A Green Approach to the Synthesis of α-Amino Phosphonate in Water Medium: Carbene Insertion into the N-H Bond by Cu(I) Catalyst

Article abstract of DOI:10.1021/acs.joc.6b01940

Synthesis of amino phosphonates is more important owing to their significant applications in the biological systems. There are few methods already known in the literature to make these molecules; however, known methods have their own disadvantages. In this regard, synthesis of different kinds of amino phosphonates have been achieved via phosphonate substituted carbene insertion into the N-H bond of aniline catalyzed by readily available copper salt under mild reaction conditions in water. In order to find an efficient catalyst for carbene insertion reaction in neat water, a large number of transition metal catalysts were screened, and we found that the [Cu(CH₃CN)₄]ClO₄ was the best catalyst under employed reaction conditions. Using this environmentally benign methodology (copper catalyzed reaction in water), a large number of biologically important amino phosphonates have been synthesized, isolated (37 examples), and characterized using standard analytical and spectroscopic techniques.

Full text of DOI:10.1021/acs.joc.6b01940

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Article
A Green Approach to the Synthesis of alpha-Amino Phosphate in
Water Medium: Carbene Insertion into the N-H Bond by Cu(I) Catalyst
Kankanala Ramakrishna, Jisha Mary Thomas, and Chinnappan Sivasankar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01940 • Publication Date (Web): 29 Sep 2016
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A Green Approach to the Synthesis of αꢀAmino Phosphate in Water Medium:
Carbene Insertion into the NꢀH Bond by Cu(I) Catalyst
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Kankanala Ramakrishna, Jisha Mary Thomas and Chinnappan Sivasankar*
Catalysis and Energy Laboratory (A Central University), Department of Chemistry
Pondicherry University, Puducherry 605014, India
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Email: siva.che@pondiuni.edu.in
TOC Graphic
Abstract:
Synthesis of amino phosphates are more important owing to their significant applications in the
biological systems. There are few methods already know in the literature to make these
molecules, however known methods have their own disadvantages. In this regard, synthesis of
different kinds of amino phosphates have been achieved via phosphate substituted carbene
insertion into the NꢀH bond of aniline catalyzed by readily available copper salt under mild
reaction conditions in water. In order to find an efficient catalyst for carbene insertion reaction
in neat water, a large number of transition metal catalysts were screened and found that the
[Cu(CH3CN)4]ClO4 was the best catalyst under employed reaction conditions. Using this
environmentally benign methodology (copper catalyzed reaction in water), a large number of
biologically important amino phosphates have been synthesized and isolated (37 examples) and
characterized using standard analytical and spectroscopic techniques.
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Introduction:
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Among the mimics of natural bioꢀactive molecules, αꢀamino phosphates are important owing to
their vast applications in biochemistry.1,2 As a result of continuous efforts in this area, utilization
of αꢀamino phosphates are expanding into many new channels.3,4 Among all the biological
applications of αꢀamino phosphates, more importantly it exhibits wide range of potential
activities against cancer,5–8 tuberculosis,9,10 HIV11,12 and bacterial agents etc.13–15 Amino
phosphates have been used as mimics of peptides, enzyme inhibitors and also as therapeutic
agents for many diseases.16–21 Apart from biological applications of amino phosphates, αꢀamino
phosphates are serving as synthons for the construction of many new chemical entities.22–24
Amino phosphates facilitate simple methods for the synthesis of highly functionalized indoles,
isocoumarins and many other heterocycles.25–28
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R2
O
O
NH2
OR3
P(OR3)3
or
HN
P
Lewis acid
OR3
+
+
R1
R2
HPO(OR3)2
R1
(a) Kabachnik-Fields reaction
O
R2
NH
O
Cu cat.
R1
P
R1
P
R2NH2
+
OR3
OR3
OR3
OR3
(b) ꢀCꢀH amination of alkyl phosphates
R2
N
R2
NH
R4
R1
O
O
cat. Rh, Ru, Ir, Pd etc.
H2
+
R1
P
P
OR3
OR3
OR3
OR3
(c) Iminophosphonate hydrolysis
Scheme 1. Different approroches to αꢀamino phosphate synthesis
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Therefore synthesis of amino phosphates becomes more important. In this regard, nucleophilic
addition of phosphates to the imines using Lewis acid as a catalyst is being a current practice.
This particular method is also called as Kabachnik–Fields reaction (Scheme 1a).29,30 Most of the
Lewis acids which are used as catalysts in the above method are sensitive towards water, which
is generated as a byproduct of the imine formation. To overcome this problem, these reactions
are need to be carried out in the presence of dehydrating agents or used water stable Lewis acids
such as InCl3, Mg(ClO4)2 etc.31–33 For this methodology, researchers have developed different
kinds catalysts such as homogeneous, heterogeneous which includes magnetically separable and
biphasic catalysts.34–37 Owing to the harsh reaction conditions, low selectivity and
incompatibility towards synthesis of low molecular weight amino phosphate, researchers have
focused on other methods like CꢀH activation (Scheme 1b) and reduction of imino phosphates
(Scheme 1c) etc.38–43 In the recent past, owing to the interesting applications of protein
modification and protein labeling, more research work have been done on this area.44–46 Labeling
of proteins with phosphate group may lead to interesting applications in biology, nevertheless
introduction of phosphate group into the protein fold using the above mentioned methods are
very difficult owing to the harsh reaction conditions and low selectivity.47 In order to extend the
scope of amino phosphates in biological applications, we need more efficient methods which
work under mild reaction conditions possibly in aqueous medium with wide substrate scope and
high selectivity.
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On the other hand, metal complexes catalyzed carbene insertion reactions is one of the fast
growing methodologies in the present days.48–50 Carbene insertion reactions provide several
advantages such as mild reaction conditions, excellent yields with high enantiomeric excess,51–54
chemoselective versions55–57 and viability for protein labeling and modifications.58–65 Among all
the catalysts which are used for carbene insertion reaction, copper catalysts have its own benefits
of cost economy, mild reaction conditions, bioꢀcompatibility,63 chemoselectivity55,56 and
asymmetric versions.51,66,67 In this regard few reports are available in the literature, nevertheless
these systems suffered owing to poor yields and harsh reaction conditions.68,69 By considering
the wide scope of carbene insertion reactions in water, few attempts were made to carry out the
carbene insertion reaction in aqueous medium. To the best of our knowledge Che et al.62
developed the first carbene insertion of diazo ester into aniline in neat water using ruthenium
glycosylated porphyrin catalyst, later on Roelfes et al.,70 Gillingham et al.,63 Simonneaux et al.65
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and Rhee et al.64 partially succeeded by developing methods for carbene insertion of diazo ester
into aniline in aqueous media (mixture of solvents and buffer) using Cu and Fe based catalysts.
However the reported systems were failed either by complicated catalysts or by use of additives.
As we stated earlier, by developing novel synthetic route to make amino phosphates via carbene
insertion reaction in aqueous medium or in neat water, one can make an easy way to labeling the
protein and do further modification with enantiomerically pure phosphates. By considering the
importance of amino phosphate synthesis with high selectivity in neat water and in continuation
of our research on Cu(I) catalyzed NꢀH insertion reactions,55,56,71 here with we are reporting a
viable method for amino phosphate synthesis via carbene insertion of diazo phosphates into
aniline under mild reaction conditions with very good yields in neat water (Scheme 2).
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Results and discussion:
The reaction of simple aniline with αꢀphenyl diazo phosphonate using Rh2(OAc)4 produced very
low yield <10% over 24 h (Table 1, entry 1) in water medium, though we observed 23% yield in
DCM. Subsequently we screened [(COD)RhCl]2 as a catalyst (Table 1, entry 2) and it was
observed to produce the expected product with 81% over 16 h. After conforming the product
formation by standard spectroscopic techniques, in order to enhance the yield and to reduce the
reaction time, we continued our investigation with other possible catalysts for carbene insertion
reactions (Table 1). We screened Cp*IrCl2 and [(COD)IrCl]2 for carbene insertion, however both
the catalysts were failed to produce the expected product (Table 1, entry 3 and 4). Similarly, Ru
based catalysts were also failed to offer the carbene inserted product (Table 1, entry 5, 7 and 8).
We have also tested Pt and Pd based catalysts for the carbene insertion reaction and we observed
that Pt catalysts produced only trace amount of product in water (Table 1, entry 9 and 10) while
Pd catalysts produced moderate yield in both water and DCM (Table 1, entry 11ꢀ15).
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Scheme 2. −NꢀH insertion of αꢀphenyl diazo phosphate into aniline
Further our screening process upon different types of catalysts was continued to test the coinage
metals based catalysts such as CuI, AgOTf and AuCl towards carbene insertion reaction. Among
all the coinage metals catalysts used in the present study, CuI offered very good yield of 92%
over 8h (Table 1, entry 16). In case of AgOTf we observed <10% and 26% in water and DCM
respectively (Table 1, entry 17), whereas in case of AuCl, we have not observed the expected
product. Our investigation to search for good catalysts for carbene insertion reaction, we
screened a large number of catalysts in water medium, however none of the catalysts offered
satisfactory yield (Table 1, entry 19ꢀ34). In order to reduce the reaction time we continued our
screening with various Cu catalysts. Among the screened all possible Cu based catalysts,
(CH3CN)4CuClO4 offered excellent yields of 94% and 87% in water (15 min) and in DCM (2 h)
respectively (Table 1, entry 39). The other Cu catalysts such as Cu(OTf)2, CuSO4.5H2O and
Cu(OAc)2.H2O were also offered reasonably good yields of 87%, 89% and 90% respectively
over 15 min (Table 1, entry 36, 37 and 38), however CuCl2.2H2O offered relatively low yield of
66% over 15 min (Table 1, entry 35). Though the CuSO4.5H2O and Cu(OAc)2.H2O are stable
and of environmentally benign nature, to obtain the highest yields we have carried out reactions
with (CH3CN)4CuClO4 as a catalyst for further study. When we conducted the reaction with
(CH3CN)4CuClO4 as a catalyst in open atmosphere (Table 1, entry 40), the reaction was
completed in 15 min and offered expected product with 85% yield (in closed vessel we obtained
94% (Table 1, entry 40). And this experiment proved that the carbene intermediate is not
sensitive towards open atmosphere like other carbene reactions.49
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Table 1. Optimization of the catalysts for NꢀH insertion of αꢀphenyl diazo phosphate into aniline
in water
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entrya
catalyst
catalyst load
time
yield (%)b
(mol %)
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9
1
2
3
Rh2(OAc)4
[(COD)RhCl]2
[Cp*IrCl2]2
1
1
1
24 h
16 h
24 h
<10 (23)
81
ND (trace)
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[(COD)IrCl]2
[(pꢀcymene)RuCl2]2
RuCl3.3H2O
RuCl2(PPh3)3
Pt(AcAc)2
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2.5
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5
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5
2
2
2
2
2
2
24 h
24 h
24 h
ND
ND (28)
trace
<10
24 h
24 h
24 h
24 h
trace
trace
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40d
K2PtCl4
Pd2(dba)3
Pd(PPh3)4
24 h
17
PdCl2
24 h
24 h
12 (46)
<10
Pd(OOCH3)2
Pd(OOCF3)2
CuI
24 h
18
8 h
92
AgOTf
AuCl
24 h
24 h
24 h
<10 (26)
ND (ND)
<10
FeCl2.4H2O
Fe(BF4)2.4H2O
CoCl2.6H2O
Co(OAc)2.4H2O
Co(BF4)2.4H2O
NiCl2.6H2O
Ni(OAc)2.4H2O
MnCl2
Mn(OAc)2.4H2O
CrCl3
InCl3
ZnCl2
Zn(OAc)2.2H2O
VO(SO4)2
24 h
11
24 h
<10
24 h
<10
24 h
24 h
24 h
trace
trace
ND
24 h
24 h
trace
ND
24 h
24 h
trace
ND
24 h
ND
24 h
24 h
trace
ND
VCl3
24 h
24 h
trace
trace
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DyCl3.6H2O
CuCl2.2H2O
Cu(OTf)2
15 min
15 min
15 min
15 min
15 min
15 min
87 (81)c
90
Cu(OAc)2.H2O
Cu(SO4).5H2O
(CH3CN)4CuClO4
(CH3CN)4CuClO4
89
94 (87)c
85
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aAll the reactions were carried out with 1 mmol of aniline and 1.1 mmol of diazo in 4 ml of water or DCM in a
b
c
Schlenk tube under dinitrogen atmosphere. Pure compound from column chromatography. In DCM solvent
d
reaction was completed over 2 h. Reaction was carried out in open air atmosphere. Most of the cases we observed
trace amount of water (OꢀH) inserted product. ND: not detected. Yield in DCM given in parenthesis.
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Table 2. Solvent screening for NꢀH insertion of αꢀphenyl diazo phosphate into aniline
entrya
solvent
DCM
CH3CN
THF
time
2 h
24 h
6 h
yield (%)b
1
2
3
4
87
36
74
82
Toluene
8 h
5
7c
8
DMSO
CH3OH
DMF
12 h
1 h
12 h
trace
67
55
9
H2O
15 min
94
aAll the reactions were carried out with 1 mmol of aniline and 1.1 mmol of diazo in 4 ml of solvent in a Schlenk
tube under dinitrogen atmosphere. bPure compound from column chromatography. cWe obsereved 26% of methanol
OꢀH inserted product.
After finding a suitable catalyst for carbene insertion into the NꢀH bond, we screened various
commonly used solvents for carbene insertion using (CH3CN)4CuClO4 as a catalyst. In
acetonitrile the reaction was not completed even after 24 h and offered maximum of 36% yield
(Table 2, entry 2), this could be owing to the interception of carbene generation by acetonitrile
binding to Cu(I) center. However, the carbene dimerized product was not observed and the
unreacted diazo compounds were recovered. Similar to this observation, other coordinating
solvents such as THF, DMSO and DMF were also offered low yields (Table 2, entry 3, 5 and 8).
In case of DMSO, we did not observe the NꢀH inserted product, toluene offered good yield of
82% over 8 hours (Table 2, entry 4). When we conducted the reaction in methanol, the reaction
was completed within 1 h and offered 67% of NꢀH inserted product along with 26% of methanol
OꢀH inserted product (Table 2, entry 7). The above screening processes suggested that the water
and DCM would be the right solvents for carbene insertion reaction while using our choice of
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diazo compounds to make a large number of amino phosphates. Therefore all the reactions for
the present study were carried out using (CH3CN)4CuClO4 as a catalyst in water and also in
DCM.
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Table 3. Scope of diazo phosphates for NꢀH insertion of αꢀphenyl diazo phosphates into aniline
entrya
R
product
water
yield (%)b
DCM
yield (%)b
time
15 min
15 min
15 min
30 min
12 h
time
2 h
30 min
1 h
2 h
2 h
1
2
3
C6H5
2ꢀClC6H4
4ꢀClC6H4
4ꢀMeOC6H4
benzyl
94
93
94
95
<10
28
91
84
87
81
~70
43
3a
3b
3c
3d
3e
3f
4
5c
6
COOC2H5
12 h
6
aAll the reactions were carried out with 1 mmol of aniline and 1.1 mmol of diazo in 4 ml of water or DCM with 2
mol% of the catalyst in a Schlenk tube under dinitrogen atmosphere. bPure compound from column chromatography.
cYield from crude NMR and TLC experiment.
In order to show the substrate scope for making different kinds of amino phosphates through
carbene insertion into –NꢀH bond under milled reaction conditions, we screened various diazo
phosphates. We used different kinds of αꢀaryl diazo phosphates having electron withdrawing and
electron donating substituents. In case of having electron withdrawing substituents, the carbene
carbon becomes more electrophilic in nature and becomes susceptible to attack of nucleophiles,
therefore reason the reaction was completed very fast, in particular the 2ꢀCl and 4ꢀCl substituents
produced 93% and 94% yields respectively over 15 min in water medium. In DCM, we observed
relatively low yields of 84% and 87% over 30 min and 1 h respectively (Table 3, entry 2 and 3).
In case of electron donating 4ꢀOMe substrate, the carbene carbon becomes less electrophilic in
nature and stabilizes the carbene intermediate, the reaction reason the reaction occurred
relatively at slow rate and offered excellent yield of 95% over 30 min in water, in DCM we
observed 81% product over 2 h (Table 3, entry 4) and these observed trends are comparable with
the reaction of rhodium and copper catalyzed αꢀaryl ester carbene insertion into NꢀH bond.53,71
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Furthermore, we also selected other substrates to synthesize some novel amino phosphates (note
that the corresponding products could not be synthesized by known conventional methods).72 In
this direction we studied benzyl, ester functionalized diazo phosphates towards carbene insertion
into NꢀH bond to produce novel amino phosphates. These derivatives were produced relatively
less yield in water when compared to DCM. Ester functionalized diazo phosphate, which belongs
to the acceptor/acceptor class of diazo compounds and relatively less reactive and offered the
expected product with 28% yield over 12 h in water and 43% over 6 h in DCM. When the
reaction was conducted with the benzyl diazo phosphate in water, the reaction offered <10%
over 12 h and the color of the reaction was turned to green indicating that the Cu(I) ion got
oxidized to Cu(II) (Table 3, entry 5).
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In order to show the substrate scope for various anilines, we screened a variety of electron
donating and withdrawing group substituted anilines. First we have screened anilines having
electron donating substituents, all these substrates smoothly underwent the reaction and offered
very good yields (Table 4, entry 2ꢀ6). Among all the electron donating substituents, 3ꢀmethyl
aniline offered highest yield (93% in 30 min) in water (Table 4, entry 2) and 4ꢀmethoxy aniline
offered highest yield of 94% in 4 h in DCM (Table 4, entry 5). The 3,4ꢀdimethoxy aniline
offered lowest yield in water (79% in 4 h) (Table 4, entry 6). In case of DCM, 2,4,6ꢀtrimethyl
aniline offered lowest yield over 4 h (Table 4, entry 4). The steric and electronic factors of
different anilines did not show much effect on the yields of the carbene insertion into the NꢀH
bond. We also have screened a large number of anilines having electron withdrawing groups. All
the anilines underwent the insertion reaction smoothly and offered good to excellent yields
(Table 4, entry 7ꢀ22). The anilines having halogens offered relatively very good yields when
compared to other anilines having electron withdrawing functional groups.
Among all the screened anilines, 3ꢀCl aniline offered excellent yield of 97% over 15 min in
water (Table 4, entry 10). The 3ꢀnitro aniline offered the highest yield of 93% over 2 h in DCM
(Table 4, entry 17) and the 2ꢀaminobenzonitrile offered lowest yield of 44% and 47% in water
and DCM over 12 h and 8 h respectively (Table 4, entry 19). This might be owing to the
formation of relatively stable complex of 2ꢀaminobenzonitrile with Cu(I) salt. Similarly, the
reaction was taken much longer time (8 h and 5 h) for the completion of the reaction when 4ꢀ
aminobenzonitrile was used in water and in DCM (Table 4, entry 20). When compared to the
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reaction in DCM, 2,6ꢀdifluroaniline, 4ꢀiodoaniline and 2ꢀtrifluromethaneaniline offered very
good yields in water (Table 4, entry 8, 16 and 21). Further when we used 2ꢀaminopyridine (Table
3, entry 23), interestingly the reaction was completed over 12 h and offered 73% NꢀH inserted
product. However when we used benzyl amine, we observed only trace amount of the product
even after 24 h.
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Table 4. Scope of anilines for NꢀH insertion of αꢀphenyl diazo phosphates
entrya
Ar
product
water
yield (%)b
DCM
yield (%)b
time
30 min
30 min
2 h
2 h
2 h
time
4 h
3 h
4 h
4 h
4 h
4 h
2 h
2 h
2 h
2 h
2 h
2 h
1 h
2 h
2 h
3 h
2 h
6 h
8 h
5 h
2 h
2 h
18 h
1
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5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
4ꢀMeC6H4
3ꢀMeC6H4
91
93
92
90
89
79
93
81
96
97
81
92
92
93
91
92
88
85
44
78
94
81
73
83
84
91
81
94
85
88
57
93
90
88
90
83
87
88
74
93
81
47
85
79
70
68
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
2,4ꢀ(Me)2C6H3
2,4,6ꢀ(Me)3C6H2
4ꢀOMeC6H4
3,4ꢀ(OMe)2C6H3
4ꢀFC6H4
2,6ꢀ(F)2C6H3
4ꢀClC6H4
3ꢀClC6H4
2,4,5ꢀ(Cl)3C6H2
3ꢀCl,4ꢀFC6H3
2ꢀBrC6H4
4ꢀBrC6H4
2ꢀBr,4ꢀMeC6H3
4ꢀIC6H4
4 h
15 min
15 min
15 min
15 min
30 min
30 min
15 min
15 min
15 min
15 min
15 min
15 min
12 h
3ꢀNO2C6H4
4ꢀNO2C6H4
2ꢀCNC6H4
4ꢀCNC6H4
8 h
4t
2ꢀCF3C6H4
4ꢀCH3COC6H4
2ꢀPyridine
30 min
15 min
12 h
4u
4v
4w
aAll the reactions were carried out with 1 mmol of aniline and 1.1 mmol of diazo in 4 ml of water or DCM with 2
mol% of the catalyst in a Schlenk tube under dinitrogen atmosphere. bPure compound from column chromatography.
cInstead of aniline derivative reaction was carried out with 2ꢀamino pyridine.
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In this line we screened different anilines having other functional groups such as trifluro
methane, acetyl and nitrile groups, and all these aniline derivatives underwent the reaction
smoothly and offered very good yields (Table 4, entry 17ꢀ22). Among all the screened aniline
derivatives, only few derivatives offered relatively good yield in DCM as compared in water
(Table 4, entry 5, 6, 11 and 17).
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Scheme 3. Scope of various anilines and diazo phosphates for Cu(I) catalyzed NꢀH insertion
reaction.
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After demonstrating the wide range of substrate scope for different anilines in water and in
DCM, we checked the substrate scope of various combinations of diazo phosphates and anilines
in DCM. Among the screened substrates 4ꢀmethoxyphenyl diazo phosphate offered excellent
yield of 94% and 95% with 4ꢀOMe and 4ꢀMe anilines respectively (Scheme 3, 5a and 5b)
whereas ethyl acetate phosphate diazo offered relatively lower yield among all the screened
substrates (Scheme 3, 5g and 5h).
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In conclusion, we have developed a methodology to prepare various amino phosphates via
carbene insertion into the NꢀH bond using Cu(I) complexes as catalysts in neat water. In the
screening processes of finding an efficient catalyst for carbene insertion reaction in neat water,
we screened a large number of transition metal sources as catalysts towards carbene insertion
reaction. By considering the wide range of applications of αꢀamino phosphates, we successfully
utilized the developed methodology for making a large number of amino phosphates with good
yields via carbene insertion in neat water and also in DCM, and characterized all the new and
known amino phosphates using standard analytical and spectroscopic techniques. We hope in the
near future this methodology would be much useful for protein labelling with various
phosphates. Further studies on carbene insertion reactions in neat water are under progress in
our laboratory.
EXPERIMENTAL SECTION:
General information: Unless otherwise specified all the reactions were carried out with oven
dried glassware under dry nitrogen atmosphere. All the solvents were distilled prior to use using
standard procedures. Distilled water was barged for 5 minutes with dinitrogen gas and used,
dichloromethane was distilled from the CaH2 and used. Anilines were procured from commercial
sources and used as received. Cu(I) salts of organic ligands are explosive in nature therefore
should be used with adequate care. All the diazo compounds were prepared by following the
standard literature procedures.73 TLC was performed on pre coated silica gel 60 F254 on
aluminum plates and UV light (254 nm). Column chromatography was performed on silica gel
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100ꢀ200 mesh size. H and 13C NMR spectra were recorded on 400 MHz (1H) and 100 MHz
(13C), Chemical shifts (δ) are given in ppm. The residual solvent signals were used as references
for 1H NMR and 13C NMR. HRꢀMS was recorded on UHD QꢀTOF mass spectrometer.
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General procedure for Cu(I) catalyzed carbene insertion into NꢀH bond in neat water (A):
A 20 mL Schlenk flask was charged with aniline (1 mmol) and catalyst (2 mol %), then 4 mL of
water was added to the reaction mixture. Then diazo compound (1.1 mmol) was added dropwise
to the reaction mixture, then the reaction mixture was stirred at room temperature for reported
time. The progress of the reaction was monitored by TLC experiment for every 15 minutes using
appropriate mixture of hexane and ethyl acetate (~1:1) as eluent. After completion of reaction,
the reaction mixture was extracted with 15 mL (5 mL X 3) of EtOAc. Then EtOAc was
evaporated under reduced pressure and the crude residue was purified using column
chromatography on silica gel using (3:1) hexane/ethyl acetate.
General procedures for Cu(I) catalyzed carbene insertion into NꢀH bond in DCM (B):
A 20 mL Schlenk flask was charged with aniline (1 mmol) and catalyst (2 mol %), then 3 mL of
DCM was added to the reaction mixture. The diazo compound (1.1 mmol) was dissolved in 1 mL
of DCM and dropwise added to the reaction mixture at room temperature. Then the reaction
mixture was stirred for reported time. The progress of the reaction was monitored by TLC
experiment for every 30 minutes using appropriate mixture of hexane and ethyl acetate (~1:1) as
eluent. After completion of reaction, the solvent was evaporated under reduced pressure and the
crude residue was purified using column chromatography on silica gel using (3:1) hexane/ethyl
acetate.
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Diethyl (phenyl(phenylamino)methyl)phosphonate (3a):31
1
6
7
8
9
Prepared according to the general procedure A: OffꢀWhite solid (301 mg, 94% yield); H NMR
(400 MHz, CDCl3) δ 7.50 – 7.44 (m, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.26 (dt, J = 7.5, 3.4 Hz, 1H),
7.09 (t, J = 7.9 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 7.8 Hz, 2H), 4.79 (s, 1H), 4.73 (s,
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1H), 4.18 – 4.03 (m, 2H), 3.93 (m, 1H), 3.74 – 3.60 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.11 (t, J =
13
7.1 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 146.45 (d, JCꢀP = 14.6 Hz), 136.05 (d, J CꢀP
=
2.8 Hz), 129.3, 128.7, 128.7, 128.0, 118.5, 114.0, 63.40 (d, JCꢀP = 2.9 Hz), 63.33 (d, JCꢀP = 3.0
Hz), 56.23 (d, JCꢀP = 150.4 Hz), 16.54 (d, JCꢀP = 5.8 Hz), 16.29 (d, JCꢀP = 5.8 Hz); IR (Film):
3295, 3029, 2982, 2908, 1604, 1525, 1497, 1453, 1316, 1273, 1236, 1162, 1058, 1018, 966, 798,
768, 751, 696 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C17H23NO3P) 320.1416, found
320.1421.
Diethyl ((2ꢀchlorophenyl)(phenylamino)methyl)phosphonate (3b):74
1
Prepared according to the general procedure A: OffꢀWhite solid (329 mg, 93% yield); H NMR
(400 MHz, CDCl3) δ 7.57 (dt, J = 7.3, 2.3 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.22 (ddd, J = 8.9,
7.6, 3.9 Hz, 2H), 7.11 (t, J = 7.9 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H), 5.38
(m, 1H), 4.97 (t, J = 9.1 Hz, 1H), 4.21 (m, 2H), 3.95 – 3.84 (m, 1H), 3.69 – 3.57 (m, 1H), 1.33 (t,
13
J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 145.83 (d, JCꢀP
=
14.7 Hz), 134.27 (d, JCꢀP = 7.4 Hz), 129.54 (d, JCꢀP = 2.4 Hz), 129.4, 129.19 (d, JCꢀP = 3.2 Hz),
129.02 (d, JCꢀP = 4.2 Hz), 127.47 (d, JCꢀP = 3.0 Hz), 63.58 (d, JCꢀP = 4.1 Hz), 63.51 (d, JCꢀP = 3.9
Hz), 51.66 (d, JCꢀP = 152.9 Hz), 16.55 (d, JCꢀP = 5.9 Hz), 16.19 (d, JCꢀP = 5.8 Hz); IR (Film):
3299, 3107, 3058, 3028, 2984, 2932, 2910, 1602, 1521, 1497, 1477, 1443, 1389, 1269, 1235,
1059, 1014, 981, 802, 786, 752, 722, 693 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for
C17H22ClNO3P) 354.1026, found 354.1021.
Diethyl ((4ꢀchlorophenyl)(phenylamino)methyl)phosphonate (3c):74
1
Prepared according to the general procedure A: OffꢀWhite solid (333 mg, 94% yield); H NMR
(400 MHz, CDCl3) δ 7.41 (dd, J = 8.5, 2.1 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.10 (t, J = 7.9 Hz,
2H), 6.71 (t, J = 7.3 Hz, 1H), 6.56 (d, J = 8.4 Hz, 2H), 4.87 – 4.63 (m, 2H), 4.20 – 4.05 (m, 2H),
4.02 – 3.91 (m, 1H), 3.83 – 3.72 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H);
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13C{1H} NMR (100 MHz, CDCl3) δ 146.12 (d, JCꢀP = 14.6 Hz), 134.70 (d, JCꢀP = 3.1 Hz), 133.79
(d, JCꢀP = 3.9 Hz), 129.3, 129.24 (d, JCꢀP = 5.4 Hz), 128.88 (d, JCꢀP = 2.7 Hz), 118.7, 113.9, 63.51
(d, JCꢀP = 7.1 Hz), 63.42 (d, JCꢀP = 7.0 Hz), 55.62 (d, JCꢀP = 150.5 Hz), 16.52 (d, JCꢀP = 5.8 Hz),
16.34 (d, JCꢀP = 5.7 Hz); IR (Film): 3414, 3305, 3050, 3026, 2978, 2905, 1603, 1522, 1499,
1485, 1311, 1288, 1268, 1243, 1230, 1054, 1025, 938, 753, 692 cmꢀ1; HRMSꢀESI (m/z): [M+H]+
calculated (for C17H22ClNO3P) 354.1026, found 354.1035.
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Diethyl ((4ꢀmethoxyphenyl)(phenylamino)methyl)phosphonate (3d):37
1
Prepared according to the general procedure A: OffꢀWhite solid (332 mg, 95% yield); H NMR
(400 MHz, CDCl3) δ 7.38 (dd, J = 8.7, 2.2 Hz, 2H), 7.10 (t, J = 7.8 Hz, 2H), 6.86 (d, J = 8.6 Hz,
2H), 6.68 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.1 Hz, 2H), 4.74 (s, 1H), 4.68 (s, 1H), 4.16 – 4.05
(m, 2H), 3.99 – 3.89 (m, 1H), 3.77 (s, 3H), 3.73 – 3.65 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.13 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.29 (d, JCꢀP = 3.1 Hz), 146.35 (d, JCꢀP
=
14.9 Hz), 129.1, 128.95 (d, JCꢀP = 5.6 Hz), 127.66 (d, JCꢀP = 2.9 Hz), 118.3, 114.05 (d, JCꢀP = 2.5
Hz), 113.9, 63.26 (d, JCꢀP = 4.0 Hz), 63.19 (d, JCꢀP = 4.0 Hz), 55.34 (d, JCꢀP = 151.2 Hz), 55.2,
16.45 (d, JCꢀP = 5.8 Hz), 16.27 (d, JCꢀP = 5.8 Hz); IR (Film): 3463, 3294, 3030, 2984, 2932, 2909,
2838, 1600, 1511, 1492, 1442, 1309, 1262, 1232, 1182, 1159, 1061, 1020, 973, 836, 757, 694
cmꢀ1. HRMSꢀESI (m/z): [M+H]+ calculated (for C18H25NO4P) 350.1521, found 350.1539.
Ethyl 2ꢀ(diethoxyphosphoryl)ꢀ2ꢀ(phenylamino)acetate (3f):75
1
Prepared according to the general procedure A: OffꢀWhite solid (89 mg, 28% yield); H NMR
(400 MHz, CDCl3) δ 7.18 (dd, J = 11.0, 4.4 Hz, 2H), 6.79 (td, J = 7.4, 0.7 Hz, 1H), 6.67 (d, J =
8.2 Hz, 2H), 4.63 – 4.43 (m, 2H), 4.29 – 4.13 (m, 6H), 1.30 (m, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 168.5, 146.28 (d, JCꢀP = 11.3 Hz), 129.4, 119.5, 114.1, 64.11 (d, JCꢀP = 6.7 Hz), 63.63
(d, JCꢀP = 7.1 Hz), 62.3, 56.54 (d, JCꢀP = 148.6 Hz), 16.47 (t, JCꢀP = 5.5 Hz), 14.2; IR (Film):
3292, 3114, 2987, 2934, 2908, 1750, 1604, 1527, 1502, 1394, 1301, 1274, 1256, 1214, 1187,
1169, 1144, 1028, 985, 967, 838, 755, 695 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for
C14H23NO5P) 316.1314, found 316.1323.
Diethyl (phenyl(pꢀtolylamino)methyl)phosphonate (4a):74
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Prepared according to the general procedure A: OffꢀWhite solid (304 mg, 91% yield); H NMR
(400 MHz, CDCl3) δ 7.46 (dd, J = 7.3, 1.3 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.27 – 7.22 (m, 1H),
6.90 (d, J = 8.2 Hz, 2H), 6.51 (d, J = 8.4 Hz, 2H), 4.73 (d, J = 24.2 Hz, 1H), 4.16 – 4.02 (m, 2H),
3.98 – 3.88 (m, 1H), 3.73 – 3.63 (m, 1H), 2.17 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1
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13
Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 144.09 (d, JCꢀP = 15.1 Hz), 136.15 (d, JCꢀP = 2.7
Hz), 129.7, 128.64 (d, JCꢀP = 2.7 Hz), 128.0, 127.9, 127.9, 127.7, 114.1, 63.35 (d, JCꢀP = 6.0 Hz),
63.29 (d, JCꢀP = 5.9 Hz), 56.46 (d, JCꢀP = 150.5 Hz), 20.4, 16.52 (d, JCꢀP = 5.8 Hz), 16.28 (d, JCꢀP
= 5.8 Hz); IR (Film): 3297, 3029, 2982, 2908, 1616, 1522, 1238, 1056, 1024, 978,821, 803, 773,
699 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C18H25NO3P) 334.1572, found 334.1575.
Diethyl (phenyl(mꢀtolylamino)methyl)phosphonate (4b):37
Prepared according to the general procedure A: White solid (310 mg, 93% yield); 1H NMR (400
MHz, CDCl3) δ 7.48 – 7.43 (m, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 6.96 (t, J =
7.8 Hz, 1H), 6.52 – 6.35 (m, 3H), 4.78 (s, 1H), 4.72 (d, J = 7.3 Hz, 1H), 4.17 – 4.04 (m, 2H),
3.97 – 3.87 (m, 1H), 3.72 – 3.61 (m, 1H), 2.19 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1
13
Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 146.42 (d, JCꢀP = 14.3 Hz), 138.9, 136.1, 129.1,
128.58 (d, JCꢀP = 2.6 Hz), 127.90 (d, JCꢀP = 1.5 Hz), 127.8, 119.4, 114.8, 110.8, 63.3, 63.2, 56.09
(d, JCꢀP = 150.4 Hz), 21.6, 16.46 (d, JCꢀP = 5.7 Hz), 16.21 (d, JCꢀP = 5.8 Hz); IR (Film): 3298,
3040, 2985, 2909, 2867, 1607, 1532, 1490, 1453, 1321, 1275, 1236, 1172, 1059, 1018, 969, 771,
697 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C18H25NO3P) 334.1572, found 334.1567.
Diethyl (((2,4ꢀdimethylphenyl)amino)(phenyl)methyl)phosphonate (4c):
Prepared according to the general procedure A: Light brown thick liquid (320 mg, 92% yield);
1H NMR (400 MHz, CDCl3) δ 7.48 – 7.43 (m, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.27 – 7.23 (m, 1H),
6.88 (s, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.30 (d, J = 8.1 Hz, 1H), 4.77 (d, JHꢀP = 24.1 Hz, 1H), 4.54
(s, 1H), 4.20 – 4.04 (m, 2H), 4.00 – 3.89 (m, 1H), 3.76 – 3.65 (m, 1H), 2.25 (s, 3H), 2.16 (s, 3H),
1.27 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.07 (d,
JCꢀP = 14.6 Hz), 136.14 (d, JCꢀP = 3.0 Hz), 131.2, 128.66 (d, JCꢀP = 2.7 Hz), 127.93 (d, JCꢀP = 3.3
Hz), 127.80 (d, JCꢀP = 5.4 Hz), 127.33, 127.27, 123.1, 111.6, 63.41 (d, JCꢀP = 7.0 Hz), 63.29 (d,
JCꢀP = 6.9 Hz), 56.43 (d, JCꢀP = 150.0 Hz), 20.4, 17.6, 16.53 (d, JCꢀP = 5.8 Hz), 16.30 (d, JCꢀP = 5.8
Hz); IR (Film): 3425, 2982, 2910, 1619, 1514, 1451, 1390, 1308, 1243, 1162, 1095, 1053, 1023,
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969, 801, 699 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C19H27NO3P) 348.1729, found
348.1720.
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Diethyl ((mesitylamino)(phenyl)methyl)phosphonate (4d):
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Prepared according to the general procedure A: Light yellow solid (326 mg, 80% yield); Mp:
85−88 °C; 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.39 (m, 2H), 7.32 – 7.25 (m, 3H), 6.72 (s, 2H),
4.43 (d, J = 22.4 Hz, 1H), 4.18 – 4.10 (m, 2H), 4.06 (s, 1H), 3.94 – 3.85 (m, 1H), 3.61 (m, 1H),
2.17 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 141.64 (d, JCꢀP = 10.2 Hz), 137.3, 131.1, 129.6, 128.9, 128.5, 128.46 – 128.39 (m), 127.90 (d,
JCꢀP = 2.3 Hz), 62.93 (t, JCꢀP = 7.2 Hz), 59.40 (d, JCꢀP = 148.3 Hz), 20.9, 18.9, 16.50 (d, JCꢀP = 6.0
Hz), 16.21 (d, JCꢀP = 5.7 Hz); IR (Film): 3355, 3060, 3032, 2977, 2938, 2859, 2731, 1482, 1452,
1390, 1310, 1228, 1161, 1095, 1028, 954, 859, 795, 723, 702 cmꢀ1; HRMSꢀESI (m/z): [M+H]+
calculated (for C20H29NO3P) 362.1885, found 362.1874.
Diethyl (((4ꢀmethoxyphenyl)amino)(phenyl)methyl)phosphonate (4e):31
Prepared according to the general procedure A: White solid (311 mg, 89% yield); 1H NMR (400
MHz, CDCl3) δ 7.48 – 7.43 (m, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.27 – 7.22 (m, 1H), 6.68 (t, J =
6.1 Hz, 2H), 6.55 (t, J = 6.1 Hz, 2H), 4.69 (d, JHꢀP = 24.0 Hz, 1H), 4.15 – 4.03 (m, 2H), 3.97 –
3.88 (m, 1H), 3.67 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 152.7, 140.5, 140.3, 136.1, 128.63 (d, JCꢀP = 2.6 Hz), 127.95 (d, JCꢀP = 5.7 Hz),
115.3, 114.8, 63.29 (t, JCꢀP = 6.7 Hz), 57.06 (d, JCꢀP = 150.5 Hz), 55.70, 16.50 (d, JCꢀP = 5.8 Hz),
16.26 (d, JCꢀP = 5.8 Hz); IR (Film): 3333, 3037, 2988, 2933, 2907, 2832, 1513, 1456, 1316, 1265,
1233, 1177, 1089, 1052, 1014, 965, 819, 792, 758, 726, 697 cmꢀ1; HRMSꢀESI (m/z): [M+H]+
calculated (for C18H25NO4P) 350.1521, found 350.1516.
Diethyl (((3,4ꢀdimethoxyphenyl)amino)(phenyl)methyl)phosphonate (4f):76
Prepared according to the general procedure A: Light brown solid (301 mg, 79% yield); 1H NMR
(400 MHz, CDCl3) δ 7.48 – 7.44 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 6.8 Hz, 1H), 6.62
(d, J = 8.6 Hz, 1H), 6.26 (d, J = 2.5 Hz, 1H), 6.06 (dd, J = 8.6, 2.6 Hz, 1H), 4.70 (d, JHꢀP = 23.9
Hz, 1H), 4.19 – 4.08 (m, 2H), 3.97 – 3.91 (m, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.71 – 3.65 (m,
1H), 1.30 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 149.9,
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142.2, 141.06 (d, JCꢀP = 15.8 Hz), 136.19 (d, JCꢀP = 3.0 Hz), 128.71 (d, JCꢀP = 2.7 Hz), 128.03 (d,
JCꢀP = 3.3 Hz), 127.93 (d, JCꢀP = 5.5 Hz), 112.9, 104.8, 100.1, 63.40 (d, JCꢀP = 3.5 Hz), 63.33 (d,
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JCꢀP = 3.6 Hz), 57.02 (d, JCꢀP = 149.6 Hz), 56.58, 55.74, 16.56 (d, JCꢀP = 5.8 Hz), 16.31 (d, JCꢀP =
5.8 Hz); IR (Film): 3312, 2984, 2832, 1615, 1515, 1452, 1235, 1166, 1140, 1052, 1025, 968,
767, 700 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C19H27NO5P) 380.1627, found
380.1634.
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Diethyl (((4ꢀfluorophenyl)amino)(phenyl)methyl)phosphonate (4g):76
Prepared according to the general procedure A: OffꢀWhite solid (315 mg, 93% yield); 1H NMR
(400 MHz, CDCl3) δ 7.47 – 7.41 (m, 2H), 7.33 (t, J = 7.3 Hz, 2H), 7.26 (dd, J = 8.4, 5.9 Hz, 1H),
6.80 (dd, J = 12.2, 5.1 Hz, 2H), 6.52 (dt, J = 6.8, 4.0 Hz, 2H), 4.69 (m, 2H), 4.18 – 4.05 (m, 2H),
3.97 – 3.87 (m, 1H), 3.72 – 3.61 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 156.38 (d, JCꢀF = 236.3 Hz), 142.71 (d, JCꢀF = 15.3 Hz),
135.8, 128.75 (d, JCꢀP = 2.7 Hz), 128.12 (d, JCꢀP = 3.2 Hz), 127.95 (d, JCꢀP = 5.5 Hz), 115.74 (d,
JCꢀF = 22.4 Hz), 114.94 (d, JCꢀF = 7.5 Hz), 63.39 (t, JCꢀP = 7.5 Hz), 56.85 (d, JCꢀP = 150.6 Hz),
16.53 (d, JCꢀP = 5.8 Hz), 16.29 (d, JCꢀP = 5.8 Hz); IR (Film): 3296, 3064, 2985, 2930, 2908, 2885,
1508, 1448, 1390, 1367, 1305, 1269, 1238, 1183, 1157, 1123, 1076, 1029, 978, 825, 793, 777,
701 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C17H22FNO3P) 338.1321, found 338.1318.
Diethyl (((2,6ꢀdifluorophenyl)amino)(phenyl)methyl)phosphonate (4h):
Prepared according to the general procedure A: White solid (289 mg, 81% yield); Mp: 60−62 °C;
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.7 Hz, 2H), 7.30 (t, J = 7.3 Hz, 2H), 7.26 – 7.22 (m,
1H), 6.74 (dd, J = 17.4, 8.8 Hz, 2H), 6.64 (dt, J = 9.3, 6.4 Hz, 1H), 5.04 (dd, JHꢀF = 23.2 Hz, JHꢀP
= 11.3 Hz, 1H), 4.70 (dd, JHꢀP = 10.7 Hz, JHꢀH = 8.1 Hz, 1H), 4.23 – 4.15 (m, 2H), 3.98 – 3.89
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(m, 1H), 3.71 – 3.62 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H); C{1H} NMR
(100 MHz, CDCl3) δ 154.11 (dd, JCꢀF = 242.1 Hz, JCꢀP = 7.0 Hz), 136.2, 128.63 (d, JCꢀP = 2.2 Hz),
128.4, 128.20 (d, JCꢀP = 2.9 Hz), 127.97 (d, JCꢀP = 5.9 Hz), 127.2, 123.92 (q, JCꢀF = 13.9 Hz),
119.46 (t, JCꢀF = 9.6 Hz), 111.62 (dd, JCꢀF = 16.7 Hz, JCꢀP = 7.1 Hz), 63.41 (d, JCꢀP = 3.9 Hz),
63.35 (d, JCꢀP = 3.8 Hz), 57.56 (dt, JCꢀP = 151.4, JCꢀF = 4.1 Hz), 16.55 (d, JCꢀP = 5.8 Hz), 16.25
(d, JCꢀP = 5.8 Hz); IR (Film): 3285, 3068, 2980, 2911, 1598, 1489, 1462, 1390, 1279, 1251, 1227,
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1209, 1098, 1051, 1027, 998, 967, 943, 812, 788, 753, 738, 694 cmꢀ1; HRMSꢀESI (m/z): [M+H]+
calculated (for C17H21F2NO3P) 356.1227, found 356.1205.
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Diethyl (((4ꢀchlorophenyl)amino)(phenyl)methyl)phosphonate (4i):37
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1
Prepared according to the general procedure A: OffꢀWhite solid (341 mg, 96% yield); H NMR
(400 MHz, CDCl3) δ 7.48 – 7.39 (m, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.29 – 7.25 (m, 1H), 7.03 (d,
J = 8.7 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H), 4.86 (d, J = 5.9 Hz, 1H), 4.69 (dd, JHꢀP = 24.0 Hz, JHꢀH
= 7.4 Hz, 1H), 4.21 – 4.03 (m, 2H), 3.97 – 3.87 (m, 1H), 3.72 – 3.60 (m, 1H), 1.29 (t, J = 7.1 Hz,
3H), 1.10 (t, J = 7.1 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 145.03 (d, JCꢀP = 15.0 Hz),
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135.6, 129.1, 128.8, 128.8, 127.9, 127.9, 115.1, 63.52 (d, JCꢀP = 7.0 Hz), 63.37 (d, JCꢀP = 7.0 Hz),
56.33 (d, JCꢀP = 150.7 Hz), 16.54 (d, JCꢀP = 5.7 Hz), 16.30 (d, JCꢀP = 5.8 Hz); IR (Film): 3293,
2982, 2905, 1599, 1516, 1492, 1312, 1235, 1094, 1058, 1026, 979, 820, 700 cmꢀ1; HRMSꢀESI
(m/z): [M+H]+ calculated (for C17H22ClNO3P) 354.1026, found 354.1033.
Diethyl (((3ꢀchlorophenyl)amino)(phenyl)methyl)phosphonate (4j):77
Prepared according to the general procedure A: White solid (343 mg, 97% yield); 1H NMR (400
MHz, CDCl3) δ 7.48 – 7.40 (m, 2H), 7.34 (t, J = 7.3 Hz, 2H), 7.30 – 7.24 (m, 1H), 6.99 (t, J =
8.0 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 6.59 (s, 1H), 6.45 (dd, J = 8.2, 1.6 Hz, 1H), 4.97 (bs, 1H),
4.71 (dd, JHꢀP = 24.1 Hz, JHꢀH =7.7 Hz, 1H), 4.18 – 4.05 (m, 2H), 3.92 (m, 1H), 3.70 – 3.59 (m,
1H), 1.28 (d, J = 7.0 Hz, 3H), 1.10 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
147.69 (d, JCꢀP = 14.7 Hz), 135.6, 135.0, 130.3, 128.82 (d, JCꢀP = 2.5 Hz), 128.24 (d, JCꢀP = 3.2
Hz), 127.92 (d, JCꢀP = 5.4 Hz), 118.4, 113.8, 112.1, 63.55 (d, JCꢀP = 7.0 Hz), 63.38 (d, JCꢀP = 7.0
Hz), 56.03 (d, JCꢀP = 150.9 Hz), 16.55 (d, JCꢀP = 5.8 Hz), 16.30 (d, JCꢀP = 5.8 Hz); IR (Film):
3292, 3067, 2981, 2908, 1598, 1523, 1480, 1453, 1321, 1282, 1235, 1163, 1092, 1056, 1017,
970, 768, 699, 683 cmꢀ1; HRMSꢀESI (m/z): [M+Na]+ calculated (for C17H21ClNNaO3P)
376.0845, found 376.0849.
Diethyl (phenyl((2,4,5ꢀtrichlorophenyl)amino)methyl)phosphonate (4k):
Prepared according to the general procedure A: White solid (343 mg, 81% yield); Mp: 90−93 °C;
1H NMR (400 MHz, CDCl3) δ 7.46 – 7.41 (m, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.34 – 7.27 (m, 2H),
6.52 (s, 1H), 5.45 (dd, J = 9.8, 7.9 Hz, 1H), 4.69 (dd, JHꢀP = 23.9 Hz, JHꢀH = 7.5 Hz, 1H), 4.16 –
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4.04 (m, 2H), 4.00 – 3.92 (m, 1H), 3.78 – 3.68 (m, 1H), 1.29 (t, J = 7.0 Hz, 3H), 1.14 (t, J = 7.0
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Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 142.02 (d, JCꢀP = 14.2 Hz), 134.48 (d, JCꢀP = 3.3
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Hz), 131.6, 130.1, 129.00 (d, J = 2.7 Hz), 128.57 (d, JCꢀP = 3.2 Hz), 127.70 (d, JCꢀP = 5.3 Hz),
120.7, 118.8, 113.5, 63.58 (d, JCꢀP = 7.2 Hz), 63.50 (d, JCꢀP = 7.2 Hz), 55.92 (d, JCꢀP = 151.4 Hz),
16.42 (d, JCꢀP = 5.7 Hz), 16.20 (d, JCꢀP = 5.8 Hz); IR (Film): 3390, 2982, 2932, 1591, 1498, 1442,
1377, 1294, 1225, 1099, 1053, 1023, 964, 939, 878, 759, 697, 674 cmꢀ1; HRMSꢀESI (m/z):
[M+Na]+ calculated (for C17H19Cl3NNaO3P) 444.0066, found 444.0067.
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Diethyl (((3ꢀchloroꢀ4ꢀfluorophenyl)amino)(phenyl)methyl)phosphonate (4l):78
Prepared according to the general procedure A: OffꢀWhite solid (343 mg, 92% yield); 1H NMR
(400 MHz, CDCl3) δ 7.46 – 7.41 (m, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.30 (dd, J = 7.1, 1.6 Hz, 1H),
6.86 (t, J = 8.8 Hz, 1H), 6.61 (dd, J = 6.0, 2.9 Hz, 1H), 6.41 (dt, J = 8.9, 3.3 Hz, 1H), 4.85 (t, J =
8.4 Hz, 1H), 4.65 (dd, JHꢀP = 24.0 Hz, JHꢀH = 7.5 Hz, 1H), 4.18 – 4.05 (m, 2H), 3.97 – 3.86 (m,
1H), 3.70 – 3.59 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 151.36 (d, JCꢀF = 238.7 Hz), 143.34 (dd, JCꢀF = 15.3 Hz, JCꢀP = 2.2 Hz), 135.28
(d, JCꢀP = 2.7 Hz), 128.71 (d, JCꢀP = 2.6 Hz), 128.17 (d, JCꢀP = 3.2 Hz), 127.83 (d, JCꢀP = 5.5 Hz),
121.00 (d, JCꢀF = 18.6 Hz), 116.68 (d, JCꢀF = 22.0 Hz), 115.2, 112.90 (d, JCꢀP = 6.3 Hz), 63.47 (d,
JCꢀP = 7.0 Hz), 63.27 (d, JCꢀP = 7.0 Hz), 56.38 (d, JCꢀP = 151.4 Hz), 16.42 (d, JCꢀP = 5.8 Hz), 16.17
(d, JCꢀP = 5.7 Hz); IR (Film): 3301, 3117, 3061, 2980, 2906, 2850, 1610, 1532, 1502, 1452, 1392,
1331, 1235, 1051, 1024, 977, 864, 810, 790, 774, 698 cmꢀ1; HRMSꢀESI (m/z): [M+H]+
calculated (for C17H21ClFNO3P) 372.0932, found 372.0933.
Diethyl (((2ꢀbromophenyl)amino)(phenyl)methyl)phosphonate (4m):79
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Prepared according to the general procedure A: Colorless thick liquid (367 mg, 92% yield); H
NMR (400 MHz, CDCl3) δ 7.47 – 7.41 (m, 3H), 7.34 (t, J = 7.5 Hz, 2H), 7.29 – 7.25 (m, 1H),
7.03 – 6.97 (m, 1H), 6.56 (td, J = 7.8, 1.3 Hz, 1H), 6.45 – 6.40 (m, 1H), 5.51 – 5.37 (m, 1H),
4.79 (dd, JHꢀP = 24.3 Hz, JHꢀH = 7.2 Hz, 1H), 4.16 – 3.98 (m, 3H), 3.86 – 3.77 (m, 1H), 1.27 (t, J
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= 7.0 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 143.45 (d, JCꢀP
=
14.4 Hz), 135.32 (d, JCꢀP = 3.3 Hz), 132.6, 128.77 (d, JCꢀP = 2.8 Hz), 128.41 (d, JCꢀP = 2.8 Hz),
128.17 (d, JCꢀP = 3.3 Hz), 127.79 (d, JCꢀP = 5.3 Hz), 119.1, 112.8, 110.6, 63.70 (d, JCꢀP = 7.0 Hz),
63.50 (d, JCꢀP = 6.9 Hz), 56.28 (d, JCꢀP = 150.5 Hz), 16.53 (d, JCꢀP = 5.7 Hz), 16.35 (d, JCꢀP = 5.8
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Hz); IR (Film): 3396, 2983, 1714, 1593, 1508, 1455, 1433, 1317, 1249, 1096, 1051, 1021, 969,
743, 699 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C17H22BrNO3P) 398.0521, found
398.0508.
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Diethyl (((4ꢀbromophenyl)amino)(phenyl)methyl)phosphonate (4n):74
Prepared according to the general procedure A: OffꢀWhite solid (371 mg, 93% yield); 1H NMR
(400 MHz, CDCl3) δ 7.46 – 7.40 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.30 – 7.25 (m, 1H), 7.17 (d,
J = 8.8 Hz, 2H), 6.47 (d, J = 8.8 Hz, 2H), 4.90 (t, J = 8.6 Hz, 1H), 4.69 (dd, JHꢀP = 24.1 Hz, JHꢀH
= 7.6 Hz, 1H), 4.18 – 4.04 (m, 2H), 3.92 (m, 1H), 3.65 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.10 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.44 (d, JCꢀP = 14.9 Hz), 135.49 (d, JCꢀP
=
2.9 Hz), 132.0, 128.79 (d, JCꢀP = 2.7 Hz), 128.20 (d, JCꢀP = 3.2 Hz), 127.89 (d, JCꢀP = 5.5 Hz),
115.6, 110.3, 63.53 (d, JCꢀP = 7.0 Hz), 63.37 (d, JCꢀP = 7.0 Hz), 56.16 (d, JCꢀP = 150.7 Hz), 16.54
(d, JCꢀP = 5.8 Hz), 16.29 (d, JCꢀP = 5.8 Hz); IR (Film): 3292, 2981, 2905, 1593, 1515, 1489, 1450,
1391, 1313, 1273, 1236, 1098, 1025, 978, 817, 798, 763, 733, 699, 628, 607 cmꢀ1; HRMSꢀESI
(m/z): [M+H]+ calculated (for C17H22BrNO3P) 398.0521, found 398.0508.
Diethyl (((2ꢀbromoꢀ4ꢀmethylphenyl)amino)(phenyl)methyl)phosphonate (4o):80
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Prepared according to the general procedure A: Light orange solid (376 mg, 91% yield); H
NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.28 – 7.24 (m,
2H), 6.81 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 8.3 Hz, 1H), 5.36 – 5.22 (m, 1H), 4.76 (dd, JHꢀP = 24.3
Hz, JHꢀH = 7.4 Hz, 1H), 4.16 – 3.97 (m, 3H), 3.81 (m, 1H), 2.16 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H),
1.18 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 141.18 (d, JCꢀP = 14.8 Hz), 135.56
(d, JCꢀP = 3.3 Hz), 133.0, 129.0, 128.75 (d, J = 2.8 Hz), 128.7, 128.11 (d, JCꢀP = 3.3 Hz), 127.84
(d, JCꢀP = 5.3 Hz), 112.8, 110.5, 63.68 (d, JCꢀP = 7.0 Hz), 63.43 (d, JCꢀP = 6.9 Hz), 56.54 (d, JCꢀP
=
150.4 Hz), 20.1, 16.57 (d, JCꢀP = 5.7 Hz), 16.39 (d, JCꢀP = 5.9 Hz); IR (Film): 3399, 3060, 3029,
2974, 2922, 1716, 1610, 1514, 1452, 1396, 1369, 1314, 1253, 1224, 1158, 1098, 1057, 1019,
972, 808, 782, 757, 692 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C18H24BrNO3P)
412.0677, found 412.0680.
Diethyl (((4ꢀiodophenyl)amino)(phenyl)methyl)phosphonate (4p):81
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Prepared according to the general procedure A: OffꢀWhite solid (410 mg, 92% yield); H NMR
(400 MHz, CDCl3) δ 7.46 – 7.40 (m, 2H), 7.33 (t, J = 8.0 Hz, 4H), 7.29 – 7.25 (m, 1H), 6.37 (d,
J = 8.7 Hz, 2H), 4.96 – 4.85 (m, 1H), 4.69 (dd, JHꢀP = 24.1 Hz, JHꢀH = 7.6 Hz, 1H), 4.16 – 4.05
(m, 2H), 3.96 – 3.85 (m, 1H), 3.70 – 3.59 (m, 1H), 1.28 (t, J = 7.1 Hz, 1H), 1.10 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.06 (d, JCꢀP = 14.9 Hz), 137.9, 135.46 (d, JCꢀP = 3.0
Hz), 128.80 (d, JCꢀP = 2.6 Hz), 128.21 (d, JCꢀP = 3.2 Hz), 127.88 (d, JCꢀP = 5.4 Hz), 116.2, 79.5,
63.54 (d, JCꢀP = 7.0 Hz), 63.37 (d, JCꢀP = 7.0 Hz), 55.99 (d, JCꢀP = 150.7 Hz), 16.54 (d, JCꢀP = 5.8
Hz), 16.29 (d, JCꢀP = 5.8 Hz); IR (Film): 3287, 3063, 3027, 2981, 2927, 2906, 1591, 1508, 1486,
1452, 1392, 1313, 1294, 1271, 1233, 1064, 1028, 978, 797, 766, 698, 602 cmꢀ1; HRMSꢀESI
(m/z): [M+H]+ calculated (for C17H22INO3P) 446.0382, found 446.0376.
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Diethyl (((3ꢀnitrophenyl)amino)(phenyl)methyl)phosphonate (4q):81
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Prepared according to the general procedure A: Yellow solid (322 mg, 88% yield); H NMR
(400 MHz, CDCl3) δ 7.50 (t, J = 6.2 Hz, 4H), 7.35 (t, J = 7.3 Hz, 2H), 7.31 – 7.26 (m, 1H), 7.19
(t, J = 8.0 Hz, 1H), 6.88 (dd, J = 8.1, 1.6 Hz, 1H), 5.80 (s, 1H), 4.81 (dd, JHꢀP = 24.2 Hz, JHꢀH
=
8.1 Hz, 1H), 4.23 – 4.12 (m, 2H), 3.96 (m, 1H), 3.72 – 3.61 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H),
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1.11 (t, J = 7.1 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 149.3, 147.7, 135.1, 129.7, 128.9,
128.4, 128.10 (d, JCꢀP = 5.5 Hz)., 119.2, 112.6, 108.4, 63.82 (d, JCꢀP = 7.0 Hz), 63.39 (d, JCꢀP
=
7.1 Hz), 55.85 (d, JCꢀP = 152.5 Hz).16.56 (d, JCꢀP = 5.8 Hz), 16.27 (d, JCꢀP = 5.8 Hz); IR (Film):
3287, 3082, 2979, 1622, 1585, 1533, 1480, 1351, 1283, 1233, 1055, 1016, 976, 802, 770, 737,
699, 677 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C17H22N2O5P) 365.1266, found
365.1269.
Diethyl (((4ꢀnitrophenyl)amino)(phenyl)methyl)phosphonate (4r):81
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Prepared according to the general procedure A: Yellow solid (310 mg, 85% yield); H NMR
(400 MHz, CDCl3) δ 7.99 (dd, J = 8.1, 3.4 Hz, 2H), 7.48 (d, J = 6.4 Hz, 2H), 7.39 – 7.28 (m,
3H), 6.62 (dd, J = 9.2, 2.4 Hz, 2H), 6.24 (d, J = 8.5 Hz, 1H), 4.89 – 4.79 (m, 1H), 4.22 – 4.10 (m,
2H), 3.93 (m, 1H), 3.69 – 3.55 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 152.40 (d, JCꢀP = 13.5 Hz), 138.6, 134.79 (d, JCꢀP = 2.6 Hz),
128.80 (d, JCꢀP = 2.5 Hz), 128.42 (d, JCꢀP = 3.1 Hz), 127.91 (d, JCꢀP = 5.4 Hz), 126.0, 112.3, 63.83
(d, JCꢀP = 7.1 Hz), 63.36 (d, JCꢀP = 7.2 Hz), 55.39 (d, JCꢀP = 152.4 Hz), 16.43 (d, JCꢀP = 5.7 Hz),
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16.17 (d, JCꢀP = 5.6 Hz); IR (Film): 3273, 3193, 3068, 2981, 1597, 1547, 1500, 1480, 1313, 1285,
1239, 1111, 1046, 1022, 973, 844, 798, 753, 699 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for
C17H22N2O5P) 365.1266, found 365.1271.
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Diethyl (((2ꢀcyanophenyl)amino)(phenyl)methyl)phosphonate (4s):
Prepared according to the general procedure A: Light orange solid (152 mg, 44% yield); Mp:
78−80 °C; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 6.9 Hz, 2H), 7.42 – 7.24 (m, 5H), 6.70 (dd,
J = 9.5, 5.2 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 5.67 – 5.42 (m, 1H), 4.82 (dd, JHꢀP = 24.1 Hz, JHꢀH
= 7.0 Hz, 1H), 4.12 – 3.97 (m, 3H), 3.94 – 3.85 (m, 1H), 1.29 – 1.19 (m, 6H); C{1H} NMR
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(100 MHz, CDCl3) δ 148.80 (d, JCꢀP = 13.3 Hz), 134.76 (d, JCꢀP = 3.5 Hz), 134.1, 132.9, 128.87
(d, JCꢀP = 2.7 Hz), 128.66 – 128.11 (m), 127.64 (d, JCꢀP = 5.3 Hz), 118.1, 117.3, 112.3, 97.5,
63.66 (d, JCꢀP = 7.1 Hz), 63.44 (d, JCꢀP = 7.1 Hz), 55.86 (d, JCꢀP = 150.3 Hz), 16.36 (d, JCꢀP = 5.5
Hz), 16.25 (d, JCꢀP = 5.8 Hz); IR (Film): 3402, 2981, 2911, 2208, 1605, 1579, 1510, 1459, 1326,
1275, 1253, 1230, 1055, 1014, 976, 748, 700 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for
C18H22N2O3P) 345.1368, found 345.1360.
Diethyl (((4ꢀcyanophenyl)amino)(phenyl)methyl)phosphonate (4t):31
Prepared according to the general procedure A: White solid (267 mg, 78% yield); 1H NMR (400
MHz, CDCl3) δ 7.44 (d, J = 6.9 Hz, 2H), 7.38 – 7.27 (m, 5H), 6.59 (d, J = 8.3 Hz, 2H), 5.64 –
5.49 (m, 1H), 4.76 (dd, JHꢀP = 24.1 Hz, JHꢀP = 7.6 Hz, 1H), 4.20 – 4.06 (m, 2H), 3.96 – 3.86 (m,
1H), 3.68 – 3.57 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 150.0 (t, JCꢀP = 15.1 Hz), 134.9, 133.65 (d, JCꢀP = 3.3 Hz), 128.9, 128.5, 127.84
(d, JCꢀP = 4.8 Hz), 120.1, 113.6, 100.2, 63.80 (d, JCꢀP = 6.7 Hz), 63.38 (d, JCꢀP = 7.1 Hz), 55.55
(d, JCꢀP = 151.3 Hz), 16.52 (d, JCꢀP = 5.7 Hz), 16.26 (d, JCꢀP = 5.7 Hz); IR (Film): 3305, 3160,
3086, 3034, 2986, 2931, 2920, 2211, 1604, 1527, 1506, 1341, 1285, 1232, 1174, 1097, 1060,
1026, 975, 833, 807, 701 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C18H22N2O3P)
345.1368, found 345.1362.
Diethyl (phenyl((2ꢀ(trifluoromethyl)phenyl)amino)methyl)phosphonate (4u):82
Prepared according to the general procedure A: OffꢀWhite solid (365 mg, 94% yield); 1H NMR
(400 MHz, CDCl3) δ 7.46 (d, J = 7.5 Hz, 3H), 7.35 (t, J = 7.5 Hz, 2H), 7.31 – 7.27 (m, 1H), 7.20
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(t, J = 7.8 Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 5.55 – 5.42 (m, 1H), 4.81
(dd, J = 24.6, 6.9 Hz, 1H), 4.13 – 3.97 (m, 3H), 3.88 – 3.79 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H),
1.18 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.95 (d, JCꢀF = 14.7 Hz), 135.20
(d, JCꢀP = 3.6 Hz), 133.0, 128.80 (d, JCꢀP = 2.8 Hz), 128.19 (d, JCꢀP = 3.3 Hz), 127.66 (d, JCꢀP
=
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5.2 Hz), 126.71 (q, JCꢀF = 5.5 Hz), 126.5, 117.3, 114.76 (q, JCꢀF = 29.5 Hz), 113.1, 63.64 (d, JCꢀP
= 7.0 Hz), 63.45 (d, JCꢀP = 7.0 Hz), 55.75 (d, JCꢀP = 149.7 Hz), 16.38 (d, JCꢀP = 5.6 Hz), 16.22 (d,
JCꢀP = 5.9 Hz); IR (Film): 3465, 3030, 2987, 2910, 1612, 1588, 1523, 1478, 1456, 1328, 1286,
1255, 1162, 1127, 1106, 1066, 1020, 969, 786, 751, 695, 653 cmꢀ1; HRMSꢀESI (m/z): [M+H]+
calculated (for C18H22F3NO3P) 388.1289, found 388.1281.
Diethyl (((4ꢀacetylphenyl)amino)(phenyl)methyl)phosphonate (4v):81
Prepared according to the general procedure A: White solid (293 mg, 81% yield); 1H NMR (400
MHz, CDCl3) δ 7.75 (d, J = 8.7 Hz, 2H), 7.47 – 7.44 (m, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.31 –
7.27 (m, 1H), 6.59 (d, J = 8.8 Hz, 2H), 5.42 (t, J = 8.8 Hz, 1H), 4.82 (dd, JHꢀP = 24.1Hz, JHꢀH
=
7.7 Hz, 1H), 4.12 (m, 2H), 3.96 – 3.88 (m, 1H), 3.69 – 3.61 (m, 1H), 2.45 (s, 3H), 1.29 (t, J = 7.1
Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.4, 150.6, 150.5,
135.25 (d, JCꢀP = 2.9 Hz), 130.7, 128.88 (d, JCꢀP = 2.7 Hz), 128.36 (d, JCꢀP = 3.2 Hz), 128.05 –
127.74 (m), 112.81, 63.72 (d, JCꢀP = 7.0 Hz), 63.39 (d, JCꢀP = 7.1 Hz), 55.62 (d, JCꢀP = 150.9 Hz),
26.1, 16.41 (d, JCꢀP = 5.8 Hz), 16.16 (d, JCꢀP = 5.8 Hz); IR (Film): 3269, 3166, 3080, 3052, 2987,
1661, 1600, 1532, 1362, 1278, 1236, 1177, 1026, 959, 839, 797, 703 cmꢀ1; HRMSꢀESI (m/z):
[M+H]+ calculated (for C19H25NO4P) 362.1521, found 362.1514.
Diethyl (phenyl(pyridinꢀ2ꢀylamino)methyl)phosphonate (4w):81
Prepared according to the general procedure A: White solid (235 mg, 73% yield); 1H NMR (400
MHz, CDCl3) δ 8.11 – 8.03 (m, 1H), 7.54 – 7.49 (m, 2H), 7.37 – 7.30 (m, 3H), 7.29 – 7.25 (m,
1H), 6.60 – 6.54 (m, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.57 – 5.45 (m, 2H), 4.18 – 4.03 (m, 2H),
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3.96 (m, 1H), 3.74 (m, 1H), 1.24 (td, J = 7.1, 1.7 Hz, 3H), 1.11 (td, J = 7.1, 0.9 Hz, 3H); C
NMR (100 MHz, CDCl3) δ 157.11 (d, JCꢀP = 11.5 Hz), 148.1, 137.4, 136.3, 128.60 (d, JCꢀP = 1.7
Hz), 128.13 (d, JCꢀP = 5.8 Hz), 127.9, 114.0, 108.52 (d, JCꢀP = 3.9 Hz), 63.3, 63.2, 52.81 (d, JCꢀP
=
148.9 Hz), 16.49 (d, JCꢀP = 5.8 Hz), 16.29 (d, JCꢀP = 5.8 Hz); IR (Film): 3307, 2979, 2936, 2831,
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1602, 1515, 1483, 1421, 1364, 1291, 1227, 1065, 1020, 973, 954, 777, 742 cmꢀ1; HRMSꢀESI
(m/z): [M+H]+ calculated (for C16H22N2O3P) 321.1368, found 321.1376.
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Diethyl (((4ꢀchlorophenyl)amino)(4ꢀmethoxyphenyl)methyl)phosphonate (5a):83
Prepared according to the general procedure B: White solid (362 mg, 94% yield); 1H NMR (400
MHz, CDCl3) δ 7.39 – 7.30 (m, 2H), 7.09 – 6.99 (m, 2H), 6.90 – 6.80 (m, 2H), 6.55 – 6.45 (m,
2H), 4.64 (d, JHꢀP = 23.7 Hz, 1H), 4.15 – 4.03 (m, 2H), 3.97 – 3.89 (m, 1H), 3.77 (d, J = 6.1 Hz,
3H), 3.72 – 3.63 (m, 1H), 1.32 – 1.25 (m, 3H), 1.13 (td, J = 7.1, 0.5 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 159.56 (d, JCꢀP = 3.0 Hz), 145.07 (d, JCꢀP = 15.0 Hz), 129.1, 129.05 (d, J = 5.6
Hz), 127.3, 123.2, 115.2, 114.28 (d, JCꢀP = 2.5 Hz), 63.50 (d, JCꢀP = 6.9 Hz), 63.34 (d, JCꢀP = 7.1
Hz), 55.64 (d, JCꢀP = 151.5 Hz), 55.4, 16.58 (d, JCꢀP = 5.8 Hz), 16.39 (d, JCꢀP = 5.7 Hz); IR (Film):
3459, 3294, 2981, 2908, 2838, 1610, 1596, 1510, 1491, 1461, 1442, 1307, 1268, 1238, 1180,
1075, 1020, 979, 836, 805, 766, 657 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for
C18H24ClNO4P) 384.1131, found 384.1127.
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Diethyl ((4ꢀmethoxyphenyl)(pꢀtolylamino)methyl)phosphonate (5b):83
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Prepared according to the general procedure B: OffꢀWhite solid (347 mg, 95% yield); H NMR
(400 MHz, CDCl3) δ 7.37 (dd, J = 8.8, 2.3 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.5 Hz,
2H), 6.51 (d, J = 8.4 Hz, 2H), 4.68 (d, JHꢀP = 23.9 Hz, 1H), 4.15 – 4.05 (m, 2H), 3.98 – 3.91 (m,
1H), 3.76 (s, 3H), 3.73 – 3.62 (m, 1H), 2.17 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz,
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3H); C{1H} NMR (100 MHz, CDCl3) δ 159.35 (d, JCꢀP = 3.0 Hz), 144.2, 144.0, 129.7, 129.0
(d, JCꢀP = 5.6 Hz), 127.92 (d, JCꢀP = 2.8 Hz), 127.6, 114.1, 63.32 (d, JCꢀP = 6.1 Hz), 63.25 (d, JCꢀP
= 6.0 Hz), 55.73 (d, JCꢀP = 151.3 Hz), 55.3, 20.4, 16.53 (d, JCꢀP = 5.8 Hz), 16.35 (d, JCꢀP = 5.8
Hz); IR (Film): 3313, 3296, 2983, 2907, 1611, 1303, 1511, 1275, 1255, 1237, 1176, 1050, 1023,
969, 826, 817, 801 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for C19H27NO4P) 364.1678,
found 364.1677.
Diethyl (((4ꢀacetylphenyl)amino)(4ꢀchlorophenyl)methyl)phosphonate (5c):
Prepared according to the general procedure B: White solid (341 mg, 86% yield); Mp: 170−172
°C; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.6 Hz, 2H), 7.41 (dd, J = 8.3, 1.6 Hz, 2H), 7.32
(d, J = 8.3 Hz, 2H), 6.62 – 6.52 (m, 2H), 5.49 (s, 1H), 4.80 (dd, J HꢀP = 24.3, J HꢀH = 7.5 Hz, 1H),
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4.19 – 4.08 (m, 2H), 4.02 – 3.94 (m, 1H), 3.82 – 3.69 (m, 1H), 2.46 (s, 3H), 1.30 (t, J = 7.0 Hz,
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3H), 1.16 (t, J = 7.0 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 196.4, 150.28 (d, JCꢀP = 13.9
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Hz), 134.1, 134.0, 130.6, 129.16 (d, JCꢀP = 5.3 Hz), 129.0, 128.1, 112.8, 63.72 (d, JCꢀP = 6.9 Hz),
63.56 (d, JCꢀP = 7.0 Hz), 55.02 (d, JCꢀP = 151.4 Hz), 26.1, 16.52 (d, JCꢀP = 5.7 Hz), 16.34 (d, JCꢀP
= 5.6 Hz); IR (Film): 3284, 3162, 3088, 2987, 2904, 2865, 1665, 1598, 1531, 1486, 1358, 1333,
1274, 1234, 1180, 1054, 1019, 978, 952, 844, 827, 815, 753 cmꢀ1; HRMSꢀESI (m/z): [M+H]+
calculated (for C19H24ClNO4P) 396.1131, found 396.1143.
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Diethyl ((4ꢀchlorophenyl)((4ꢀmethoxyphenyl)amino)methyl)phosphonate (5d):34
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Prepared according to the general procedure B: OffꢀWhite solid (354 mg, 92% yield); H NMR
(400 MHz, CDCl3) δ 7.40 (dd, J = 8.4, 1.9 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.71 – 6.66 (m,
2H), 6.51 (d, J = 8.7 Hz, 2H), 4.66 (d, JHꢀP = 24.1 Hz, 1H), 4.16 – 4.06 (m, 2H), 4.02 – 3.95 (m,
1H), 3.84 – 3.76 (m, 1H), 3.68 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 152.9, 140.09 (d, JCꢀP = 15.4 Hz), 134.86 (d, JCꢀP = 3.1 Hz), 133.70
(d, JCꢀP = 4.0 Hz), 129.26 (d, JCꢀP = 5.5 Hz), 128.82 (d, JCꢀP = 2.7 Hz), 115.3, 114.8, 63.48 (d, JCꢀP
= 7.0 Hz), 63.30 (d, JCꢀP = 6.9 Hz), 56.51 (d, JCꢀP = 150.6 Hz), 55.7, 16.50 (d, JCꢀP = 5.8 Hz),
16.32 (d, JCꢀP = 5.7 Hz); IR (Film): 3299, 3100, 3055, 2992, 2961, 2929, 2906, 2832, 1508,
1491, 1263, 1231, 1175, 1021, 977, 949, 835, 802, 768, 713, 676 cmꢀ1; HRMSꢀESI (m/z):
[M+H]+ calculated (for C18H24ClNO4P) 384.1131, found 384.1142.
Diethyl (1ꢀ((4ꢀmethoxyphenyl)amino)ꢀ2ꢀphenylethyl)phosphonate (5e):
Prepared according to the general procedure B: OffꢀWhite solid (306 mg, 84% yield); Mp:
84−86 °C; 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.16 (m, 5H), 6.69 (d, J = 8.9 Hz, 2H), 6.50 (d,
J = 8.7 Hz, 2H), 4.14 – 4.03 (m, 3H), 3.99 – 3.84 (m, 2H), 3.70 (s, 3H), 3.28 – 3.20 (m, 1H),
3.00 – 2.91 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 152.6, 141.05 (d, JCꢀP = 6.0 Hz), 137.61 (d, JCꢀP = 11.7 Hz), 129.4, 128.4, 126.6, 115.3,
114.7, 62.87 (d, JCꢀP = 7.0 Hz), 62.09 (d, JCꢀP = 7.4 Hz), 55.7, 53.96 (d, JCꢀP = 155.8 Hz), 36.51
(d, JCꢀP = 4.5 Hz), 16.46 (t, JCꢀP = 6.0 Hz); IR (Film): 3306, 3189, 3126, 3064, 3028, 2979, 2930,
2906, 2837, 1619, 1540, 1506, 1478, 1453, 1442, 1264, 1238, 1213, 1183, 1170, 1044, 1010,
967, 949, 817, 799, 783, 756, 740, 696 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for
C19H27NO4P) 364.1678, found 364.1688.
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Diethyl (2ꢀphenylꢀ1ꢀ(pꢀtolylamino)ethyl)phosphonate (5f):
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Prepared according to the general procedure B: OffꢀWhite solid (327 mg, 94% yield); Mp:
9
1
106−108 °C; H NMR (400 MHz, CDCl3) δ 7.26 – 7.16 (m, 5H), 6.91 (d, J = 8.2 Hz, 2H), 6.47
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(d, J = 8.3 Hz, 2H), 4.11 – 4.02 (m, 3H), 4.00 – 3.91 (m, 2H), 3.24 (td, J = 13.7, 4.8 Hz, 1H),
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3.01 – 2.95 (m, 1H), 2.20 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); C{1H}
NMR (100 MHz, CDCl3) δ 144.6, 137.54 (d, JCꢀP = 11.3 Hz), 129.7, 129.5, 128.4, 127.5, 126.7,
113.9, 62.96 (d, JCꢀP = 7.0 Hz), 62.12 (d, JCꢀP = 7.3 Hz), 52.98 (d, JCꢀP = 156.0 Hz), 36.5, 20.5,
16.47 (t, JCꢀP = 6.0 Hz); IR (Film): 3726, 3702, 3626, 3448, 3312, 3027, 2991, 2913, 2858,
1738, 1617, 1529, 1509, 1228, 1213, 1052, 1011, 968, 820, 804, 735, 701, 668 cmꢀ1; HRMSꢀESI
(m/z): [M+H]+ calculated (for C19H27NO3P) 348.1729, found 348.1736.
Ethyl 2ꢀ((4ꢀbromophenyl)amino)ꢀ2ꢀ(diethoxyphosphoryl)acetate (5g):
Prepared according to the general procedure B: White solid (241 mg, 61% yield); Mp: 79−81 °C;
1H NMR (400 MHz, CDCl3) δ 7.29 – 7.26 (m, 2H), 6.62 – 6.49 (m, 2H), 4.59 (d, J = 6.5 Hz,
1H), 4.44 (dd, JHꢀP = 22.5 Hz, JHꢀH = 8.6 Hz, 1H), 4.35 – 4.04 (m, 6H), 1.36 – 1.26(m, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 168.1, 145.28 (d, JCꢀP = 11.5 Hz), 132.1, 115.6, 111.2, 64.09
(d, JCꢀP = 6.4 Hz), 63.69 (d, JCꢀP = 6.5 Hz), 62.4, 56.35 (d, JCꢀP = 148.1 Hz), 16.4, 14.1; IR (Film):
3726, 3308, 3171, 3111, 3049, 2979, 2931, 1750, 1597, 1536, 1491, 1316, 1296, 1240, 1210,
1174, 1155, 1044, 1010, 972, 954, 824, 805, 621 cmꢀ1; HRMSꢀESI (m/z): [M+H]+ calculated (for
C14H22BrNO5P) 394.0419, found 394.0408.
Ethyl 2ꢀ(diethoxyphosphoryl)ꢀ2ꢀ((2,4ꢀdimethylphenyl)amino)acetate (5h):
1
Prepared according to the general procedure B: Light Brown Liquid (187 mg, 54% yield); H
NMR (400 MHz, CDCl3) δ 6.91 (s, 1H), 6.89 (s, 1H), 6.48 (d, J = 8.8 Hz, 1H), 4.51 (dd, JHꢀP
=
22.9 Hz, JHꢀH = 9.4 Hz, 1H), 4.35 (dd, J = 9.2, 6.0 Hz, 1H), 4.27 – 4.18 (m, 6H), 2.23 (s, 3H),
2.22 (s, 3H), 1.36 – 1.27 (m, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.80 (d, JCꢀP = 2.3 Hz),
142.18 (d, JCꢀP = 11.6 Hz), 131.4, 128.5, 127.4, 124.0, 111.5, 64.13 (d, JCꢀP = 6.7 Hz), 63.59 (d,
JCꢀP = 7.0 Hz), 62.2, 57.00 (d, JCꢀP = 149.1 Hz), 20.4, 17.4, 16.48 (t, JCꢀP = 5.5 Hz), 14.2; IR
(Film): 3403, 2983, 2931, 2128, 1740, 1620, 1515, 1257, 1179, 1160, 1097, 1024, 974, 803 cmꢀ
1; HRMSꢀESI (m/z): [M+H]+ calculated (for C16H27NO5P) 344.1627, found 344.1635.
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
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Eꢀmail: siva.che@pondiuni.edu.in. Tel.: +91 413 2654709. Fax: +91 413 2655987.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
C. S gratefully acknowledges the Council of Scientific and Industrial Research (CSIR), New
Delhi, India for the financial support (No. 01(2535)/11/EMRꢀII). K.R. gratefully
acknowledges the UGC for a Senior Research Fellowship. We thank Dr. N. Dastagiri Reddy and
his group, who allowed us to conduct few reactions in their laboratory. We also thank the Central
Instrumentation Facility, Pondicherry University, for NMR spectra and DSTꢀFIST for the ESIꢀ
MS facility.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications.
1H and 13C NMR Spectra
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