reaction of p-aminobenzonitrile in the presence of ZnCl2/Et3N gave desired unstable 1-
aminobisphosphonate (entry 23, TLC and NMR analysis of the reaction mixture showed the product
was obtained, but it has no enough stability for further purification). Thus, the conditions reported
herein tolerate double hydrophosphonylation reaction of a wide variety of nitriles.
To increase the various derivatives of 1-aminobisphosphonates, the coupling reaction of 3c with
phenylboronic acid in the presence of Pd(OAc)2 was examined. Treatment 3c with phenylboronic acid
in the presence of Pd(OAc)2 (10 mol%) and K2CO3 (1.5 equiv) in H2O-Etahnol (1:1) at reflux for 12 hrs
gave 1-amino bisphosphonate 4 in 64% yield (SCHEME 3).
O
O
O
Pd(OAc)2 (10 mol%)
K2CO3 (1.5 equiv)
P(OEt)2
NH2
P(OEt)2
P(OEt)2
NH2
P(OEt)2
+
Ph
Ph B(OH)2
Br
H2O:EtOH (1:1)
reflux, 12 h
O
4
3c
SCHEME 3: Coupling reaction of 3c with phenylboronic acid in the presence of Pd(OAc)2
ACS Paragon Plus Environment
8

Page 9 of 20
The Journal of Organic Chemistry
A proposed mechanism was outlined in SCHEME 4. The double hydrophosphonylation was occurred
1
2
3
4
5
6
7
8
via activation of nitrile and diethylphosphite in the presence of ZnCl2/Et3N system to yield the
monohydrophosphonylated imine, which subsequently reacted with a second equivalent of phosphite to
yield the 1-aminobisphosphonate 3.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N CR
O
ClZn
OEt
OEt
ClZn
OEt
OEt
OEt
ZnCl2
R CN
OEt
H P(OR')2
O P
O P
HO P
O
Et3N
-HCl
OEt
O
O
HO P
OEt
Et3N
P(OEt)2
N CR
Zn
O P
P(OEt)2
HN C R
P(OEt)2
work-up
HCl
P(OEt)2
N CR
3
OEt
OEt
ClZn
ClZn
O
SCHEME 4: Proposed mechanism for the synthesis of compound 3
Aldehydes are readily accessible compare than nitriles. In other attempt, one-pot conversion of
aldehydes to nitriles27 followed by double hydrophosphonylation in the presence of ZnCl2/Et3N was also
examined. In a typical experiment, treatment of m-nitrobenzaldehyde with hydroxylamine hydrochloride
(1.1 equiv) in DMSO at 90 °C for 2 hrs and followed by double hydrophosphonylation with
diethylphosphite in one-pot process, without any separation, in the presence ZnCl2 (1 eq) and Et3N (2
equiv) at 70 °C for 6 hrs gave 3g in 60 % yield. The above method was applied to other aldehydes and
the results were collected in Table 3.
In summary, we report the first double hydrophosphonylation of nitriles in the presence of ZnCl2 and
Et3N. Under mild reaction conditions, aromatic and aliphatic nitriles could be converted into 1-amino
bisphosphonates in good to modest yields. We also report a one-pot synthesis of 1-
aminobisphosphonates from aldehydes. The reported method is highly efficient, easy to handle, air and
moisture insensitive, readily available starting materials and reagents and a simple method compared
with previously reported methods.
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 20
Table 3 One-pot synthesis of 1-aminobisphosphonates from aldehydesa
1
2
3
4
5
6
7
1. NH2OH.HCl (1.1 equiv)
O R
(EtO)2P
O
DMSO, MS, 90 °C, 2 h
NH2
+
RCHO
2H P(OEt)2
2. ZnCl2 (1 equiv),
Et3N (2 equiv),
70 °C, 6 h
P(OEt)2
O
3
6
2
8
9
O2N
Cl
O
O
O
O
P(OEt)2
NH2
P(OEt)2
P(OEt)2
NH2
P(OEt)2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
P(OEt)2
NH2
P(OEt)2
P(OEt)2
NH2
P(OEt)2
MeS
MeO2C
O
O
O
O
3e (52%)
3r (63%)
3g (60%)
3f (63%)
O
O
O
P(OEt)2
NH2
P(OEt)2
P(OEt)2
NH2
P(OEt)2
O
P(OEt)2
NH2
O
P(OEt)2
O
3t (0%)
3k (47%)
3m (61%)
a Yields in parenthesis refers to the isolated pure products.
Experimental Section
General: NMR spectra were obtained on a 400 NMR Spectrometer (1H NMR: 400 MHz, C NMR:
100 MHz, and 31P NMR: 162 MHz). HRMS measurements were obtained on an ESI-TOF-Ms machine.
Analytical TLC was carried out with plates precoated with silica gel 60 F254 (0.25 mm thick). Column
chromatography was performed either with Silica gel 60 (70-230 mesh) in common glass columns. All
solvents were distillated before use.
13
General procedure for the double hydrophosphonylation of nitriles in the presence of
ZnCl2/Et3N system
Nitrile (1 mmol) was added to a solution of ZnCl2 (1 mmol, 136 mg, quick weighting) in CH2Cl2 (3
mL). Dialkylphosphite (2.2 mmol) was added to the mixture and the mixture stirred for 5 min at rt
without using any inert gas. Triethyl amine (2 mmol, 0.28 mL) was added to the mixture and stirred for
12 hrs at reflux (oil bath). Ethyl acetate (10 mL) was added to the reaction mixture and the solid were
collected by filtration. The solute was washed with distilled water (2 X 5 mL) and dried over sodium
ACS Paragon Plus Environment
10

Page 11 of 20
The Journal of Organic Chemistry
sulfate. The solvent was evaporated and the crude product was purified by a short column
chromatography with MeOH-EtOAc (1:9) to give compound 3 as the clear yellow oil.
1
2
3
4
5
6
7
8
9
General procedure for the one-pot synthesis of 1-aminobisphosphonates from aldehydes
A mixture of aldehyde (1 mmol) and hydroxylamine hydrochloride (1.1 mmol, 75 mg) in DMSO (4 mL)
was stirred for 2 hrs at 90 °C (oil bath) in the presence of Molecular sieve 3A (50 mg). The mixture was
cooled down to 70 °C and the ZnCl2 (1 mmol, 136 mg) was added to reaction mixture. Dialkylphosphite
(2.2 mmol) was added to the mixture and the mixture stirred for 5 min at 70 °C (oil bath). Triethyl
amine (2 mmol, 0.28 mL) was added to the mixture and stirred for 12 hrs at 70 °C (oil bath). Ethyl
acetate (10 mL) was added to the reaction mixture and the solid were collected by filtration. The solute
was washed with distilled water (3 X 5 mL) and dried over sodium sulfate. The solvent was evaporated
and the crude product was purified by a short column chromatography with MeOH-EtOAc (1:9) to give
compound 3 as the clear yellow oil.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Procedure for the preparation of compound 4
Pd(OAc)2 (15 mg) was added to a mixture of phenylboronic acid (1.5 mmol, 183 mg) and compound 3c
(0.75 mmol) in a solvent mixture of H2O-EtOH (1:1, 5 mL). K2CO3 (2 mmol, 280 mg) was added to
reaction mixture and the mixture was stirred at 80 °C for 12 hrs. Ethyl acetate (10 mL) was added to the
reaction mixture and the solution was washed with deionized water (3x5 mL) and dried over sodium
sulfate. The solvent was evaporated and the crude product was purified by a short column
chromatography with MeOH-EtOAc (1:9) to give compound 4 as the clear yellow oil in 64% yield.
Tetraethyl 1-amino-1-(4-chlorophenyl)methane-1,1-diyldiphosphonate (3a): Yellow oil (74%, 305
mg); 1H NMR (400 MHz, CDCl3) δ: 1.11 (t, J = 7.0 Hz, 6H), 1.23 (t, J = 7.0 Hz, 6H), 2.10-2.20 (br, 2H, -NH2),
3.78 – 4.26 (m, 8H), 7.29 (d, J = 8.1 Hz, 2H), 7.79 (d, J =8.4 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ: 16.2
(t, J = 3.0 Hz), 16.3 (t, J = 9.6 Hz) 61.3 (t, J = 141.0 Hz), 63.7 (t, J = 4 Hz), 63.9 (t, J = 4 Hz), 128.1, 128.7 (t, J
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 20
= 4.9 Hz), 132.9, 133.7. 31P{1H} NMR (162 MHz, CDCl3) δ: 18.76. HRMS (ESI): Calcd for C15H26NO6ClNaP2
1
2
3
[M+Na]+ : 436.0821, Found: 436.0808.
4
5
6
7
8
Tetraethyl 1-amino-1-phenylmethane-1,1-diyldiphosphonate (3b): Yellow oil (45%, 181 mg); 1H NMR
(400 MHz, CDCl3) δ: 1.11 (t, J = 7.1 Hz, 6H), 1.25 (t, J = 7.0 Hz, 6H), 2.25-230 (br, 2H, -NH2), 3.75 – 3.90 (m,
2H), 3.95 – 4.05 (m, 2H), 3.95 – 4.20 (m, 4H), 7.21 – 7.43 (m, 3H), 7.87 (d, J = 7.5 Hz, 2H); 13C{1H} NMR (101
MHz, CDCl3) δ: 16.1 (t, J = 2 Hz), , 16.2 (t, J = 2 Hz), 60.1 (t, J = 140.0 Hz), 63.7 (t, J = 4 Hz), 63.9 (t, J = 4 Hz),
127.2 (t, J = 4.9 Hz), 127.7, 127.9, 133.8; 31P{1H} NMR (162 MHz, CDCl3) δ: 19.14; HRMS (ESI): Calcd for
C15H27NO6NaP2 [M+Na]+: 402.1210 , Found: 402.1207.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tetraethyl 1-amino-1-(4-bromoophenyl)methane-1,1-diyldiphosphonate (3c): Yellow oil (46%, 221
mg); 1H NMR (400 MHz, CDCl3) δ: 1.16 (t, J = 7.1 Hz, 6H), 1.27 (t, J = 7.1 Hz, 6H), 2.23 (s, 2H, NH2), 3.81–
4.28 (m, 8H), 7.48 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 7.9 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ: 16.2 (t, J =
2.8), 16.3 (t, J = 2.8), 60.1 (t, J = 139.0 Hz), 63.8 (t, J = 4 Hz), 64.0 (t, J = 3.0 Hz), 122.1 (t, J = 3.0 Hz), 129.1
(t, J = 4.9 Hz), 131.07 (t, J = 2.4 Hz), 133.53; 31P{1H} NMR (162 MHz, CDCl3) δ: 18.66; HRMS (ESI): Calcd
for C15H26NO6BrNaP2 [M+Na]+ : 480.0316 , Found: 480.0313.
Tetraethyl 1-amino-1-(4-nitrophenyl)methane-1,1-diyldiphosphonate (3d): Yellow oil (75%, 318 mg);
1H NMR (400 MHz, CDCl3) δ: 1.18 (t, J = 7.1 Hz, 6H), 1.28 (t, J = 7.1 Hz, 6H), 2.39 (s, 2H, NH2), 3.96 – 4.23
(m, 8H), 8.02-8.12 (m, 2H), 8.20-8.23 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ: 16.2 (t, J = 3.0 Hz), 16.3 (t,
J = 3.0 Hz), 60.92 (t, J = 139.3 Hz), 64.1-64.2 (m), 122.9 (t, J = 2.3 Hz), 128.4 (t, J = 4.7 Hz), 142.4 (t, J = 4.9
Hz), 147.3; 31P{1H} NMR (162 MHz, CDCl3) δ: 18.04; HRMS (ESI): Calcd for C15H26N2O8NaP2 [M+Na]+ :
447.1061 , Found: 447.1060.
Tetraethyl 1-amino-1-(4-methylthiophenyl)methane-1,1-diyldiphosphonate (3e): Yellow oil (52%,
221 mg); 1H NMR (400 MHz, CDCl3) δ: 1.17 (t, J = 7.1 Hz, 6H), 1.29 (t, J = 7.1 Hz, 6H), 2.22 (s, 2H, NH2), 2.49
(s, 3H), 3.84 – 4.22 (m, 8H), 7.25 (d, J = 8.8 Hz, 2H), 7.78 – 7.83 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3)
δ:15.4, 16.3 (t, J = 3 Hz), 16.4 (t, J = 3 Hz), 60.0 (t, J = 141.0 Hz), 63.7 (t, J = 3.4 Hz), 64.0 (t, J = 3.4 Hz),125.7
(t, J = 2.7 Hz) , 130.6 (t, J = 5.5 Hz), 138.2; 31P{1H} NMR (162 MHz, CDCl3) δ: 19.11. HRMS (ESI): Calcd for
C16H29NO6SNaP2 [M+Na]+: 448.1088 , Found: 448.1066.
ACS Paragon Plus Environment
12

Page 13 of 20
The Journal of Organic Chemistry
Tetraethyl 1-amino-1-(3-chlorophenyl)methane-1,1-diyldiphosphonate (3f): Yellow oil (70%, 290
mg); 1H NMR (400 MHz, CDCl3) δ: 1.13 (t, J = 7.1 Hz, 6H), 1.25 (t, J = 7.1 Hz, 6H), 2.32 (s, 2H, NH2), 3.90 –
4.25 (m, 8H), 7.51 (t, J = 8.0 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 7.3 Hz, 1H), 8.69 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ: 16.2 (t, J = 2.8 Hz), 16.3 (t, J = 2.8 Hz), 60.2 (t, J = 140.2 Hz), 64.0 (t, J = 3.4 Hz),
64.2 (t, J = 3.4 Hz), 122.2 (t, J = 5.0 Hz), 122.6 (d, J = 2.6 Hz), 128.7, 132.9 (t, J = 4.3 Hz), 137.4 (t, J = 4.5 Hz),
148.0; 31P{1H} NMR (162 MHz, CDCl3) δ: 18.76 ppm; 31P NMR (162 MHz, CDCl3) δ: 19.01; HRMS (ESI):
Calcd for C15H26NO6ClNaP2 [M+Na]+ : 436.0821 , Found: 436.0809.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tetraethyl 1-amino-1-(3-nitrophenyl)methane-1,1-diyldiphosphonate (3g): Yellow oil (63%, 267 mg);
1H NMR (400 MHz, CDCl3) δ: 1.15 (t, J = 7.1 Hz, 6H), 1.23 (t, J = 7.1 Hz, 6H), 2.32 (s, 2H, NH2), 3.92 – 4.22
(m, 8H), 7.51 (t, J = 8.0 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 7.3 Hz, 1H, 8.69 (s, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ: 16.2 (t, J = 2.8 Hz), 16.3 (t, J= 2.8 Hz), 60.2 (t, J = 140.0 Hz), 64.1 (t, J = 3.4 Hz), 64.1 (t, J
= 3.4 Hz), 122.2 (t, J = 5.0 Hz), 122.7, 128.7, 133.9 (t, J = 4.3 Hz), 137.4 (t, J = 4.5 Hz), 148.0; 31P{1H} NMR
(162 MHz, CDCl3) δ: 18.34; HRMS (ESI): Calcd for C15H26N2O8NaP2 [M+Na]+ : 447.1067 , Found: 447.1059.
Tetraethyl 1-amino-2-(4-chlorophenyl)ethane-1,1-diyldiphosphonate (3h): Yellow oil (56%, 239 mg);
1H NMR (400 MHz, CDCl3) δ: 1.21 – 1.32 (m, 12H), 1.80-2.20 (br, 2H, NH2), 3.26 (t, J = 14.2 Hz, 2H), 4.06 –
4.23 (m, 8H), 7.22 – 7.25 (m, 2H), 7.27 – 7.31 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ: 16.3-16.4 (m), 38.2
(t, J = 2.0 Hz), 57.3 (t, J = 143.1 Hz), 63.2 (t, J = 3.4 Hz), 63.4 (t, J = 3.4 Hz), 127.8, 132.6, 132.9, 133.6 (t, J =
8.5 Hz); 31P{1H} NMR (162 MHz, CDCl3) δ: 21.95; HRMS (ESI): Calcd for C16H28NO6ClNaP2 [M+Na]+ :
450.0977 , Found: 450.0970.
Tetraethyl 1-amino-2-(4-methoxyphenyl)ethane-1,1-diyldiphosphonate (3i): Yellow oil (40%, 170
mg); 1H NMR (400 MHz, CDCl3) δ: 1.28-1.30 (m, 12H), 1.78 (s, 2H, NH2), 3.29 (t, J = 14.0 Hz, 2H), 3.81 (s,
3H), 4.11 – 4.27 (m, 8H), 6.83 – 6.86 (m, 2H),7.25-7.32 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ: 16.4 (t, J
= 2.9 Hz), 37.83, 55.3, 57.5 (t, J = 143.1 Hz), 63.0 (t, J = 3.4 Hz), 63.2 (t, J = 3.4 Hz), 113.2, 126.9 (t, J = 8.5 Hz)
132.36, 158.7; 31P{1H} NMR (162 MHz, CDCl3) δ: 22.41 ppm; HRMS (ESI): Calcd for C17H31NO7NaP2
[M+Na]+ : 446.1439 , Found: 446.1467.
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 20
Tetraethyl 1-amino-2-(3-methoxyphenyl)ethane-1,1-diyldiphosphonate (3j): Yellow oil (35%, 148
mg); 1H NMR (400 MHz, CDCl3) δ: 1.22-1.29 (m, 12H), 2.19 (s, 2H, NH2), 3.29 (t, J = 14.4 Hz, 2H), 3.79 (s,
1
2
3
4
5
6
7
8
9
3H), 4.10 – 4.22 (m, 8H), 6.80 (dd, J = 8.1, 2.2 Hz, 1H), 6.91 – 6.96 (m, 2H), 7.16 – 7.21 (m, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ: 16.3 (t, J = 2.9 Hz), 38.7, 55.1, 57.5 (t, J = 147.02 Hz), 63.1 (t, J = 3.4 Hz), 63.3 (t, J = 3.4
Hz), 112.53, 116.86, 123.7, 128.7, 136.4(t, J = 8.7 Hz), 159.1; 31P{1H} NMR (162 MHz, CDCl3) δ: 22.08 ppm;
HRMS (ESI): Calcd for C17H31NO7NaP2 [M+Na]+ : 446.1439 , Found: 446.1467.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tetraethyl 1-amino-3-phenylpropane-1,1-diyldiphosphonate (3k): Yellow oil (47%, 190 mg); 1H NMR
(400 MHz, CDCl3) δ: 1.39 (t, J = 7.1 Hz, 12H), 1.87 (s, 2H, NH2), 2.15 – 2.30 (m, 2H), 2.90 – 2.98 (m, 2H), 4.23
– 4.32 (m, 8H), 7.18 – 7.25 (m, 2H),7.28 – 7.33 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ: 16.7 , 30.4 (t, J =
5.6 Hz), 36.5, 56.7 (t, J = 143.2 Hz), 63.2-63.4 (m), 126.0, 128.4, 128.5, 142.0; 31P{1H} NMR (162 MHz, CDCl3)
δ: 23.13 ppm; HRMS (ESI): Calcd for C17H31NO6NaP2 [M+Na]+ : 430.1523 , Found: 430.1515.
Tetraethyl 1-amino-3-phenylpropene-1,1-diyldiphosphonate (3l): Yellow oil (70%, 280 mg); 1H NMR
(400 MHz, CDCl3) δ: 1.28 – 1.36 (m, 12H), 2.19 (s, 2H), 4.12 – 4.31 (m, 8H), 6.46 – 6.57 (dt, J = 15.7, 5.2 Hz,
1H), 6.82 (dt, J = 15.7, 5.2 Hz, 1H), 7.21 – 7.28 (m, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 7.5 Hz, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ: 16.4 – 16.40 (m), 60.2 (t, J = 143.3 Hz), 63.6 (t, J = 3.5 Hz), 64.1(t, J = 3.5
Hz), 122.8 (t, J = 8.8 Hz), 126.7, 127.9, 128.6, 131.5 (t, J = 11.0 Hz), 136.4 (t, J = 3.6 Hz); 31P{1H} NMR (162
MHz, CDCl3) δ: 18.88 ppm; HRMS (ESI): Calcd for C17H29NO6NaP2 [M+Na]+ : 428.1367 , Found: 428.1360.
Tetraethyl 1-amino-1-(2-naphthyl)methane-1,1-diyldiphosphonate (3m): Yellow oil (60%, 257 mg);
1H NMR (400 MHz, CDCl3) δ: 1.09 – 1.17 (m, 6H), 1.20 – 1.37 (m, 6H), 2.44 (s, 2H, NH2), 3.80 – 3.92 (m, 2H),
4.0 – 4.10 (m, 2H), 4.12-4.25 (m, 4H), 7.44 – 7.54 (m, 2H), 7.79 – 7.94 (m, 3H), 8.10-8.15 (m, 1H), 8.28 – 8.30
(s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ: 16.3 (t, J = 2.8 Hz), 16.4 (t, J = 2.8 Hz), 61.3 (t, J = 142.5 Hz), 63.7
(t, J = 3.5 Hz), 64.0 (t, J = 3.5 Hz), 125.5–126.5 (complex peaks), 127.4 (d, J = 10.3 Hz), 128.4, 131.67, 132.7,
133.0; 31P{1H} NMR (162 MHz, CDCl3) δ: 19.16; HRMS (ESI): Calcd for C19H29NO6NaP2 [M+Na]+ : 452.1367 ,
Found: 452.1359.
Tetraisopropyl 1-amino-1-(4-nitrophenyl)methane-1,1-diyldiphosphonate (3n): Yellow oil (54%, 260
mg); 1H NMR (400 MHz, CDCl3) δ: 1.09 (d, J = 6.2 Hz, 6H), 1.26 – 1.33 (m, 18H), 2.28 (s, 2H, NH2), 4.44 –
ACS Paragon Plus Environment
14

Page 15 of 20
The Journal of Organic Chemistry
4.85 (m, 4H), 8.10 – 8.14 (m, 2H), 8.22 (d, J = 8.9 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ: 23.4 (t, J = 3.2
Hz), 23.6 (t, J = 3.3 Hz), 24.2, 61.0 (t, J = 143.1Hz), 72.9 (d, J = 3.0 Hz), 122.7, 128.6 (t, J = 4.6 Hz), 143.2,
147.1; 31P{1H} NMR (162 MHz, CDCl3) δ 16.45; HRMS (ESI): Calcd for C19H34N2O8NaP2 [M+Na]+ : 503.1687 ,
Found: 503.1687.
1
2
3
4
5
6
7
8
9
Tetraisopropyl-amino-3-phenylpropene-1,1-diyldiphosphonate (3o): Yellow oil (51%, 235 mg); 1H
NMR (400 MHz, CDCl3) δ: 1.30-1.40 (m, 24H), 2.07 (s, 2H), 4.75 – 4.88 (m, 4H), 6.51 (dt, J = 16.0, 5.8 Hz, 1H),
6.80 (dt, J = 16.0, 5.4 Hz, 1H), 7.24 – 7.30 (m, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.42 (d, J = 7.6 Hz, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ: 23.6 (t, J = 3.3 Hz), 23.8 (d, J = 3.1 Hz), 24.4 (d, J = 14.2 Hz), 60.34 (t, J = 144.3
Hz), 72.2 (t, J = 3.7 Hz), 72.2 (t, J = 3.7 Hz), 126.6, 127.7, 128.6, 131.1; 31P{1H} NMR (162 MHz, CDCl3) δ:
17.49 ppm; HRMS (ESI): Calcd for C21H37NO6NaP2 [M+Na]+ : 484.1993 , Found: 484.1987.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tetraethyl 1-amino-2-(2-indolyl)ethane-1,1-diyldiphosphonate (3p): Yellow oil (43%, 185 mg); 1H
NMR (400 MHz, CDCl3) δ: 1.23 – 1.32 (m, 12H), 1.85 (s, 2H, NH2), 3.57 (t, J = 14.1 Hz, 2H), 4.06 – 4.28 (m,
8H), 7.09 – 7.20 (m, 2H), 7.26 (d, J = 2.3 Hz, 1H), 7.35 – 7.40 (m, 1H), 8.80 (d, J = 13.1 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ: 15.2 – 17.20 (m), 28.5, 57.8 (t, J = 143.4 Hz), 62.43 – 63.79 (m), 107.90 – 109.10 (m),
111.0, 119.3, 119.7, 121.6, 125.2, 128.9, 136.0; 31P{1H} NMR (162 MHz, CDCl3) δ: 22.94 ppm; HRMS (ESI):
Calcd for C18H30N2O6NaP2 [M+Na]+ : 455.1476 , Found: 455.1472.
Tetraethyl 1-amino-1-(4-cyanophenyl)methane-1,1-diyldiphosphonate (3q): Yellow oil (74%, 300 mg); 1H
NMR (400 MHz, CDCl3) δ: 1.12 (t, J = 7.1 Hz, 6H), 1.22 (t, J = 7.1 Hz, 6H), 2.25 (s, 2H, NH2), 3.85-3.95 (m,
2H), 3.97-4.07 (m, 2H), 4.10 – 4.20 (m, 4H), 7.61 (d, J = 8.1 Hz, 2H), 7.95 – 8.05 (m, 2H); 13C{1H} NMR (101
MHz, CDCl3) δ: 16.2 (dt, J = 10.4, 2.8 Hz),60.7 (t, J = 139.9 Hz), 64.2 ,111.5 (t, J = 2.8 Hz), 118.6, 128.1 (t, J =
4.8 Hz), 131.6 (t, J = 2.1 Hz), 140.1 (t, J = 4.8 Hz); 31P{1H} NMR (162 MHz, CDCl3) δ 18.05 ppm; HRMS (ESI):
Calcd for C16H26N2O6NaP2[M+Na]+ : 427.1164, Found: 427.1157.
Methyl 4-{1-amino-1,1-bis(diethoxyphosphoryl)methyl}benzoate (3r): Yellow oil (63%, 275 mg); 1H NMR
(400 MHz, CDCl3) δ: 1.16 (t, J = 7.1 Hz, 6H), 1.27 (t, J = 7.1 Hz, 6H), 2.30 (s, 2H, NH2), 3.92 (s, 3H), 3.77 –
4.44 (m, 8H), 7.99 (dt, J = 8.0 and 2.1 Hz, 2H), 8.05 (d, J = 8.0 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ:
16.2 (t, J = 2.8 Hz), 16.3 (t, J = 2.9 Hz),52.1,60.7 (t, J = 139.7 Hz), 63.9 (t, J = 3.4 Hz), 64.0 (t, J = 3.4 Hz), 127.4
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 20
(t, J = 4.8 Hz), 129.1,129.4, 139.6 (t, J = 5.0 Hz), 166.9; 31P{1H} NMR (162 MHz, CDCl3) δ: 18.50 ppm; HRMS
1
2
3
(ESI): Calcd for C17H29NO8NaP2 [M+Na]+ : 460.1266, Found: 460.1259.
4
5
6
7
8
Tetraethyl 1-amino-1-(4-phenyl phenyl)methane-1,1-diyldiphosphonate (4): Yellow oil (64%, 218
mg); 1H NMR (400 MHz, CDCl3) δ: 1.19 (t, J = 7.0 Hz, 6H), 1.32 (t, J = 7.0 Hz, 6H), 2.43 (s, 2H, NH2), 3.89 –
4.31 (m, 8H), 7.37 (d, J = 7.3 Hz, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.96 – 8.01 (m, 4H);
13C{1H} NMR (101 MHz, CDCl3) δ: 16.1–16.3 (m), 60.2 (t, J = 142.07 Hz), 63.7–63.9 (m), 126.32 (s), 126.6,
127.0, 127.5, 127.7, 128.8, 133.1, 140.4 (d, J = 7.0 Hz); 31P{1H} NMR (162 MHz, CDCl3) δ: 19.19; HRMS
(ESI): Calcd for C21H31NO6NaP2 [M+Na]+ : 478.1523 , Found: 478.1523.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information
General experimental procedures, characterization data and copies of 1H NMR, 13C NMR, and 31P NMR
of all products. This material is available free of charge via the Internet at http://pubs.acs.org)
AUTHOR INFORMATION
Corresponding Author
* Email: kaboudin@gmail.com.
Acknowledgment. The Institute for Advanced Studies in Basic Sciences is thanked for supporting this
work. The authors also wish to thank Mr. Haruhiko Fukaya, Tokyo University of Pharmacy and Life
Sciences, for his help carrying out the HRMS measurements.
References and Notes
(1) a) Leon, A.; Liu, L.; Yang, Y.; Hudock, M. P.; Hall, P.; Yin, F.; Oldfield, E. Isoprenoid
biosynthesis as a drug target: bisphosphonate inhibition of Escherichia coli K12 growth and
synergistic effects of fosmidomycin. J. Med. Chem. 2006, 49, 7331-7341. b) Suzuki, F.; Fujikawa,
Y.; Yamamoto, S.; Mizutani, H.; Funabashi, C.; Ohya, T.; Ikai, T.; Oguchi, T. Pharmaceutical
Compositions Containing Geminal Diphosphonates. US 5583122 A, 1 February 1979. c)
Chmielewska, E.; Kempińska, K.;
ACS Paragon Plus Environment
16

Page 17 of 20
The Journal of Organic Chemistry
(2) a) Wietrzyk, J.; Piątek, A.; Kuryszko, J.J.; Kiełbowicz, Z.; Kafarski, P. Novel Bisphosphonates
and Their Use. WO2015159153 A1, 22 October 2015. b) Sanders, J. M.; Song, Y.; Oldfield, E.;
Zhang, Y. Bisphosphonate compounds and methods for bone resorption diseases, cancer, bone
pain, immune disorders, and infectious diseases. US 7358361 B2, 8 October 2004.
(3) Zhang, Y.; Cao, R.; Yin, F.; Hudock, M. P.;Guo, R. T.; Krysiak, K. Lipophilic bisphosphonates as
dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation. J.
Am. Chem. Soc. 2009, 131, 5153-5162.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) Kotsikorou, E.; Song, Y.; Chan, J. M.; Faelens, S.; Tovian, Z.; Broderick, E.; Oldfield, E.
Bisphosphonate inhibition of the exopolyphosphatase activity of the Trypanosomabrucei soluble
vacuolar pyrophosphatase. J. Med. Chem. 2005, 48, 6128-6139.
(5) Sietsema, W. K.; Ebetino, F. H.; Salvagno, A. M.; Bevan, J. A. Antiresorptive dose-response
relationships across three generations of bisphosphonates. Drugs. Exp. Clin. Res. 1989, 15, 389-
396.
(6) Sanders, J. M.; Gómez, A. O.; Mao, J.; Meints, G. A.; Van Brussel, E. M.; Burzynska, A.;
Oldfield, E. 3-D QSAR Investigations of the Inhibition of Leishmania m ajor Farnesyl
Pyrophosphate Synthase by Bisphosphonates. J. Med. Chem. 2003, 46, 5171-5183.
(7) Russell, R. G. G.; Watts, N. B.; Ebetino, F. H.; Rogers, M. J. Mechanisms of action of
bisphosphonates: Similarities and differences and their potential influence on clinical efficacy.
Osteoporos. Int. 2008, 19, 733–759.
(8) Russell, R. G. Bisphosphonates: The First 40 Years. Bone 2011, 49, 2–19.
(9) Lin, J. H. Bisphosphonates: A Review of Their Pharmacokinetic Properties. Bone 1996, 18, 75–
85.
(10) a) Zhang, S.; Gangal, G.; Uludag, H. Magic bullets for bone diseases: Progress in rational design
of bone-seeking medicinal agents. Chem. Soc. Rev. 2007, 36, 507–531. b) Chmielewska, E.;
Kafarski, D. Synthetic Procedures Leading toward Aminobisphosphonates. Molecules, 2016, 21,
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 20
1474. c) Abdou, W. M.; Shaady, A. A. The development of bisphosphonates for therapeutic uses,
and bisphosphonate structure-activity consideration. Arkivoc, 2009, 9, 143-182.
1
2
3
4
5
6
7
8
9
(11) Puljula, E.; Turhanen, P.; Vepsalainen, J.; Monteil, M.; Lecouvey, M.; Weisell, J. Structural
Requirements for Bisphosphonate Binding on Hydroxyapatite: NMR Study of Bisphosphonate
Partial Esters. ACS Med Chem Lett. 2015, 6, 397-401.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) a) Keller, R. K.; Fliesler, S. J. Mechanism of aminobisphosphonate action: characterization of
alendronate inhibition of the isoprenoid pathway. Biochem. Biophys. Res. Commun. 1999, 266,
560-563. b) Parhami, F.; Stappenbeck, F.; Chamberlain, B.T. Bone-selective osteogenic oxysterol
bisphosphonate analogs. US 20170022244 A1, 2 May 2014.
(13) Jobke, B.; Milovanovic, P.; Amling, M.; Busse, B. Bisphosphonate-osteoclasts: changes in
osteoclast morphology and function induced by antiresorptive nitrogen-containing bisphosphonate
treatment in osteoporosis patients. Bone, 2014, 59, 37-43.
(14) Polascik, T. J.; Mouraviev, V. Zoledronic acid in the management of metastatic bone disease.
Ther. Clin. Risk Manag. 2008, 4, 261-268.
(15) a) Xin, Z. F.; Kim, Y. K.; Jung, S. T. Risedronate inhibits human osteosarcoma cell invasion. J.
Exp. Clin. Cancer Res. 2009, 28: 105. b) Uludag, H. Bisphosphonates as a foundation of drug
delivery to bone. Curr. Pharm. Design. 2002, 8, 1929-1944.
(16) Farrell, K. B.; Karpeisky, A.; Thamm, D. H.; Zinnen, S. Bisphosphonate conjugation for bone
specific drug targeting. Bone Rep. 2018, 9, 47-60.
(17) a) Simoni, D.; Gebbia, N.; Invidiata, F. P.; Eleopra, M.;Marchetti, P.; Rondanin, R.; Marinelli,
L. Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in
vivo antitumor activity through a γδ-T lymphocytes-mediated activation mechanism. J. Med.
Chem. 2008, 51, 6800-6807. b) Reszka, A. A.; Rodan, G. A. Nitrogen-containing bisphosphonate
mechanism of action. Mini Rev. Med. Chem. 2004, 4, 711-719. c) Leung, C. Y.; Park, J.; De
Schutter, J. W.; sebag, M.; Berghuis, A. M.; Tsantrizos, Y. S. Thienopyrimidine Bisphosphonate
(ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and
ACS Paragon Plus Environment
18

Page 19 of 20
The Journal of Organic Chemistry
Characterization of the Mode of Inhibition. J. Med. Chem. 2013, 56, 7939-7950. d) Gałęzowska,
J.; Czapor-Irzabek, H.; Chmielewska, E.; Kafarski, P.; Janek, T. Aminobisphosphonates based on
cyclohexane backbone as coordinating agents for metal ions. Thermodynamic, spectroscopic and
biological studies. New J. Chem. 2018, 42, 7723-7736. e) Wang, L.; Yang, Z.; Gao, J.; Xu, K.; Gu,
H.; Zhang, B.; Xu, B. A biocompatible method of decorporation: bisphosphonate-modified
magnetite nanoparticles to remove uranyl ions from blood. J. Am. Chem. Soc. 2006, 128, 13358-
13359.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18) a) Kafarski, P.; Lejczak, B.; Forlani, G. Herbicidally active aminomethylenebisphosphonic
acids. Heteroatom Chem. 2000, 11, 449-453. b) Rao, D. V. N. S.; Dandala, R.; Lenin, R.;
Sivakumaran, M.; Shivashankar, S.; Naidu, A. A facile one pot synthesis of bisphosphonic acids
and their sodium salts from nitriles. Arkivoc 2007, 14, 34-38.
(19) Yokomatsu, T.; Yoshida, Y.; Nakabayashi, N.; Shibuya, S. Simple and Efficient Method for
Preparation of Conformationally Constrained Aminomethylene gem-Diphosphonate Derivatives
via Beckmann Rearrangement. J. Org. Chem. 1994, 59, 7562-7564.
(20) Kaboudin, B.; Alipour, S. A Microwave-assisted Solvent- and Catalyst-Free Synthesis of
Aminomethylene Bisphosphonates. Tetrahedron Lett. 2009, 50, 4243-4245.
(21) a) Gancarz, R.; Wieczorek, J. S. A Useful Method for the Preparation of 1-
Aminoalkanephosphonic Acids. Synthesis 1977, 1977, 625-626. b) Midrier, C.; Lantsoght, M.;
Volle, J. N.; Pirat, J. L.; Virieux, D.; Stevens, C. V. Hydrophosphonylation of alkenes or nitriles
by double radical transfer mediated by titanocene/propylene oxide. Tetrahedron Lett. 2011, 52,
6693-6696.
(22) Lecerclé, D.; Gabillet, S.; Gomis, J-.M.; Taran, F. A facile synthesis of aminomethylene
bisphosphonates through rhodium carbenoid mediated N–H insertion reaction. Application to the
preparation of powerful uranyl ligands. Tetrahedron Lett. 2008, 49, 2083-2087.
(23) Wang, A. E.; Chang, Z.; Sun, W. T.; Huang, P. Q. General and chemoselective
bisphosphonylation of secondary and tertiary amides. Org. Lett.2015, 17, 732-735.
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 20
(24) a) Rassukana, Y. V.; Yelenich, I. P.; Bezdudny, A. V.; Mironov, V. F.; Onys’ko, P. P.
Chemoselectivity of the reactions of haloacetonitriles with hydrogen phosphonates: the dramatic
effect of the nature of the halogen atom. Tetrahedron Lett. 2014, 55, 4771−4773. b) Rassukana, Y.
V.; Yelenicha, I. P.; Synytsya, A. D.; Onys’k, P. P. Fluorinated NH-iminophosphonates and
iminocarboxylates: novelsynthons for the preparation of biorelevanta-aminophosphonatesand
carboxylates. Tetrahedron, 2014, 70, 2928-2937.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(25) Bolotin, D. S.; Kulish, K. I.; Bokach, N. A.; Starova, G. L.; Gurzhiy, V. V.; Kukushkin, V. Y.
Zinc (ii)-mediated nitrile–amidoxime coupling gives new insights into h+-assisted generation of 1,
2, 4-oxadiazoles. Inorg. Chem. 2014, 53, 10312-10324.
(26) a) Basiouny, M. M.; Schmidt, J. A. Lanthanum-catalyzed double hydrophosphinylation of
nitriles. Organometallics. 2017, 36, 721-729. b) Islas, R. E.; Garcia, J. J. Nickel‐Catalyzed
Hydrophosphonylation and Hydrogenation of Aromatic Nitriles Assisted by Lewis Acid.
ChemCatChem, 2019, 11, 1337-1345.
(27) Augustine, J. K.; Bombrun, A.; Atta, R. N. A Practical and Cost-Efficient, One-Pot Conversion
of Aldehydes into Nitriles Mediated by ‘Activated DMSO’. Synlett 2011, 2223-2227.
ACS Paragon Plus Environment
20