Synthesis of α-Aminophosphonates via Phosphonylation of an Aryne-Imine Adduct

Article abstract of DOI:10.1021/acs.joc.0c01410

Multicomponent phosphonylation is accomplished upon the reaction of an imine with an aryne generated in situ in the presence of a dialkyl phosphite. This transition-metal-free protocol shows a broad substrate scope, providing a variety of α-aminophosphonates in moderate to good yields. A plausible mechanism for the reaction is proposed based on a deuterium exchange experiment.

Full text of DOI:10.1021/acs.joc.0c01410

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Note
Synthesis of #-aminophosphonates via
phosphonylation of an aryne–imine adduct
TAEHYUN LIM, and Byeong Moon Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01410 • Publication Date (Web): 14 Sep 2020
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Page 1 of 10
The Journal of Organic Chemistry
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Synthesis of -aminophosphonates via phosphonylation of an aryne–
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imine adduct
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Taehyun Lim and Byeong Moon Kim *
Department of Chemistry, College of Natural Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826,
Republic of Korea
Supporting Information Placeholder
R3
H
Transition-
metal-free
R3
N
N
R2
OTf
O
R1
P
H
R1
R4
R4(R4')
P
TMS
R4
R4(R4')
R2
O
ABSTRACT: Multicomponent phosphonylation is accomplished upon the reaction of an imine with an aryne generated in situ in the
presence of a dialkyl phosphite. This transition-metal-free protocol shows a broad substrate scope, providing a variety of -
aminophosphonates in moderate to good yields. A plausible mechanism for the reaction is proposed based on a deuterium exchange
experiment.
and their resulting aryl anions capture various electrophiles.20
Especially, Cheng and Tian groups reported that the zwitterion
Organophosphorus compounds are becoming increasingly
important in many applications, such as agricultural and
medicinal chemistry. In particular, -aminophosphonic acids
1
species generated from N-heteroarenes/imines with arynes can
2
1
and -aminophosphonates are expected to possess a diverse
abstract a proton from protic nucleophiles (Scheme 1b, eq 1).
range of biological activities because they are structurally
Scheme 1. Synthetic strategies for -aminophosphonates
2
3
analogous to many enzyme inhibitors and antitumor and
antibiotic agents.
4
a) Synthetic routes to -aminophosphonates
Lewis acid catalyst
ZnBr2, BiCl3, SmI2, LiClO4 or Al2O3.)
Several methods have been developed toward the synthesis
of -aminophosphonates. General reaction protocols
employing a conventional nucleophilic addition reaction
O
O
R1
R2
(
NH
H
P
R4
R3
R3
H
R4
R1
N
R3
R4
R2
5
between a phosphonate and imine (Pudovik reaction) and the
O
R1
O
P
6
Kabachnik– Fields reaction, which involves a three-component
N
H
P
R4
R4
R2
Metal cataylst
(Ni, Rh, Co, Ru, Fe, etc.)
R4
reaction consisting of an amine, carbonyl compound, and H-
phosphonate, have been previously reported.
b) Aryne-based three-component reactions with N-heteroarenes/imines
In addition, the reaction of an imine generated from an
aldehyde and an amine or an amino acid derivative with an H-
phosphonate in the presence of a Lewis acid catalyst such as
Previous work
OTf
N
KF or CsF
N
H
Nu-H
(1)
7
8
9
10
TMS
Nu
ZnBr
2
, BiCl
3
, SmI
2
, LiClO
4
2 3
and Al O (with microwave
(NuH= CH3CN, CHCl3,
1
1
12
Ph
H, etc.)
irradiation) or a transition metal catalyst containing [Ni],
Rh], [Co],14 [Ru], [Fe], or others has recently attracted
13
15
16
17
This work
[
R3
N
R3
H
O
OTf
considerable attention. However, many of these methods
require harsh reaction conditions or stoichiometric amounts of
toxic metal reagents, which are expensive and sensitive to
moisture and/or air (Scheme 1a).
N
KF
R2
R1
H
P
R4
(2)
R1
R2
R4(R4')
transition-
metal-free
P
TMS
R4
R4(R4')
O
Inspired by these works, we have developed a one-pot
multicomponent phosphonylation reaction of an aryne, imine,
and dialkyl phosphite toward the synthesis of a variety of -
aminophosphonates (Scheme 1b, eq 2). This method provides
an efficient and mild procedure applicable to various substrates,
which removes the need for transition-metal-based catalysis.
To overcome the drawbacks of these existing methods and
expand the substrate scope in the classical imine-phosphite
reaction, we envisioned the use of arynes as a new type of
substrate. Arynes have been successfully used toward the
construction of several useful synthetic intermediates and the
total synthesis of natural products in the absence of transition
1
8
For our initial reaction optimization study, we used imine 1a,
metal catalysts. Generally, arynes play a major role in the
1
9
a
(
commercially
trimethylsilyl)phenyl trifluoromethanesulfonate (2a), and
diethyl phosphite (3a) as model substrates (Table 1).
available benzyne
precursor, 2-
construction of -insertion compounds. Notably, arynes can
serve as an electrophile toward diverse nitrogen nucleophiles
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Page 2 of 10
corresponding products (4a–4u) in moderate to good yields
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1. Optimization of the Reaction Conditionsa
except for a few cases. A series of para-substituted aromatic N-
alkyl imines, including those with electron-donating or
withdrawing substituents, were examined under the optimized
reaction conditions. The reactions of aromatic N-methylimines
bearing electron-donating substituents at the para-position
proceeded smoothly to give their corresponding products (4b
and 4c) in high yield. Electron-withdrawing groups such as
halogen, trifluoromethyl, and nitrile were well tolerated in the
reaction and the reactions of the substrates gave 4e–4i in 58–90%
yield. Furthermore, the reactions of aromatic N-methylimines
bearing electron-donating substituents at the meta- or ortho-
position of the aryl group proceeded to provide their
corresponding products (4k and 4l) in good yields. The
reactions using bulky imines also afforded 4m and 4n in 71 and
57% yield, respectively. Notably, the reaction of 2,6-di-tert-
butyl-4-((methylimino)methyl)phenol furnished in 48% yield
the desired phosphorylation product 4o, which is a known
N
OTf
O
F- source, additive
solvent, rt, 12 h
N
H
P
EtO H OEt
P
TMS
EtO
OEt
O
1a
2a
3a
4a
F- source
additive
3a
solvent
(M)
CN (0.15)
entry
yield (%)b
(equiv)
(equiv)
(equiv)
1
2
3
4
5
6
7
8
9c
CsF (3.0)
KF (3.0)
-
-
-
-
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
3.0
5.0
5.0
5.0
CH
3
trace
0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
THF (0.15)
THF (0.15)
THF (0.15)
THF (0.15)
THF (0.15)
THF (0.15)
THF (0.15)
THF (0.15)
THF (0.6)
THF (0.6)
THF (1.0)
THF (1.0)
neat
TBAF (3.0)
TBAT (3.0)
TBAF (3.0)
TBAT (3.0)
CsF (3.0)
KF (3.0)
0
15
0
18-crown-6 (3.0)
18-crown-6 (3.0)
18-crown-6 (3.0)
18-crown-6 (3.0)
18-crown-6 (3.0)
18-crown-6 (3.0)
18-crown-6 (3.0)
18-crown-6 (3.0)
18-crown-6 (3.0)
18-crown-6 (3.0)
18-crown-6 (2.0)
21
23
58
44
70
74
77
82
78
84
2
2
matrix metalloproteinase inhibitor. In the case of heteroaryl
substituted imines, the reaction using N-methyl-1-(furan-2-
yl)methanimine gave 4q in 36% yield, whereas N-methyl-1-
KF (3.0)
1
1
1
1
1
1
0
1
2
3
4
5
KF (3.0)
(pyridin-2-yl)methanimine did not give the desired product
KF (3.0)
under the standard reaction conditions.
KF (3.0)
Scheme 2. Scope of the Imine Substrates Used in the
KF (3.0)
a,b
Reaction
KF (3.0)
R'
R'
N
N
R
KF (2.0)
THF (1.0)
OTf
O
KF, 18-crown-6
THF, rt
H
P
a
EtO H OEt
P
O
4
Reaction conditions: 1a (0.15 mmol), 2a (0.23 mmol), 3a, fluoride
TMS
EtO
OEt
R
b
source, additive, solvent, rt, 12 h. Yield of the isolated product.
1
2a
3a
c
The reaction was carried out at 0 C.
R2
R1
MeO
N
N
Several commonly used fluoride sources were screened under
various conditions. In the reaction employing cesium fluoride,
trace amount of 4a was detected in the absence of an additive
(entry 1). The use of other common fluoride sources including
tetrabutylammonium-fluoride (TBAF), or potassium fluoride
did not provide the desired product (entries 2 and 3). Use of
tetrabutylammonium difluorotriphenylsilicate (TBAT) could
promote this phosphonylation reaction to give 15% yield of the
desired product (entry 4). Even with the use of 18-crown-6 as
an additive with TBAF, the desired product was not obtained
N
N
P
P
P
EtO
OEt
P
EtO
OEt
EtO
OEt
EtO
OEt
O
O
O
O
a, R1 = H, 84%
4j
, R2 = Me, 80%
4k, R2 = OMe, 82%
4l, 86%
4m, 71%
4
4
b, R1 = Me, 82%
4c, R1 = OMe, 83%
t-Bu
4
d, R1 = CO2Me, 62%
e, R1 = Cl, 77%
OH
Fe
4
4f, R1 = Br, 80%
N
P
N
P
N
t-Bu
4
g, R1 = F, 90%
P
EtO
O
4h, R1 = CF3, 58%
EtO
OEt
EtO
OEt
OEt
O
O
4i, R1 = CN, 71%
4n, 57%
4o, 48%
4p, 93%
OMe
R3
N
(
entry 5). On the other hand, use of the fluoride source such as
TBAT, cesium fluoride or potassium fluoride in the presence of
8-crown-6 provided the desired product 4a in 21, 23 and 58%
n-Pr
O
N
N
N
P
EtO
O
P
1
P
EtO
OEt
OEt
P
EtO
OEt
EtO
OEt
O
O
O
yield, respectively (entries 6, 7 and 8). In addition, there was an
observable temperature effect as a lower yield (44%) of 4a was
detected when the reaction was carried out at 0 C (entry 9). The
results obtained upon varying the reaction concentration
indicate that increasing the concentration improved the yield of
the desired product (entry 8 and entries 10–13). Therefore, we
carried out the reaction under solvent-free conditions, which
proceeded to give 4a, albeit in a slightly decreased yield,
presumably due to the poor solubility of the reagents (entry 14).
Finally, performing the reaction using KF/18-crown-6 (2.0
equiv) and 5.0 equiv of diethyl phosphite resulted in the
formation of 4a in 84% yield (Table 1, entry 15).
4s, R3 = Bn, 72%
4t, R3 = t-Bu, 23%c
4
q, 36%
4r, 75%
4u, 46% (1.2 : 1)d
aReaction conditions: 1 (0.15 mmol), 2a (0.23 mmol), 3a (0.75
mmol), KF (0.30 mmol), 18-crown-6 (0.30 mmol), THF (1.0 M),
b
c
rt, 12 h. Yield of isolated product. The reaction was carried out at
5
d
1
0 C. Determined using H NMR analysis of the reaction mixture.
Next, the reactions of other N-alkyl-substituted aromatic and
alkyl imines were studied. N-propyl- and N-benzyl-1-
phenylmethanimines gave phosphonylation products 4r and 4s
in 76 and 72%, respectively. However, the reaction of bulky N-
t-butyl-1-phenylmethanimine was sluggish. The desired
product 4t was obtained in 23% yield, even upon heating at 50

C. The reaction of (S,E)-2-methyl-N-(1-phenylethyl)propan-1-
Under the optimized reaction conditions, we then explored
the scope of the imine substrate. As illustrated in Scheme 2, the
three-component phosphonylation of 2a and diethyl phosphite
imine, an imine derived from an aliphatic aldehyde containing
a stereocenter, also furnished the desired product (4u) in
moderate yield (46%) as a 1.2:1 mixture of diastereoisomers.
(3a) with a variety of aromatic N-alkylimines gave their
2
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The Journal of Organic Chemistry
Finally, we examined various phosphites under the optimized
reaction conditions. The reactions carried out using dimethyl
and dibutyl phosphite gave 4ad and 4ae in 84 and 78% yield,
respectively. Furthermore, dibenzyl and diisopropyl phosphites
also provided -aminophosphates 4af and 4ag in 73 and 61%
yield, respectively. However, the reaction of di-tert-butyl
phosphite with benzyne precursor 2a gave the desired product
Table 2. Scope of the Substituted Arynes Used in the
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a,b
Reaction
N
H
OTf
O
KF, 18-crown-6
THF, rt
N
P
EtO H OEt
P
O
4
R
TMS
EtO
OEt
R
1a
2
3a
(
4ah) in only 18% yield under the same conditions. In addition,
the reaction of ethyl phosphinate under the optimized
conditions gave 1:1 diastereomeric mixture of
entry
aryne precursor
product(s), yield (ratio)
O
OTf
EtO
OEt
a
N
P
1
phosphonylation product 4ai in 44% yield. In the reaction using
diphenylphosphine oxide as an alternative phosphine source,
we obtained the desired product 4ag in 50% yield. The structure
TMS
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
P
EtO
OEt
4v+4v', 82% (1.2:1)c
O
2
b
c
2
4
of 4aj was confirmed by single-crystal X-ray analysis
OTf
N
N
2
3
Scheme 3. Scope of the Phosphites Used in the Reaction and
a Crystal Structure of 4aj
P
P
TMS
EtO
OEt
EtO
OEt
a,b
O
O
2
4
w+4w', 82% (1.2:1)c
OTf
MeO
N
N
N
OTf
O
KF, 18-crown-6
THF, rt
N
R
P
P
P
MeO
TMS
EtO
OEt
MeO
EtO
OEt
OEt
H
R
H R(R')
P
O
4
O
O
TMS
2d
4
x+4x', 80% (2:1)c
R(R')
1a
2a
3
OTf
N
F
N
4
5
N
N
N
P
N
P
P
F
TMS
F
EtO
OEt
EtO
O
4y+4y', 53% (5.2:1)c
O
2e
P
P
P
i
MeO
OMe
BuO
OBu
BnO
OBn
iPrO
O Pr
O
O
O
O
OTf
4ad, 84%
4ae, 78%
4af, 73%
4ag, 61%
N
2f
4z, 81%
TMS
P
EtO
OEt
OMe
O
N
P
N
P
OMe
tBuO
t
O Bu
EtO
Ph
O
O
R
R
OTf
R
R
N
2g, R = OMe
h, R = F
4aa, R = OMe, 84%
4ab, R = F, 49%
6
7
4ah, 18%
4ai, 44%
2
P
TMS
EtO
OEt
O
N
OTf
N
P
Ph
Ph
2i
4ac, 50%
O
P
TMS
EtO
OEt
4aj, 50%
O
x-ray of 4aj
aReaction conditions: 1a (0.15 mmol), 2 (0.23 mmol), 3a (0.75
aReaction conditions: 1a (0.15 mmol), 2a (0.23 mmol), 3 (0.75
mmol), KF (0.30 mmol), 18-crown-6 (0.30 mmol), THF (1.0 M),
mmol), KF (0.30 mmol), 18-crown-6 (0.30 mmol), THF (1.0
b
c
1
31
rt, 12 h. Yield of the isolated product. Determined using H or
NMR spectroscopy.
P
b
M), rt, 12 h. Yield of the isolated product.
With these results in hand, we examined the scope of this
reaction using a variety of substituted arynes. Various
disubstituted aryne precursors were assessed in terms of the
yield and regioselectivity for the -aminophosphonate formed
To highlight the utility of this synthetic approach, we
investigated the gram-scale synthesis starting from N-
methylimine 1a (10.0 mmol), benzyne precursor 2a and diethyl
phosphite 3a. The reaction afforded 2.74g of 4a in 82% isolated
yield under the optimized reaction conditions (Scheme 4). This
is the first preparation of compound 4a without the use of
transition-metal reagents.
(Table 2). When unsymmetrical 3-methyl- and 4-
methylbenzyne were generated from 2b and 2c, respectively, an
inseparable 1.2:1 mixture of their regioisomers was obtained.
The reaction with 4-methoxybenzyne 2d proceeded smoothly,
giving 4x and 4x’ in 2:1 ratio and 80% yield, while higher
regioselectivity (5.2:1) was observed in the reaction of 4-
fluorobenzyne 2e, with decreased yield of 53%. Notably, 3-
methoxybenzyne generated from 2f afforded 4z as the sole
product in 81% yield upon the reaction with imine 1a and
phosphonate 3a. These results could be attributed to the
different degrees of aryne distortions as predicted by Houk,
Scheme 4. Scale-up Experiment
N
OTf
O
N
standard conditions
H
P
EtO H OEt
P
O
TMS
EtO
OEt
1a
2a
3a
4a
10.0 mmol
2.74 g, 82%
2
3
We subsequently investigated the mechanism of the three-
component phosphonylation reaction, as shown in Scheme 5.
Treating N-methyl imine 1a with aryne precursor 2a in the
effecting the observed regioselectivity. In the case of 4,5-
disubstituted dimethoxy- and 4,5-difluoroarynes (2g and 2h),
their corresponding phosphonylation products (4aa and 4ab)
were also formed in 84 and 49% yield, respectively. In addition,
the reaction carried out using symmetrical naphthalyne afforded
2
presence of deuterated diethyl phosphite ( H-3a) under the
optimized reaction conditions resulted in the formation of the
-aminophosphonate
product
with
87% deuterium
4
ac in 50% yield.
incorporation at the 2-position of the benzene ring (Scheme 5a,
3
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eq 1). Subsequently, when we performed the reaction using 1a
and 2a in the presence of 3a in THF-d . The reaction afforded
chromatography was performed on silica gel (Merck 9385 Kiesel
1
19
1
31
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
gel 60) using hexane/ethyl acetate as an eluent. H, F{ H}, P{ H}
8
1
3
1
and C{ H} NMR spectra were recorded on an Agilent 400–MR
4a with no incorporation of deuterium at the 2-position (Scheme
5a, eq 2). This demonstrates that the deprotonated phosphite IV
undergoes nucleophilic addition to iminium intermediate III to
furnish -aminophosphonate 4a. To understand the mechanism
of multicomponent reaction, a control experiment was carried
out (Scheme 5b). When the reaction of 1a and 3a was
performed in the absence of 2a under the standard conditions,
the reaction did not produce the desired product A, leaving 1a
unchanged. This result indicates that the reaction proceeds
through a three-component reaction involving an aryne, which
is an essential component in this reaction system.
1
19
1
31
1
DD2 ( H, 400 MHz; F{ H}, 376 MHz; P{ H}, 162 MHz;
1
3
1
13
1
C{ H}, 101 MHz) or C{ H} NMR spectra was recorded on a
1
3
1
Varian/Oxford As-500 ( C{ H}, 126 MHz) spectrophotometer.
Chemical shift values were recorded as parts per million (δ) relative
to tetramethylsilane as an internal standard and coupling constants
in Hertz (Hz). The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. GC analyses were carried out with a 7980A GC system
from Agilent Technologies, equipped with an HP-5 column. High–
resolution mass spectra were obtained on a JEOL JMS–700 gas
chromatography–mass spectrometer using double focusing mass
spectrometer (magnetic sector and electrostatic sector) via electron
impact (EI) mode or fast atom bombardment (FAB) mode.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Mechanistic Study
(a) Deuterium labeling studies
N
H
KF (2.0 eq), 18-crown-6 (2.0 eq)
THF (1.0 M), rt
General Procedure for the Multicomponent Reaction
of Imines, Aryne Precursors, and Dialkyl Phosphites.
A flame-dried Schlenk tube containing KF (17.4 mg, 0.300
mmol) and 18-crown-6 (79.4 mg, 0.300 mmol) was evacuated
and purged with nitrogen gas for three times. To the flask were
then added imine (1) (1.00 equiv, 0.150 mmol), aryne precursor
OTf
O
P
D
N
D
EtO
OEt
P
(1)
(2)
TMS
EtO
OEt
O
73%
2H-3a
2H-4a (87% D)
1
a
a
2a
2a
O
P
KF (2.0 eq), 18-crown-6 (2.0 eq)
N
1
H
P
EtO
OEt
H
THF-d8 (1.0 M), rt
EtO
OEt
O
84%
3a
4a (0% D)
(2) (0.230 mmol), dialkyl phosphite (3) (0.750 mmol) and THF
(
b) Control experiment
TMS
OTf
(0.15 mL) via syringes. The reaction mixture was allowed to stir
at rt for 12 h. The reaction mixture was treated with water (15
mL), and the resulting mixture was extracted with ethyl acetate
(15 mL), dried over MgSO , filtered and concentrated in vacuo.
4
The crude product was purified by silica gel flash
chromatography (hexane/ethyl acetate as an eluent).
A Large Scale Synthesis of 4a. A flame-dried Schlenk tube
containing KF (1.16 g, 20.0 mmol) and 18-crown-6 (5.28 g,
20.0 mmol) was evacuated and purged with nitrogen gas three
times. To the flask were then added N-methylimine 1a (1.24 mL,
10.0 mmol), aryne precursor 2a (3.64 mL, 15.0 mmol), diethyl
phosphite 3a (6.44 mL, 50.0 mmol) and THF (10.0 mL) via
syringes. The reaction mixture was allowed to stir at rt for 12 h.
The reaction mixture was treated with water (100 mL), and the
resulting mixture was extracted with ethyl acetate (100 mL),
N
HN
O
N
OEt
OEt
H
P
H
KF (2.0 eq), 18-crown-6 (2.0 eq)
P
2a
EtO
OEt
OEt
OEt
X
O
P
THF (1.0 M)
O
1a
3a
A, no reaction
4a
(
c) Proposed mechanism
N
OTf
O
P
N
H
R
R(R')
TMS
H
P
R
R(R')
O
4
2a
1a
3
F
N
O
P
H
R
R(R')
3
N
H
N
R(R')
1a
P
R
O
II
I
III
IV
Based upon these observations, a plausible reaction
mechanism was proposed (Scheme 5c). Iminium zwitterion II,
which is generated via nucleophilic addition of imine 1a to
aryne I, abstracts a proton from dialkyl phosphite 3 leading to
the formation of phosphite anion IV. Phosphite anion IV adds
to the iminium carbon in III, which results in the formation of
the desired -aminophosphonate product (4a).
In conclusion, we have developed a one-pot multicomponent
phosponylation reaction consisting of an aryne, imine, and
dialkyl phosphite as an efficient synthetic method for the
construction of -aminophosphonates. This method does not
require the use of transition-metal-based catalysts. The reaction
of a wide range of imines, arynes, and phosphites can efficiently
be carried out under the optimized conditions.
4
dried over MgSO , filtered and concentrated in vacuo. The
crude product was purified by silica gel flash chromatography
(hexane/ethyl acetate as an eluent) to give 2.74 g of 4a in 82%
yield.
Deuterium Labeling Experiment in Presence of
Deuterium Substituted Diethyl Phosphite. A flame-
dried Schlenk tube containing KF (17.4 mg, 0.300 mmol) and
1
8-crown-6 (79.4 mg, 0.300 mmol) was evacuated and purged
with nitrogen gas three times. To the flask were then added N-
methylimine 1a (0.150 mmol), aryne precursor 2a (0.230
2
mmol), deuterium substituted diethyl phosphite ( H-3a) (104
μL, 0.750 mmol) and THF (0.15 mL) via syringes. The reaction
mixture was allowed to stir at rt for 12 h. The reaction mixture
was treated with water (15 mL), and the resulting mixture was
4
extracted with ethyl acetate (15 mL), dried over MgSO , filtered
EXPERIMENTAL SECTION
and concentrated in vacuo. The crude product was purified by
silica gel flash chromatography (hexane/ethyl acetate as an
eluent).
General Information. Unless otherwise stated, all reactions
were carried out using standard Schlenk techniques. THF was
purified from distillation over sodium/benzophenone and was
Deuterium Labeling Experiment with THF-d . A
8
transferred under argon. 18-crown-6 was recrystallized from
flame-dried Schlenk tube containing KF (17.4 mg, 0.300 mmol)
and 18-crown-6 (79.4 mg, 0.300 mmol) was evacuated and
purged with nitrogen gas three times. To the flask were then
added N-methylimine 1a (0.150 mmol), aryne precursor 2a
o
CH
3
CN and KF was vacuum-dried at 110 C. Thin layer
chromatography (TLC) was performed using Merck silica gel 60
254 and spots were visualized under 254 nm UV light and/or
stained by ceric ammonium molybdate solutions. Column
F
4
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The Journal of Organic Chemistry
1
3
1
(
0.230 mmol), diethyl phosphite 3a (97.0 μL, 0.750 mmol) and
– 3.87 (m, 4H), 2.91 (s, 3H), 1.25 – 1.15 (m, 6H). C{ H} NMR
(126 MHz, CDCl ) δ 150.2 (d, J = 7.1 Hz), 134.0, 133.2 (d, J =
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
THF-d
(0.15 mL) via syringes. The reaction mixture was
8
3
allowed to stir at rt for 12 h. The reaction mixture was treated
with water (15 mL), and the resulting mixture was extracted
7.4 Hz), 130.3 (d, J = 8.3 Hz), 129.4, 128.8, 118.5, 114.2, 63.3
(d, J = 6.9 Hz), 62.3 (dd, J = 27.8, 4.9 Hz), 60.9 (d, J = 2.6 Hz),
3
1
1
with ethyl acetate (15 mL), dried over MgSO
4
, filtered and
34.9, 16.6 (d, J = 5.4 Hz), 16.5 (d, J = 4.8 Hz). P{ H} NMR
+
concentrated in vacuo. The crude product was purified by silica
gel flash chromatography (hexane/ethyl acetate as an eluent).
Diethyl ((methyl(phenyl)amino)(phenyl)methyl)phosphonate
(162 MHz, CDCl
P 367.1104; found 367.1105.
((4-bromophenyl)(methyl(phenyl)amino)-
f
methyl)phosphonate (4f). Pale yellow oil (49.5 mg, 80%); R =
3
) δ 21.4. HRMS (EI) m/z: [M] calcd for
18 3
C H23ClNO
Diethyl
(
4a). Pale yellow oil (42.0 mg, 84%); R
f
= 0.23 (ethyl acetate/n-
hexane, 1:2); H NMR (400 MHz, CDCl ) δ 7.50 (d, J = 7.3 Hz,
H), 7.34 – 7.22 (m, 5H), 6.88 (d, J = 8.3 Hz, 2H), 6.78 (t, J =
.3 Hz, 1H), 5.33 (d, J = 24.8 Hz, 1H), 4.20 – 3.97 (m, 4H),
1
1
3
3
0.29 (ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl )
2
7
δ 7.45 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.25 (t, J =
7.9 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H),
5.25 (d, J = 25.0 Hz, 1H), 4.26 – 3.95 (m, 4H), 2.93 (s, 3H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
2.95 (s, 3H), 1.20 (q, J = 6.9 Hz, 6H). C{ H} NMR (126 MHz,
CDCl ) δ 150.3 (d, J = 7.3 Hz), 134.6 (d, J = 7.1 Hz), 129.3,
129.0 (d, J = 8.3 Hz), 128.6, 128.0, 118.1, 113.9, 63.1 (d, J =
.1 Hz), 62.5, 62.2 (d, J = 7.2 Hz), 61.2, 34.9, 16.6 (d, J = 5.6
1
3
1
3
1.25 – 1.19 (m, J = 7.0, 3.5 Hz, 6H). C{ H} NMR (101 MHz,
CDCl ) δ 150.1 (d, J = 7.4 Hz), 133.7 (d, J = 7.4 Hz), 131.8,
3
7
130.6 (d, J = 8.2 Hz), 129.4, 122.2, 118.5, 114.1, 63.4 (d, J =
7.1 Hz), 62.4 (d, J = 8.9 Hz), 60.7 (d, J = 3.9 Hz), 34.8, 16.6 (d,
3
1
1
Hz), 16.4 (d, J = 5.7 Hz). P{ H} NMR (162 MHz, CDCl
3
) δ
+
31
1
2
1.9. HRMS (EI) m/z: [M] calcd for C18
found 333.1497.
Diethyl ((methyl(phenyl)amino)(p-tolyl)methyl)phosphonate
4b). Pale yellow oil (42.7 mg, 82%); R = 0.25 (ethyl acetate/n-
hexane, 1:2); H NMR (400 MHz, CDCl ) δ 7.38 (d, J = 7.9 Hz,
H), 7.24 (t, J = 7.4 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.88 (d,
H
24NO
3
P 333.1494;
J = 4.9 Hz), 16.5 (d, J = 5.9 Hz). P{ H} NMR (162 MHz,
+
CDCl
411.0599; found 411.0595.
Diethyl ((4-fluorophenyl)(methyl(phenyl)amino)-
f
methyl)phosphonate (4g). Pale yellow oil (47.4 mg, 90%); R =
3 3
) δ 21.3. HRMS (EI) m/z: [M] calcd for C18H23BrNO P
(
f
1
3
1
2
3
0.29 (ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl )
J = 8.3 Hz, 2H), 6.78 (t, J = 7.3 Hz, 1H), 5.29 (d, J = 24.6 Hz,
δ 7.48 (dd, J = 8.5, 5.6 Hz, 2H), 7.26 (t, 2H), 7.01 (t, J = 8.6 Hz,
2H), 6.87 (d, J = 8.3 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 5.28 (d,
J = 24.8 Hz, 1H), 4.22 – 3.97 (m, 4H), 2.93 (s, 3H), 1.21 (q, J =
1H), 4.24 – 3.95 (m, 4H), 2.93 (s, 3H), 2.32 (s, 3H), 1.25 – 1.17
1
3
1
(m, J = 7.1, 4.7 Hz, 6H). C{ H} NMR (126 MHz, CDCl
150.3 (d, J = 7.4 Hz), 137.6, 131.3 (d, J = 7.2 Hz), 129.1, 128.8
d, J = 8.6 Hz), 117.9, 113.9, 63.0 (d, J = 7.1 Hz), 62.1 (d, J =
3
) δ
1
3
1
3
7.2 Hz, 6H). C{ H} NMR (101 MHz, CDCl ) δ 163.7 (d),
(
161.3, 150.2 (d, J = 7.4 Hz), 130.7 (t, J = 8.3 Hz), 129.4, 118.4,
115.5 (d, J = 21.4 Hz), 114.1, 63.3 (d, J = 7.1 Hz), 62.2 (d, J =
12.4 Hz), 60.5 (d, J = 3.7 Hz), 34.7, 16.6 (d, J = 5.4 Hz), 16.4
6
1
.9 Hz), 60.9 (d, J = 3.1 Hz), 34.6, 21.1, 16.5 (d, J = 5.6 Hz),
3
1
1
6.3 (d, J = 5.5 Hz). P{ H} NMR (162 MHz, CDCl
3
) δ 22.2.
+
19
1
HRMS (EI) m/z: [M] calcd for C19
47.1653.
Diethyl ((4-methoxyphenyl)(methyl(phenyl)amino)methyl)-
phosphonate (4c). Pale yellow oil (45.2 mg, 83%); R = 0.28
ethyl acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl ) δ
H
26NO
3
P 347.1650; found
3
(d, J = 5.7 Hz). F{ H} NMR (376 MHz, CDCl ) δ -114.2.
3
1
1
+
3
P{ H} NMR (162 MHz, CDCl
calcd for C18 P 351.1400; found 351.1398.
Diethyl ((methyl(phenyl)amino)(4-(trifluoromethyl)phenyl)-
f
methyl)phosphonate (4h). Pale yellow oil (34.9 mg, 58%); R =
3
) δ 21.7. HRMS (EI) m/z: [M]
H
23FNO
3
f
1
(
3
1
7.42 (d, J = 8.6 Hz, 2H), 7.26 – 7.23 (m, 2H), 6.86 (dd, J = 15.4,
8.5 Hz, 4H), 6.79 (t, J = 7.2 Hz, 1H), 5.26 (d, J = 24.6 Hz, 1H),
4.24 – 3.95 (m, 4H), 3.79 (s, 3H), 2.92 (s, 3H), 1.21 (q, J = 7.1
3
0.25 (ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl )
δ 7.64 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.27 (t, J =
7.7 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.82 (t, J = 7.2 Hz, 1H),
5.35 (d, J = 25.4 Hz, 1H), 4.27 – 3.97 (m, 4H), 2.97 (s, 3H),
1
3
1
Hz, 6H). C{ H} NMR (126 MHz, CDCl
3
) δ 159.2, 150.3 (d),
1
3
1
1
30.2 (d, J = 8.8 Hz), 129.1, 126.3 (d), 118.0, 114.0, 113.8, 63.0
3
1.23 (t, J = 7.0 Hz, 6H). C{ H} NMR (101 MHz, CDCl ) δ
3
1
1
(d), 62.0 (d, J = 19.8 Hz), 60.6 (d), 55.2, 34.5, 16.5, 16.3. P{ H}
150.0 (d, J = 7.1 Hz), 139.0, 129.4, 129.1 (d, J = 7.9 Hz), 125.6
(d), 125.6 (d), 118.6, 114.0, 63.5 (d, J = 7.2 Hz), 62.4 (d, J =
+
3
NMR (162 MHz, CDCl ) δ 22.1. HRMS (EI) m/z: [M] calcd
1
9
1
for C19
H
26NO
4
P 363.1599; found 363.1600.
7.1 Hz), 60.9, 35.0, 16.6 (d), 16.5 (d). F{ H} NMR (376 MHz,
31
1
Methyl
4-((diethoxyphosphoryl)(methyl(phenyl)amino)-
CDCl
3
) δ -62.7. P{ H} NMR (162 MHz, CDCl
3
) δ 21.1.
+
methyl)benzoate (4d). Pale yellow oil (36.4 mg, 62%); R
f
= 0.14
3
HRMS (EI) m/z: [M] calcd for C19
401.1365.
23 3 3
H F NO P 401.1368; found
1
(ethyl acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl ) δ
7.99 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.26 (t, J =
7.5 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H),
Diethyl
((4-cyanophenyl)(methyl(phenyl)amino)methyl)-
= 0.32
(ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
phosphonate (4i). Pale yellow oil (38.2 mg, 71%); R
f
1
5.35 (d, J = 25.4 Hz, 1H), 4.23 – 3.99 (m, 4H), 3.91 (s, 1H),
3
1
2
.97 (s, 3H), 1.26 – 1.17 (m, 6H). 13C{ H} NMR (101 MHz,
7.63 (s, 3H), 7.26 (t, 3H), 6.85 (d, J = 8.3 Hz, 3H), 5.33 (d, J =
25.6 Hz, 1H), 4.20 – 3.99 (m, 4H), 2.96 (s, 3H), 1.23 (t, J = 6.9
CDCl
3
) δ 166.7, 149.9 (d, J = 7.2 Hz), 139.8 (d, J = 7.0 Hz),
1
3
1
1
6
=
29.7 (d, J = 7.2 Hz), 129.2, 128.6 (d, J = 7.9 Hz), 118.3, 113.9,
3
Hz, 6H). C{ H} NMR (101 MHz, CDCl ) δ 149.9 (d, J = 6.9
3.3 (d), 62.3 (d), 60.9 (d), 52.1 (d, J = 2.9 Hz), 34.9, 16.6 (d, J
Hz), 140.5 (d, J = 7.4 Hz), 132.5, 129.5, 129.4 (d, J = 7.7 Hz),
118.9, 118.7, 114.1, 112.0, 63.6 (d, J = 7.3 Hz), 62.6 (d, J = 10.7
Hz), 61.1 (d, J = 3.2 Hz), 35.1, 16.6 (d, J = 5.5 Hz), 16.5 (d, J =
3
1
1
3
5.9 Hz), 16.4 (d, J = 4.5 Hz). P{ H} NMR (162 MHz, CDCl )
+
5
δ 21.2. HRMS (EI) m/z: [M] calcd for C20H26NO P 391.1549;
31
1
found 391.1549.
5.3 Hz). P{ H} NMR (162 MHz, CDCl
3
) δ 20.6. HRMS (EI)
P 358.1446; found 358.1447.
Diethyl ((methyl(phenyl)amino)(m-tolyl)methyl)phosphonate
(4j). Pale yellow oil (41.7 mg, 80%); R = 0.29 (ethyl acetate/n-
) δ 7.27 – 7.21 (m, 2H),
+
Diethyl
((4-chlorophenyl)(methyl(phenyl)amino)methyl)-
= 0.31
(ethyl acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl ) δ
23 2 3
m/z: [M] calcd for C19H N O
phosphonate (4e). Pale yellow oil (42.5 mg, 77%); R
f
1
3
f
1
7.43 (d, J = 8.5 Hz, 2H), 7.30 – 7.20 (m,4H), 6.85 (d, J = 8.2
Hz, 2H), 6.79 (t, J = 7.3 Hz, 1H), 5.25 (d, J = 25.0 Hz, 1H), 4.24
hexane, 1:1); H NMR (400 MHz, CDCl
3
7.20 – 7.11 (m, 3H),7.02 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 8.1
5
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The Journal of Organic Chemistry
Page 6 of 10
1
Hz, 2H), 6.71 (t, J = 7.1 Hz, 1H), 5.22 (d, J = 24.7 Hz, 1H), 4.17
– 3.83 (m, 4H), 2.89 (s, 3H), 2.21 (s, 3H), 1.19 – 1.08 (m, 6H).
34.1, 16.7 (d, J = 5.4 Hz), 16.5 (d, J = 5.6 Hz). 31P{ H} NMR
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(162 MHz, CDCl
P 383.1650; found 383.1652.
((3,5-di-tert-butyl-4-hydroxyphenyl)(methyl-
(phenyl)amino)methyl)phosphonate (4o). Orange oil (33.2 mg,
) δ 22.6. HRMS (EI) m/z: [M] calcd for
3
1
3
1
C{ H} NMR (101 MHz, CDCl
134.5 (d, J = 7.1 Hz), 129.5 (d, J = 8.7 Hz), 129.3, 128.8, 128.4,
26.0 (d, J = 8.2 Hz), 118.0, 113.8, 63.1 (d, J = 7.1 Hz), 62.4
dd, J = 25.0, 5.5 Hz), 60.9 (d, J = 3.8 Hz), 34.9, 21.6, 16.6 (d,
3
) δ 150.3 (d, J = 7.1 Hz), 138.2,
22 3
C H26NO
Diethyl
1
(
1
48%); R
f
= 0.23 (ethyl acetate/n-hexane, 1:2); H NMR (400
) δ 7.29 (s, 2H), 7.26 – 7.22 (m, J = 7.5 Hz, 2H),
6.89 (d, J = 8.2 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 5.25 (d, J =
24.6 Hz, 1H), 5.18 (s, 1H), 4.13 – 3.93 (m, 4H), 2.93 (s, 3H),
1.39 (s, 18H), 1.19 (q, J = 7.2 Hz, 6H). C{ H} NMR (101
MHz, CDCl ) δ 153.5 (d, J = 0.9 Hz), 150.7 (d, J = 7.0 Hz),
137.3 (d, J = 0.9 Hz), 135.8, 129.2, 125.7 (d, J = 8.6 Hz), 124.9
(d, J = 7.4 Hz), 117.9, 116.6 (d, J = 4.6 Hz), 114.2, 62.9 (d, J =
7.0 Hz), 62.7, 62.2 (d, J = 7.3 Hz), 61.1, 34.5, 30.4, 30.2, 16.7
3
1
1
J = 5.4 Hz), 16.4 (d, J = 5.6 Hz). P{ H} NMR (162 MHz,
MHz, CDCl
3
+
CDCl
47.1650; found 347.1647.
Diethyl
methyl)phosphonate (4k). Pale yellow oil (44.7 mg, 82%); R
3
) δ 22.0. HRMS (EI) m/z: [M] calcd for C19
H
26NO
3
P
3
1
3
1
((3-methoxyphenyl)(methyl(phenyl)amino)-
f
=
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0
.28 (ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl
3
)
δ 7.28 – 7.21 (m, J = 7.9, 3.0 Hz, 3H), 7.12 – 7.05 (m, 2H), 6.87
(d, J = 8.3 Hz, 2H), 6.83 (dd, J = 8.2, 2.2 Hz, 1H), 6.78 (t, J =
7.2 Hz, 1H), 5.29 (d, J = 25.0 Hz, 1H), 4.25 – 3.95 (m, 4H),
3
1
1
(d, J = 5.4 Hz), 16.5 (d, J = 5.6 Hz). P{ H} NMR (162 MHz,
+
3
.77 (s, 3H), 2.97 (s, 3H), 1.27 – 1.19 (m, J = 15.1, 8.0 Hz, 6H).
C{ H} NMR (101 MHz, CDCl ) δ 159.7, 150.3 (d, J = 7.2 Hz),
3
CDCl
461.2695; found 461.2694.
Diethyl (ferrocenylethyl(methyl(phenyl)amino)methyl)-
phosphonate (4p). Orange oil (59.6 mg, 93%); R = 0.23 (ethyl
acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ 7.32 –
3 4
) δ 23.0. HRMS (EI) m/z: [M] calcd for C26H40NO P
1
3
1
1
1
36.1 (d, J = 7.2 Hz), 129.6, 129.3, 121.2 (d, J = 8.1 Hz), 118.1,
14.5 (d, J = 8.5 Hz), 113.9, 113.4, 63.2 (d, J = 7.0 Hz), 62.5
f
1
(
3
dd, J = 30.8, 5.4 Hz), 61.0 (d, J = 3.7 Hz), 55.3 (d, J = 2.6 Hz),
3
3
1
1
4.9, 16.6 (d, J = 4.3 Hz), 16.4 (d, J = 5.6 Hz). P{ H} NMR
7.22 (m, 2H), 6.88 (d, J = 8.3 Hz, 2H), 6.79 (t, J = 7.2 Hz, 1H),
5.23 (d, J = 22.4 Hz, 1H), 4.53 (s, 1H), 4.19 – 4.07 (m, 10H),
4.01 – 3.90 (m, 1H), 2.80 (s, 3H), 2.04 (s, 1H), 1.35 (t, J = 7.1
Hz, 3H), 1.26 (t, J = 7.1 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H). C{ H}
NMR (101 MHz, CDCl ) δ 150.2 (d, J = 5.9 Hz), 129.3, 117.8,
113.6, 69.6, 69.3, 68.2, 67.5, 63.2 (d, J = 7.1 Hz), 61.8 (d, J =
7.6 Hz), 58.9 (d, J = 3.7 Hz), 57.3 (d, J = 3.9 Hz), 34.5, 16.7 (d,
J = 4.9 Hz), 16.6 (d, J = 5.8 Hz). P{ H} NMR (162 MHz,
+
(
C
162 MHz, CDCl
3
) δ 21.9. HRMS (EI) m/z: [M] calcd for
P 363.1599; found 363.1601.
((2-methoxyphenyl)(methyl(phenyl)amino)-
methyl)phosphonate (4l). Pale yellow oil (47.0 mg, 86%); R
19 4
H26NO
Diethyl
13
1
f
=
3
1
0.32 (ethyl acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl
δ 7.94 (d, J = 7.6 Hz, 1H), 7.29 – 7.18 (m, J = 16.0, 8.5, 4.3 Hz,
H), 6.95 (t, J = 8.2 Hz, 3H), 6.81 (d, J = 8.2 Hz, 1H), 6.73 (t,
J = 7.2 Hz, 1H), 5.72 (d, J = 22.9 Hz, 1H), 4.22 – 3.86 (m, 4H),
3
)
3
1
1
3
+
CDCl
441.1156; found 441.1157.
Diethyl (furan-2-yl(methyl(phenyl)amino)methyl)-
phosphonate (4q). Pale yellow oil (17.5 mg, 36%); R = 0.20
(ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
3 3
) δ 21.9. HRMS (EI) m/z: [M] calcd for C22H28FeNO P
3
.52 (s, 3H), 2.87 (s, 3H), 1.21 – 1.10 (m, J =16.9, 7.1 Hz, 6H).
1
3
1
3
C{ H} NMR (101 MHz, CDCl ) δ 158.0 (d, J = 12.2 Hz),
1
50.8 (d, J = 6.5 Hz), 131.2 (d, J = 4.1 Hz), 129.5, 128.8, 122.9
f
1
(d, J = 10.0 Hz), 120.3, 117.7, 114.3, 110.8, 63.0 (d, J = 7.0 Hz),
3
6
5
2.2 (d, J = 7.5 Hz), 55.8 (d, J = 3.4 Hz), 55.5 (d, J = 2.0 Hz),
4.2 (d, J = 3.3 Hz), 34.4, 29.8, 16.6 (d, J = 5.4 Hz), 16.4 (d, J
7.38 (d, J = 1.7 Hz, 1H), 7.29 – 7.24 (m, 2H), 6.93 (d, J = 8.2
Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H), 6.63 – 6.60 (m, 1H), 6.37 –
6.34 (m, J = 3.2, 1.9 Hz, 1H), 5.30 (d, J = 24.6 Hz, 1H), 4.24 –
3.98 (m, 4H), 2.93 (s, 3H), 1.26 – 1.20 (m, J = 7.1, 2.1 Hz, 6H).
3
1
1
= 5.5 Hz). P{ H} NMR (162 MHz, CDCl
3
) δ 22.8. HRMS (EI)
P 363.1599; found 363.1596.
Diethyl (mesityl(methyl(phenyl)amino)methyl)phosphonate
4m). Pale yellow oil (40.0 mg, 71%); R = 0.23 (ethyl acetate/n-
hexane, 1:2); H NMR (400 MHz, CDCl ) δ 7.14 (t, J = 7.3 Hz,
H), 6.82 (s, 2H), 6.70 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 8.1 Hz,
H), 5.27 (d, J = 28.7 Hz, 1H), 4.17 – 4.02 (m, 2H), 3.86 – 3.74
+
m/z: [M] calcd for C19H26NO
4
1
3
1
3
C{ H} NMR (126 MHz, CDCl ) δ 150.5 (d, J = 6.5 Hz), 148.3
(
f
(d), 143.0 (d), 129.5, 118.8, 114.6 (d), 111.1 (d, J = 3.2 Hz),
110.7, 63.6 (d, J = 6.9 Hz), 62.9 (d, J = 7.2 Hz), 56.6 (d, J =
1
3
3
1
1
2
2
166.0 Hz), 34.8, 16.8 (d, J = 5.7 Hz), 16.7 (d, J = 5.7 Hz). P{ H}
+
NMR (162 MHz, CDCl
P 323.1286; found 323.1287.
Diethyl ((4-methoxyphenyl)(phenyl(propyl)amino)methyl)-
phosphonate (4r). Pale yellow oil (44.0 mg, 75%); R = 0.29
(ethyl acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl ) δ
3
) δ 19.6. HRMS (EI) m/z: [M] calcd
(m, 1H), 3.46 – 3.38 (m, 1H), 3.36 (s, 3H), 2.51 (s, 6H), 2.22 (s,
for C16H22NO
4
13
1
3
H), 1.31 (t, J = 6.8 Hz, 3H), 1.12 – 1.04 (m, 3H). C{ H}
) δ 150.4 (d, J = 12.6 Hz), 137.1 (d, J
3.1 Hz), 129.5, 129.0, 117.7, 113.7, 63.4 (d, J = 6.9 Hz), 61.9
(d, J = 7.7 Hz), 61.0, 59.5, 38.2 (d, J =5.2 Hz), 21.5, 20.9, 16.5
NMR (101 MHz, CDCl
3
f
1
=
3
7.44 (d, J = 8.7 Hz, 2H), 7.26 – 7.18 (m, J = 8.6, 7.4 Hz, 2H),
6.85 (dd, J = 21.3, 8.4 Hz, 4H), 6.76 (t, J = 7.2 Hz, 1H), 5.18
(d, J = 23.8 Hz, 1H), 4.21 – 3.91 (m, 4H), 3.77 (s, 3H), 3.44 –
3.34 (m, 1H), 3.19 – 3.10 (m, 1H), 1.59 – 1.48 (m, 1H), 1.18
3
1
1
(t, J = 5.6 Hz). P{ H} NMR (162 MHz, CDCl
3
) δ 22.6. HRMS
P 375.1963; found 375.1966.
Diethyl ((methyl(phenyl)amino)(naphthalen-1-yl)methyl)-
phosphonate (4n). Pale yellow oil (32.8 mg, 57%); R = 0.33
ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
+
(EI) m/z: [M] calcd for C21H30NO
3
1
3
1
f
(dd, J = 15.4, 7.1 Hz, 6H), 0.75 (t, J = 7.4 Hz, 3H). C{ H}
NMR (101 MHz, CDCl ) δ 159.3, 148.8 (d, J = 6.3 Hz), 130.8
1
(
3
3
8
8
.34 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.51 (d, J =
.1 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.25
(d, J = 9.3 Hz), 129.2, 127.1 (d, J = 8.3 Hz), 118.2, 115.7, 113.8,
62.9 (d, J = 7.1 Hz), 62.6, 62.1 (d, J = 7.3 Hz), 61.0, 55.3, 48.7,
20.4 (d, J = 1.3 Hz), 16.6 (d, J = 5.7 Hz), 16.5 (d, J = 5.6 Hz),
(t, J = 4.2 Hz, 1H), 7.00 (d, J = 8.3 Hz, 2H), 6.83 (t, J = 7.3 Hz,
31
1
1
H), 5.92 (d, J = 21.6 Hz, 1H), 4.27 – 3.93 (m, 4H), 2.79 (s,
11.4. P{ H} NMR (162 MHz, CDCl
3
) δ 22.4. HRMS (EI) m/z:
P 391.1912; found 391.1915.
Diethyl ((benzyl(phenyl)amino)(phenyl)methyl)phosphonate
(4s). Pale yellow oil (44.2 mg, 72%); R = 0.21 (ethyl acetate/n-
hexane, 1:2); H NMR (400 MHz, CDCl ) δ 7.59 (d, J = 7.1 Hz,
13
1
+
3
H), 1.24 – 1.15 (m, J = 11.7, 7.1 Hz, 6H). C{ H} NMR (101
) δ 149.8 (d, J = 4.5 Hz), 134.1 (d, J = 1.9 Hz),
[M] calcd for C21H30NO
4
MHz, CDCl
3
132.6 (d, J = 14.7 Hz), 130.8 (d, J = 10.1 Hz), 129.5, 129.1,
129.0, 128.8 (d, J = 4.8 Hz), 126.7, 125.8, 125.1, 123.8, 117.9,
f
1
3
1
13.6 (d, J = 1.4 Hz), 62.7 (dd, J = 113.7, 7.2 Hz), 58.6, 56.9,
2H), 7.35 – 7.26 (m, 3H), 7.19 – 7.05 (m, J = 4.2 Hz, 7H), 6.88
6
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
(
d, J = 8.2 Hz, 2H), 6.74 (t, J = 7.3 Hz, 1H), 5.45 (d, J = 24.5 MHz, CDCl ) δ 150.4 (d, J = 7.4 Hz), 148.3 (d, J = 8.0 Hz),
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hz, 1H), 4.91 (d, J = 16.9 Hz, 1H), 4.61 (d, J = 16.9 Hz, 1H),
4.16 – 3.85 (m, 4H), 1.18 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz,
3H). C{ H} NMR (101 MHz, CDCl
1
1
139.0, 134.7, 134.6, 134.5 (d, J = 7.6 Hz), 129.8, 129.1 (d, J =
7.9 Hz), 129.0, 128.9, 128.6, 128.5, 127.9, 127.5, 119.1, 114.7,
114.4, 111.2, 63.3 (d, J = 3.7 Hz), 63.2 (d, J = 2.7 Hz), 62.7 (d,
J = 3.9 Hz), 62.2, 61.7 (d, J = 3.7 Hz), 61.1 (d, J = 3.7 Hz), 34.9
(d, J = 3.8 Hz), 22.0, 20.40, 16.6 (d, J = 3.0 Hz), 16.4 (d, J =
1
3
1
3
) δ 148.7 (d, J = 6.2 Hz),
38.9, 134.9 (d, J = 7.1 Hz), 129.7 (d, J = 8.6 Hz), 129.0, 128.6,
28.2, 128.1, 127.0, 126.3, 118.8, 116.3, 63.5, 62.6 (d, J = 8.5
3
1
1
31
1
Hz), 62.0, 51.6, 16.5 (d), 16.4 (d, J = 5.6 Hz). P{ H} NMR
5.1 Hz). P{ H} NMR (162 MHz, CDCl
3
) δ 22.1, 22.0. HRMS
+
+
(
C
162 MHz, CDCl
P 409.1807; found 409.1809.
((tert-butyl(phenyl)amino)(phenyl)methyl)-
phosphonate (4t). Pale yellow oil (13.0 mg, 23%); R = 0.32
ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
3
) δ 22.3. HRMS (EI) m/z: [M] calcd for
(EI) m/z: [M] calcd for C19H26NO P 347.1650; found 347.1647.
3
24
H
28NO
3
Diethyl (((3-methoxyphenyl)(methyl)amino)(phenyl)methyl)-
phosphonate (4x) and diethyl (((4-methoxyphenyl)-
(methyl)amino)(phenyl)methyl)phosphonate (4x’). Pale yellow
Diethyl
f
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
(
3
oil (43.6 mg, 80%); R
f
= 0.31 (ethyl acetate/n-hexane, 1:2); H
) δ 7.50 (d, J = 7.3 Hz, 2H), 7.45 (d, J
7.25 – 7.09 (m, 8H), 7.01 – 6.94 (m, 2H), 4.88 (d, J = 25.8 Hz,
1H), 4.24 – 4.13 (m, 2H), 3.84 – 3.47 (m, 2H), 1.33 (t, J = 7.1
Hz, 3H), 1.20 (s, 9H), 0.93 (t, J = 7.1 Hz, 3H). C{ H} NMR
NMR (500 MHz, CDCl
3
= 7.0 Hz, 4H), 7.35 – 7.28 (m, J = 12.7, 6.2 Hz, 9H), 7.16 (t, J
= 8.2 Hz, 1H), 6.84 (s, 8H), 6.51 (d, J = 8.1 Hz, 1H), 6.41 (s,
1H), 6.36 (d, J = 8.1 Hz, 1H), 5.31 (d, J = 24.9 Hz, 1H), 5.14
(d, J = 24.6 Hz, 2H), 4.26 – 3.93 (m, 12H), 3.78 (s, 3H), 3.76
(s, 6H), 2.95 (s, 3H), 2.86 (s, 6H), 1.26 – 1.16 (m, J = 26.8, 12.9,
1
3
1
(126 MHz, CDCl
3
) δ 144.8, 137.1, 135.0 (d, J = 2.0 Hz), 131.9
(d, J = 9.0 Hz), 127.6, 127.6, 127.2, 126.2, 62.1, 60.2 (d, J =
3
1
1
1
66.6 Hz), 57.8 (d, J = 9.2 Hz), 30.6, 16.7 (d), 16.2 (d). P{ H}
+
13
1
NMR (162 MHz, CDCl
P 375.1963; found 375.1966.
(2-methyl-1-(phenyl((R)-1-phenylethyl)-
amino)propyl)phosphonate (4u). Pale yellow oil (26.9 mg,
3
) δ 23.4. HRMS (EI) m/z: [M] calcd
3
6.9 Hz, 18H). C{ H} NMR (126 MHz, CDCl ) δ 160.8, 152.8,
for C21
H
30NO
3
151.7 (d, J = 7.3 Hz), 145.2 (d, J = 8.9 Hz), 134.6, 134.1 (d, J =
7.5 Hz), 130.0, 129.2 (d, J = 8.8 Hz), 128.9 (d, J = 8.3 Hz),
128.6, 128.5, 128.0 (d, J = 3.2 Hz), 116.5 (d, J = 0.8 Hz), 114.7,
106.9, 102.8, 100.6, 64.5, 63.3 (d, J = 7.4 Hz), 62.6 – 62.1 (m),
61.1, 55.8, 55.3, 35.2, 35.1, 29.8, 16.7 (d, J = 5.8 Hz), 16.4 (d,
Diethyl
1
4
6%); R
f
= 0.24 (ethyl acetate/n-hexane, 1:2); H NMR (400
) δ 7.47 (d, J = 7.4 Hz, 2H), 7.34 – 7.18 (m, J =
MHz, CDCl
3
3
1
1
23.3, 15.9, 7.9 Hz, 7H), 6.92 (t, J = 7.2 Hz, 1H), 5.13 (qd, J =
6.8, 2.8 Hz, 1H), 4.03 – 3.76 (m, 4H), 3.19 (dd, J = 17.5, 10.3
Hz, 1H), 2.30 – 2.17 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H), 1.13 (q,
J = 5.7 Hz). P{ H} NMR (162 MHz, CDCl
3
) δ 22.2, 21.8.
+
HRMS (EI) m/z: [M] calcd for C19
363.1595.
H26NO P 363.1599; found
4
1
3
1
J = 7.1 Hz, 6H), 0.98 (d, J = 7.8 Hz, 6H). C{ H} NMR (101
MHz, CDCl ) δ 147.5, 143.1, 128.5, 128.4, 128.1, 127.0, 118.1,
17.2, 62.9, 61.9 (d, J = 7.3 Hz), 61.5, 60.8 (d, J = 7.8 Hz), 58.0,
Diethyl (((4-fluorophenyl)(methyl)amino)(phenyl)methyl)-
3
phosphonate (4y) and diethyl (((3-fluorophenyl)(methyl)-
1
2
=
amino)(phenyl)methyl)phosphonate (4y’). Pale yellow oil (27.9
1
9.1 (d, J = 8.6 Hz), 21.2, 20.9 (d, J = 13.4 Hz), 18.3, 16.3 (t, J
mg, 53%); R
(400 MHz, CDCl
f
= 0.35 (ethyl acetate/n-hexane, 1:1); H NMR
3
3
1
1
6.5 Hz). P{ H} NMR (162 MHz, CDCl
3
) δ 29.1. HRMS (EI)
) δ 7.48 (dd, J = 14.3, 6.8 Hz, 12.2H), 7.41 –
+
m/z: [M] calcd for C22
H
32NO
3
P 389.2120; found 389.2117.
7.28 (m, 19.1H), 7.17 (dd, J = 15.5, 8.0 Hz, 1H), 6.95 (t, J = 8.7
Hz, 9.7H), 6.86 – 6.77 (m, J = 9.1, 4.4 Hz, 10.6H), 6.63 (d, J =
8.6 Hz, 1H), 6.55 (d, J = 12.5 Hz, 1H), 6.47 (t, J = 8.1 Hz, 1H),
5.26 (d, J = 24.7 Hz, 1H), 5.16 (d, J = 24.7 Hz, 5.2H), 4.31 –
3.87 (m, 24.4H), 2.96 (s, 3H), 2.90 (s, 15.6H), 1.29 – 1.14 (m,
Diethyl ((methyl(o-tolyl)amino)(phenyl)methyl)phosphonate
(4v) and diethyl ((methyl(m-tolyl)amino)(phenyl)methyl)-
phosphonate (4v’). Pale yellow oil (42.7 mg, 82%); R
f
= 0.24
(ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
.43 (d, J = 7.1 Hz, 2H), 7.36 – 7.31 (m, 2H), 7.27 – 7.15 (m,
1
3
1
3
1
7
6
6
3
J = 20.7, 7.1 Hz, 37.7H). C{ H} NMR (126 MHz, CDCl ) δ
H), 7.11 – 7.05 (m, 2H), 6.94 – 6.86 (m, 2H), 6.70 (d, 1H),
.65 – 6.60 (m, J = 6.4 Hz, 2H), 6.54 (d, J = 7.4 Hz, 1H), 5.25
157.3, 155.4, 147.2 (d, J = 6.3 Hz), 134.1 (d, J = 7.2 Hz), 130.4,
129.2 – 128.5 (m), 128.2 (d, J = 8.4 Hz), 115.9 – 115.5 (m),
104.4, 77.4, 77.2, 76.9, 64.0, 63.2 (d, J = 7.1 Hz), 62.7, 62.6 –
62.1 (m), 60.9, 35.3, 35.1, 16.7 (d, J = 5.7 Hz), 16.5 (d, J = 5.7
(
6
(
d, J = 24.9 Hz, 1H), 4.39 (d, J = 22.8 Hz, 1H), 4.15 – 3.89 (m,
H), 3.88 – 3.77 (m, 1H), 3.62 – 3.55 (m, 1H), 2.86 (s, 3H), 2.83
s, 3H), 2.33 (s, 3H), 2.25 (s, 3H), 1.26 – 1.08 (m, 9H), 0.95 (t,
1
9
1
31
1
Hz). F{ H} NMR (376 MHz, CDCl
NMR (162 MHz, CDCl ) δ 21.8, 21.4. HRMS (EI) m/z: [M]
calcd for C18 P 351.1400; found 351.1396.
Diethyl (((3-methoxyphenyl)(methyl)amino)(phenyl)methyl)-
phosphonate (4z). Pale yellow oil (44.2 mg, 81%); R = 0.24
(ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
3
) δ -112.3, -127.0. P{ H}
13
1
+
J = 7.1 Hz, 3H). C{ H} NMR (101 MHz, CDCl
J = 11.9 Hz), 150.4 (d, J = 7.4 Hz), 139.0, 134.6 (d, J = 7.4 Hz),
33.5, 133.3 (d), 131.2, 130.4, 130.3, 129.1, 128.9 (d, J = 8.4
3
) δ 151.1 (d,
3
H
23FNO
3
1
Hz), 128.6, 128.1, 127.9 (d, J = 3.3 Hz), 126.0, 123.9, 123.3,
119.1, 114.7, 111.2, 66.4 (d), 64.9 (d), 63.2 (d), 62.7 (d), 62.5
f
1
3
(d, J = 7.1 Hz), 61.1 (d), 38.7, 34.9, 22.0, 18.5, 16.6 (d), 16.5
7.50 (d, J = 7.0 Hz, 2H), 7.36 – 7.25 (m, J = 8.0, 2.6 Hz, 3H),
7.16 (t, J = 8.2 Hz, 1H), 6.51 (dd, J = 8.3, 2.3 Hz, 1H), 6.42 (t,
J = 2.2 Hz, 1H), 6.36 (dd, J = 8.1, 2.1 Hz, 1H), 5.31 (d, J = 24.9
Hz, 1H), 4.23 – 3.96 (m, 4H), 3.78 (s, 3H), 2.95 (s, 3H), 1.25 –
3
1
1
(d), 16.4 (d), 16.3 (d). P{ H} NMR (162 MHz, CDCl
3
) δ 23.3,
H26NO P 347.1650;
+
2
2.1. HRMS (EI) m/z: [M] calcd for C19
3
found 347.1651.
1
3
1
Diethyl ((methyl(m-tolyl)amino)(phenyl)methyl)phosphonate
3
1.18 (m, J = 13.1, 7.0 Hz, 6H). C{ H} NMR (101 MHz, CDCl )
(4w) and diethyl ((methyl(p-tolyl)amino)(phenyl)methyl)-
δ 160.8, 151.7 (d, J = 7.4 Hz), 134.6 (d, J = 7.0 Hz), 130.0,
128.9 (d, J = 8.3 Hz), 128.6, 128.0, 106.9, 102.8, 100.6, 63.2 (d,
J = 7.1 Hz), 62.4 (d, J = 24.9, 5.6 Hz), 61.0 (d, J = 3.7 Hz), 55.3
(d, J = 2.6 Hz), 35.1, 16.6 (d, J = 4.6 Hz), 16.4 (d, J = 5.7
phosphonate (4w’). Pale yellow oil (42.7 mg, 82%). R
f
= 0.21
ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
.49 (t, J = 7.7 Hz, 4H), 7.35 – 7.27 (m, 6H), 7.17 – 7.10 (m,
1
(
7
3
3
1
1
1H), 7.06 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.70 (d,
J = 6.7 Hz, 2H), 6.62 (d, J = 7.4 Hz, 1H), 5.29 (t, J = 25.2 Hz,
2H), 4.24 – 3.96 (m, 8H), 2.94 (s, 3H), 2.91 (s, 3H), 2.32 (s,
Hz). P{ H} NMR (162 MHz, CDCl
3
) δ 21.8. HRMS (EI) m/z:
P 363.1599; found 363.1599.
(((3,4-dimethoxyphenyl)(methyl)amino)(phenyl)-
methyl)phosphonate (4aa). Pale yellow oil (49.6 mg, 84%); R
+
[M] calcd for C19
Diethyl
H26NO
4
1
3
1
3
H), 2.27 (s, 3H), 1.26 – 1.17 (m, 12H). C{ H} NMR (101
f
7
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1
=
0.36 (ethyl acetate/n-hexane, 1:1); H NMR (400 MHz,
J = 13.0, 6.5 Hz, 4H), 1.37 – 1.20 (m, J = 14.9, 12.4, 7.5 Hz,
1
3
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CDCl ) δ 7.48 – 7.43 (m, 2H), 7.35 – 7.28 (m, 3H), 6.78 (d, J =
8.7 Hz, 1H), 6.52 (d, J = 2.7 Hz, 1H), 6.38 (dd, J = 8.7, 2.8 Hz,
1H), 5.14 (d, J = 24.6 Hz, 1H), 4.26 – 3.94 (m, 4H), 3.85 (s,
4H), 0.84 (td, J = 7.4, 1.6 Hz, 6H). C{ H} NMR (101 MHz,
CDCl ) δ 150.2 (d, J = 7.3 Hz), 134.7 (d, J = 7.1 Hz), 129.2,
3
3
128.9 (d, J = 8.3 Hz), 128.5, 127.9, 118.0, 113.8, 66.3 (d, J =
79.9, 7.4 Hz), 65.6 (d, J = 6.0 Hz), 62.5, 60.9, 34.9, 32.7 (d, J =
5.6 Hz), 32.5 (d, J = 6.2 Hz), 18.8, 18.7 (d, J = 4.6 Hz), 13.6.
3
H), 3.83 (s, 3H), 2.88 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.19 (t,
1
3
1
J = 7.1 Hz, 3H). C{ H} NMR (101 MHz, CDCl
3
) δ 149.7,
45.8 (d, J = 8.8 Hz), 142.4, 134.1 (d, J = 7.4 Hz), 129.1 (d, J =
.7 Hz), 128.5, 128.0 (d, J = 0.6 Hz), 112.6, 106.7, 100.9, 64.7
3
1
1
+
1
8
(
P{ H} NMR (162 MHz, CDCl
3
) δ 22.0. HRMS (EI) m/z: [M]
P 389.2120; found 389.2121.
((methyl(phenyl)amino)(phenyl)methyl)-
= 0.36
(ethyl acetate/n-hexane, 1:3); H NMR (400 MHz, CDCl ) δ
calcd for C22H32NO
3
d, J = 3.9 Hz), 63.2 (d, J = 9.6, 5.5 Hz), 62.3 (d, J = 7.1 Hz),
6.5 (d, J = 2.7 Hz), 55.9 (d, J = 2.8 Hz), 35.4, 16.7 (d, J = 5.7
Hz), 16.4 (d, J = 5.8 Hz). P{ H} NMR (162 MHz, CDCl
2.0. HRMS (EI) m/z: [M] calcd for C20
Dibenzyl
5
phosphonate (4af). Pale yellow oil (50.1 mg, 73%); R
f
31
1
1
3
) δ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
2
H
28NO
5
P 393.1705;
7.54 – 7.47 (m, 2H), 7.34 – 7.14 (m, 15H), 6.86 (d, J = 8.3 Hz,
2H), 6.80 (t, J = 7.3 Hz, 1H), 5.40 (d, J = 24.8 Hz, 1H), 5.12 –
found 393.1709.
1
3
1
Diethyl
(((3,4-difluorophenyl)(methyl)amino)(phenyl)-
3
4.89 (m, 4H), 2.96 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ
methyl)phosphonate (4ab). Pale yellow oil (27.1 mg, 49%); R
f
150.2 (d, J = 7.2 Hz), 136.4 (d, J = 5.9 Hz), 136.1 (d, J = 6.0
Hz), 134.3 (d, J = 7.5 Hz), 129.3, 129.1, 129.0, 128.7, 128.6,
128.5, 128.4 (d, J = 4.5 Hz), 128.2, 128.1, 127.1, 118.3, 114.1,
1
=
0.21 (ethyl acetate/n-hexane, 1:1); H NMR (400 MHz,
3
CDCl ) δ 7.47 (d, J = 6.8 Hz, 2H), 7.37 – 7.30 (m, 3H), 7.02 (q,
J = 19.1, 9.2 Hz, 1H), 6.70 – 6.61 (m, J = 13.6, 6.7, 3.1 Hz, 1H),
3
1
1
68.1 (d), 63.0 (d, J = 3.7 Hz), 61.4 (d, J = 3.6 Hz), 35.0. P{ H}
+
6
4
.57 – 6.50 (m, 1H), 5.13 (d, J = 24.7 Hz, 1H), 4.27 – 3.94 (m,
NMR (162 MHz, CDCl
P 457.1807; found 457.1809.
((methyl(phenyl)amino)(phenyl)methyl)-
phosphonate (4ag). Pale yellow oil (33.1 mg, 61%); R = 0.33
(ethyl acetate/n-hexane, 1:3); H NMR (400 MHz, CDCl ) δ
3
) δ 22.8. HRMS (EI) m/z: [M] calcd
1
3
1
H), 2.91 (s, 3H), 1.28 – 1.15 (m, 6H). C{ H} NMR (101 MHz,
) δ 151.7 (d, J = 13.2 Hz), 149.8 (d, J = 13.2 Hz), 147.6
td, J = 7.9, 1.9 Hz), 144.4 (d, J = 12.8 Hz), 142.5 (d, J = 13.0
for C28H28NO
3
CDCl
(
3
Diisopropyl
f
1
Hz), 134.0 (d, J = 6.7 Hz), 128.9 (d, J = 8.4 Hz), 128.7, 128.3
(d, J = 0.7 Hz), 117.4 (dd, J = 17.7, 1.8 Hz), 109.3, 103.2 (dd, J
= 21.1, 1.2 Hz), 63.3, 62.9 (dd, J = 89.2, 7.2 Hz), 62.0, 35.3,
3
7.52 (d, J = 7.3 Hz, 2H), 7.35 – 7.19 (m, 5H), 6.87 (d, J = 8.4
Hz, 2H), 6.76 (t, J = 7.2 Hz, 1H), 5.27 (d, J = 25.9 Hz, 1H), 4.83
– 4.55 (m, 2H), 2.99 (s, 3H), 1.30 (dd, 6H), 1.06 (dd, J = 15.9,
1
9
1
16.6 (d, J = 5.5 Hz), 16.4 (d, J = 5.7 Hz). F{ H} NMR (376
3
1
1
13
1
MHz, CDCl
CDCl ) δ 21.4. HRMS (EI) m/z: [M] calcd for C18
69.1305; found 369.1306.
Diethyl ((methyl(naphthalen-2-yl)amino)(phenyl)methyl)-
phosphonate (4ac). Pale yellow oil (28.8 mg, 50%); R = 0.22
ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
3
) δ -136.6, -152.0. P{ H} NMR (162 MHz,
3
6.2 Hz, 6H). C{ H} NMR (101 MHz, CDCl ) δ 150.4 (d, J =
+
3
H
22
F
2
NO
3
P
8.0 Hz), 134.9 (d, J = 7.2 Hz), 129.2, 129.0 (d, J = 8.1 Hz),
128.5, 127.9 (d, J = 1.0 Hz), 117.9, 114.0, 71.5 (d, J = 90.9, 7.6
Hz), 62.9 (d, J = 3.8 Hz), 61.3 (d, J = 3.8 Hz), 34.9, 24.5 (d, J =
3
3
1
1
f
30.2 Hz), 23.7. P{ H} NMR (162 MHz, CDCl
3
) δ 20.2.
1
+
(
3
HRMS (EI) m/z: [M] calcd for C20
361.1807.
H28NO P 361.1807; found
3
7
7
4
.77 – 7.69 (m, J = 12.6, 8.6 Hz, 2H), 7.65 (d, J = 8.2 Hz, 1H),
.55 – 7.49 (m, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.35 – 7.29 (m,
H), 7.28 – 7.23 (m, 2H), 7.04 (d, J = 2.3 Hz, 1H), 5.46 (d, J =
Di-tert-butyl
((methyl(phenyl)amino)(phenyl)methyl)-
= 0.32
(ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
phosphonate (4ah). Pale yellow oil (10.5 mg, 18%); R
f
1
24.6 Hz, 1H), 4.29 – 3.96 (m, 4H), 3.03 (s, 3H), 1.25 – 1.18 (m,
3
1
3
1
J = 7.1, 3.3 Hz, 6H). C{ H} NMR (101 MHz, CDCl
3
) δ 148.2
7.51 (d, J = 7.8 Hz, 2H), 7.32 – 7.18 (m, J = 16.1, 11.6, 7.0 Hz,
6H), 6.83 (d, J = 7.3 Hz, 2H), 6.74 (t, J = 7.2 Hz, 1H), 5.16 (d,
(d, J = 7.6 Hz), 134.9, 134.3 (d, J = 7.4 Hz), 129.2, 129.0 (d, J
1
3
1
=
8.6 Hz), 128.6, 128.1, 127.6 (d, J = 18.8 Hz), 126.5 (d, J = 6.3
J = 27.1 Hz, 1H), 3.01 (s, 3H), 1.38 (d, J = 6.8 Hz, 19H). C{ H}
NMR (101 MHz, CDCl ) δ 150.6 (d, J = 8.0 Hz), 136.1 (d, J =
Hz), 122.9, 117.2, 108.7, 63.2 (d, J = 27.6 Hz), 62.4 (d, J = 7.3
Hz), 61.5 (d, J = 3.5 Hz), 35.1, 16.7 (d, J = 4.4 Hz), 16.5 (d, J =
3
6.0 Hz), 129.2, 128.7 (d, J = 7.3 Hz), 128.3, 127.4 (d, J = 1.5
Hz), 117.4, 113.5 (d, J = 1.1 Hz), 83.5 (d, J = 76.8, 10.1 Hz),
3
1
1
4
.9 Hz). P{ H} NMR (162 MHz, CDCl
3
) δ 21.8. HRMS (EI)
P 383.1650; found 383.1654.
((methyl(phenyl)amino)(phenyl)methyl)-
= 0.22
ethyl acetate/n-hexane, 1:2); H NMR (400 MHz, CDCl ) δ
+
31
1
m/z: [M] calcd for C22
H
26NO
3
65.1, 63.4, 35.0, 30.5 (d, J = 3.8 Hz). P{ H} NMR (162 MHz,
+
Dimethyl
3 3
CDCl ) δ 13.0. HRMS (EI) m/z: [M] calcd for C22H32NO P
phosphonate (4ad). Pale yellow oil (38.5 mg, 84%); R
f
389.2120; found 389.2121.
Ethyl
1
(
3
7.48 (d, J = 6.8 Hz, 2H), 7.35 – 7.22 (m, 5H), 6.88 (d, J = 8.3
Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 5.34 (d, J = 24.6 Hz, 1H), 3.74
((methyl(phenyl)amino)(phenyl)methyl)(phenyl)phosphinate
(4ai) Pale beige solid (24.1 mg, 44%); R = 0.20 (ethyl
acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl ) δ 7.86 –
f
1
(
d, J = 10.4 Hz, 3H), 3.67 (d, J = 10.7 Hz, 3H), 2.92 (s, 3H).
3
1
3
1
C{ H} NMR (101 MHz, CDCl
d, J = 7.2 Hz), 129.4, 128.9 (d, J = 8.6 Hz), 128.7, 128.2, 118.4,
14.1, 61.8 (d, J = 160.8, 3.7 Hz), 53.9 (d, J = 6.9 Hz), 52.8 (d,
3
) δ 150.2 (d, J = 7.5 Hz), 134.2
7.78 (m, 1H), 7.77 – 7.68 (m, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.50
– 7.29 (m, 6H), 7.23 – 7.16 (m, 2H), 7.05 (t, J = 7.9 Hz, 1H),
6.81 – 6.61 (m, 2H), 6.50 (d, J = 8.2 Hz, 1H), 5.36 (d, J = 18.2
Hz, 1H), 4.16 – 3.88 (m, 2H), 3.02 (d, J = 44.1 Hz, 3H), 1.26 –
(
1
3
1
1
J = 7.3 Hz), 34.8. P{ H} NMR (162 MHz, CDCl
3
) δ 24.2.
P 305.1181; found
+
13
1
HRMS (EI) m/z: [M] calcd for C16
05.1182.
Dibutyl ((methyl(phenyl)amino)(phenyl)methyl)phosphonate
4ae). Pale yellow oil (45.6 mg, 78%); R = 0.28 (ethyl
acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl ) δ 7.51 (d,
H
20NO
3
3
1.19 (m, 3H). C{ H} NMR (126 MHz, CDCl ) δ 150.5 (d, J =
3
6.1 Hz), 150.1 (d, J = 7.8 Hz), 134.8 (d, J = 2.7 Hz), 134.4 (d, J
= 7.4 Hz), 132.4, 132.4 (d, J = 1.2 Hz), 132.4, 132.2, 132.1 (d,
J = 3.0 Hz), 132.0, 129.5, 129.4 (d, J = 1.0 Hz), 129.3, 129.1,
129.0, 128.6, 128.5, 128.6, 128.5, 128.4, 128.0 (d, J = 7.7 Hz),
118.0 (d, J = 6.0 Hz), 113.9 (d, J = 5.5 Hz), 65.2 (d, J = 3.6 Hz),
64.4 (d, J = 3.5 Hz), 64.3 (d, J = 3.5 Hz), 63.5 (d, J = 3.9 Hz),
61.6, 61.3 (d, J = 6.9 Hz), 35.5, 35.0, 16.8 (d, J = 5.7 Hz), 16.6
(
f
1
3
J = 7.0 Hz, 2H), 7.30 (t, J = 7.8 Hz, 3H), 7.25 – 7.21 (m, 2H),
6.87 (d, J = 8.3 Hz, 2H), 6.78 (t, J = 7.3 Hz, 1H), 5.33 (d, J =
2
5.0 Hz, 1H), 4.14 – 3.88 (m, 4H), 2.96 (s, 3H), 1.55 – 1.47 (m,
8
ACS Paragon Plus Environment

Page 9 of 10
The Journal of Organic Chemistry
d, J = 5.3 Hz). 31P{ H} NMR (162 MHz, CDCl
1
) δ 38.1, 38.0.
(
3
L.; Waldmann, H. Inhibitors of Protein Tyrosine Phosphatases: Next-
Generation Drugs? Angew. Chem. Int. Ed. 2005, 44, 3814−3839.
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
HRMS (EI) m/z: [M] calcd for C22
H
24NO
P 365.1545; found
2
(
2) (a) Steere, J. A.; Sampson, P. B.; Honek, J. F. Synthesis of an 
Aminophosphonate Nucleoside as an Inhibitor of S-Adenosyl-
Homocysteine Hydrolase. Bioorg. Med. Chem. Lett. 2002, 12,
57−460. (b) Wang, Q.; Zhu, M.; Zhu, R.; Lu, L.; Yuan, C.; Xing, S.;
365.1543.
((Methyl(phenyl)amino)(phenyl)methyl)diphenylphosphine-
oxide (4aj). White solid (29.8 mg, 50%); R = 0.28 (ethyl
acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl ) δ 7.87 –
.74 (m, 2H), 7.65 – 7.56 (m, J = 10.2, 7.9 Hz, 2H), 7.50 – 7.28
m, 8H), 7.22 – 7.17 (m, 3H), 7.14 (t, 2H), 6.71 (t, J = 7.3 Hz,
H), 6.61 (d, J = 8.2 Hz, 2H), 5.57 (d, J = 11.4 Hz, 1H), 3.20 (s,
H). C{ H} NMR (101 MHz, CDCl
34.6 (d, J = 2.5 Hz), 133.0 (d, J = 2.4 Hz), 132.0 (d, J = 2.6
Hz), 131.9 (d, J = 2.7 Hz), 131.5, 131.4, 131.3, 129.7 (d, J = 6.0
Hz), 129.2, 128.7 (d, J = 10.4 Hz), 128.6 (d, J = 10.4 Hz), 128.5,
128.0 (d, J = 1.2 Hz), 117.9, 113.5, 64.3 (d, J = 77.8 Hz), 36.1
(d, J = 2.3 Hz). P{ H} NMR (162 MHz, CDCl
HRMS (EI) m/z: [M] calcd for C26
97.1592.
-
L
-
f
4
1
3
Fu, X.; Mei, Y.; Hang, Q. Exploration of -aminophosphonate N-
derivatives as novel, potent and selective inhibitors of protein tyrosine
phosphatases. Eur. J. Med. Chem. 2012, 49, 354−364. (c) Arya, T.;
Reddi, R.; Kishor, C.; Ganji, R. J.; Bhukya, S.; Gumpena, R.;
McGowan, S.; Drag, M.; Addlagatta, A. Identification of the Molecular
Basis of Inhibitor Selectivity between the Human and Streptococcal
Type I Methionine Aminopeptidases. J. Med. Chem. 2015, 58,
7
(
1
3
1
1
3
1
3
) δ 150.1 (d, J = 7.1 Hz),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
350−2357. (d) Chen, Z.; Marcé, P.; Resende, R.; Alzari, P. M.; Frasch,
A. C.; van den Elsen, J. M. H.; Crennell, S. J.; Watts, A. G. The
synthesis and kinetic evaluation of aryl -aminophosphonates as novel
inhibitors of T. cruzi trans-sialidase. Eur. J. Med. Chem. 2018, 158,
25−33.
(3) (a) Gu, L.; Jin, C. Synthesis and antitumor activity of α-
aminophosphonates containing thiazole[5,4-b]pyridine moiety. Org.
Biomol. Chem. 2012, 10, 7098−7102. (b) Bhattacharya, A K.; Raut, D.
S.; Rana, K. C.; Polanki, I. K.; Khan, M. S.; Iram, S. Diversity-oriented
synthesis of -aminophosphonates: A new class of potential anticancer
agents. Eur. J. Med. Chem. 2013, 66, 146−152. (c) Ye, M. Y.; Yao, G.
Y.; Pan, Y. M.; Liao, Z. X.; Zhang, Y.; Wang, H. S. Synthesis and
antitumor activities of novel -aminophosphonate derivatives
containing an alizarin moiety. Eur. J. Med. Chem. 2014, 83, 116−128.
3
1
1
3
) δ 31.1.
+
H24NOP 397.1596; found
3
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Crystal structure data for 4aj (file type, i.e., CIF)
(d) Yu, Y. C.; Kuang, W. B.; Huang, R. Z.; Fang, Y. L.; Zhang, Y.;
1
Chen, Z. F.; Ma, X. L. Design, synthesis and pharmacological
evaluation of new 2-oxo-quinoline derivatives containing -
aminophosphonates as potential antitumor agents. Med. Chem.
Commun. 2017, 8, 1158−1172.
Single-crystal data for 4aj, H NMR spectra of mechanistic studies
1
13
1
19
1
31
1
and H, C{ H}, F{ H} and P{ H} NMR spectra of compounds
(file type, i.e., PDF)
(
4) (a) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. Synthesis and
Structure-Activity Relationships of Antibacterial Phosphonopeptides
Incorporating (1-Aminoethyl)phosphonic Acid and
AUTHOR INFORMATION
Corresponding Author
(Aminomethyl)phosphonic Acid. J. Med. Chem. 1986, 291, 29−40. (b)
Ali, N.; Zakir, S.; Patel, M.; Farooqui, M. Synthesis of new -
aminophosphonate system bearing Indazole moiety and their biological
activity. Eur. J. Med. Chem. 2012, 50, 39−43.
*
E-mail: kimbm@snu.ac.kr.
ORCID
(
5) (a) Pudovik, A. N.; Konovalova, I. V. Addition Reactions of
Esters of Phosphorus(III) Acids with Unsaturated Systems. Synthesis.
979, 81−96. (b) Fields, E. K. The Synthesis of Esters of Substituted
Amino Phosphonic Acids. J. Am. Chem. Soc. 1952, 74, 1528−1531.
6) (a) Fields, E. K. The Synthesis of Esters of Substituted Amino
B. Moon Kim: 0000-0001-6924-268X
1
Notes
Any additional relevant notes should be placed here.
(
Phosphonic Acids. J. Am. Chem. Soc. 1952, 74, 1528−1531. (b)
Keglevich, G.; Bálint, E. The Kabachnik–Fields Reaction: Mechanism
and Synthetic Use. Molecules. 2012, 17, 12821−12835. (c) Kabachnik,
M. I.; Medved, T. Y. New synthesis of aminophosphonic acids. Dokl.
Akad. Nauk SSSR. 1952, 83, 689−692.
ACKNOWLEDGMENT
We thank the Nano Material Development Program for an NRF
grant funded by the Ministry of Education, Science and
Technology, Republic of Korea (NRF-2012M3A7B4049644).
(
7) Sivala , M. R.; Devinenib, S. R.; Gollac, M.; Medarametlab, V.;
Pothuru, G. K.; Chamarthic, N. R. A heterogeneous catalyst, SiO
ZnBr : An efficient neat access for -aminophosphonates and
antimicrobial activity evaluation. J. Chem. Sci. 2016, 128, 1303−1313.
8) Zhan, Z. P.; Li, J. P. Bismuth(III) Chloride–Catalyzed
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