Global Access to 3/4-Phosphorylated Heterocycles via a Carbene-Catalyzed Stetter Reaction of Vinylphosphonates and Aldehydes

Article abstract of DOI:10.1021/acs.joc.0c00150

The first global method for the preparation of 3-phosphorylated-pyrroles,-furans,-thiophenes, and 4-phosphorylated 2,5-dihydropyridazines is reported. To achieve this, the first protocol for the direct synthesis of α-phosphorylated 1,4-diketones has been developed through a carbene-catalyzed Stetter reaction of vinylphosphonates and aldehydes. This is the first synthetic method for accessing 4-phosphorylated 2,5-dihydropyridazines. This process is metal-free and produces multifunctionalized heterocycles.

Full text of DOI:10.1021/acs.joc.0c00150

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Note
Global Access to 3/4-Phosphorylated Heterocycles via Carbene
Catalyzed Stetter Reaction of Vinylphosphonates and Aldehydes
Ram Subhawan Verma, Monika Mishra, Chandra Bhan Pandey, Shailesh Kumar, and Bhoopendra Tiwari
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 26 May 2020
Downloaded from pubs.acs.org on May 26, 2020
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Page 1 of 11
The Journal of Organic Chemistry
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Global Access to 3/4-Phosphorylated Heterocycles via Carbene
Catalyzed Stetter Reaction of Vinylphosphonates and Aldehydes
Ram Subhawan Verma,† Monika Mishra,† Chandra Bhan Pandey,† Shailesh Kumar,‡ and Bhoopendra
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Tiwari*†
† Division of Molecular Synthesis & Drug Discovery, Centre of Biomedical Research, SGPGIMS-Campus, Raebareli Road,
Lucknow, India, 226014
‡ Department of Chemistry, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, India,
226025
O
P(OEt)2
O
R2
(EtO)2P
O
R1
R2
X
O
1. NHC Cat.
2. Condition
P(OEt)2
X= NH, O, S
O
R1
N
R2
N
H
R1
Ph
 First global method for accessing multifunctionalized 3/4-phosphorylated heterocycles
 First NHC-catalyzed method for the preparation of phosphorylated 1,4-diketones
 3-Phosphorylated pyrroles, furans, thiophenes; 4-phosphorylated 2,5-dihydropyridazines
 Metal-free method
 Two-step
 Up to 92% yield over two steps
ABSTRACT: The first global method for the preparation of 3-phosphorylated-pyrroles, -furans, -thiophenes, and 4-phosphorylated
2,5-dihydropyridazines is reported. To achieve this, the first protocol for the direct synthesis of α-phosphorylated 1,4-diketones has
been developed through a carbene-catalyzed Stetter reaction of vinylphosphonates and aldehydes. This is the first synthetic method
for accessing 4-phosphorylated 2,5-dihydropyridazines. This process is metal-free and produces multi-functionalized heterocycles.
Phosphorylated aryls and heteroaryls have ubiquitous
occurrence in pharmaceutics, agrochemicals, functionalized
materials, organic synthesis as ligands and intermediates, and
are closely related to life science.1 They show unique
bioactivities by virtue of P=O group acting as a strong hydrogen
bond acceptor with proteins.2 For heterocycles like pyrroles,
furans and thiophenes, accessing 3/4-phosphorylated
derivatives has remained challenging compared to 2-substituted
analogs due to a lower reactivity of the C-3/4. Several valuable
methods for their preparation have been developed. These
methods generally rely on metal-catalyzed cyclization of
phosphoryl-functionalized substrates, directing group-assisted
functionalization or metal-catalyzed substitution in aryl halides.
Some of the recent reports for the preparation of pyrroles
include Steven’s ZnCl2-catalyzed cyclization of A, Deb’s
PdCl2/Cu(OAc)2-catalyzed cyclization of B, and Lopez’s
IPr(CH3CN)AuSbF6-catalyzed cyclization of C (Scheme 1).3
The group of Jiang prepared furans using (EtO)2POH/Cs2CO3
from D.4 Hong, Yamaguchi and Muimo achieved
Scheme 1: Recent Approaches for the Preparation of 3-
Phosphorylated Pyrroles, Furans and Thiophenes
Pyrroles
R3
O
R2
NH
R1
O
P(OEt)2
R2
P(OEt)2
R1
N
Ar
A
B
C
(EtO)2P
N2
H
O
ZnCl2, CH3CN
(Stevens)
IPr(MeCN)AuSbF6
(Lopez)
PdCl2, Cu(OAc)2
(Deb)
Thiophenes
Furans
R,
O
Br
HO
OPh
O
+
(EtO)2P
EDG
S
O
R
EWG
S
D
E
F
G
S
(EtO)2POH
Cs2CO3
(Jiang)
[RhCp*Cl2]2
AgNTf2, Ag2CO3
(Hong)
Ni(OAC)2
dcypt
(Yamaguchi)
Pd(OAc)2, dppf
EtNiPr2, (EtO)2P(O)H
(Muimo)
This Work:
A global method for the preparation of 3-phosphorylated pyrroles,
furans, thiophenes; and 4-phosphorylated 2,5-dihydropyridazines
O
O
O
O
phosphorylation
of
E,
F
and
G
using
and
P(OEt)2
P(OEt)2
P(OEt)2
O
P(OEt)2
R2
R2
[RhCp*Cl2]2/AgNTf2/Ag2CO3,
Ni(OAc)2/dcypt
and
R2
NHC
Pd(OAc)2/dppf/EtNiPr2/(EtO)2P(O)H, respectively.5 Despite
the success, these methods suffer from one or multiple
limitations like: (i) suitable for one specific class of
+
R2
R1
R1
R1
2
O
O
X
N
N
3
O
X= NH, O, S
Ph
1
H
R1
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The Journal of Organic Chemistry
Table 1. Optimization of the Reaction Conditiona
Page 2 of 11
1
2
3
4
5
6
7
8
Scheme 2. Scope of Aldehydes and Vinylphosphonatesa
O
O
P(OEt)2
Ph
O
O
P(OEt)2
Ph
O
O
L
cat (20 mol %)
cat L (20 mol %)
DBU (40 mol %)
DBU (40 mol %)
P(OEt)2
R2
O
P(OEt)2
R2
O
H
CHCl3, 50 oC,16 h
O
2a
O
R
R1
H
CHCl3, 50 oC, 16 h
1a
3a
O
O
1
2
3
Entry
Deviation from the standard
condition
Yield
(%)b
0
O
O
O
O
P(OEt)2
Ph
O
O
P(OEt)2
Ph
P(OEt)2
1
2
no catalyst
H instead of L
Ph
48
9
O
O
O
3
4
I and J instead of L
K instead of L
trace
64
CH3
10
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60
CH3
3a
3b
3c
, 89%
, 95%
, 81%
5
6
7
8
9
10
11
none
95
77
61
21
26
89
67
O
O
O
O
P(OEt)2
Ph
CH2Cl2 instead of CHCl3
(CH2Cl)2 instead of CHCl3
DABCO instead of DBU
tBuOK instead of DBU
TMG instead of DBU
O
P(OEt)2
Ph
O
P(OEt)2
Ph
O
O
O
H3C
Br
Br
3d
3e
3f
, 82%
, 94%
, 87%
rt instead of 50 oC
O
O
O
O
P(OEt)2
Ph
O
P(OEt)2
Ph
P(OEt)2
Ph
O
N
N
Ar
N
HO
N
N
Mes
Mes
S
N
S
N
I
BF4
: Ar = Ph
: Ar = Mes
Me
I
Me
Cl
O
O
O
I
J
Br
H
L
K
3g
3h
3i,
91%
, 97%
NO2
O
, 89%
aStandard reaction condition, unless otherwise specified: 1a (0.15
mmol), 2a (0.10 mmol), L (20 mol %), DBU (40 mol %), CHCl3 (1.0
mL) at 50 oC for 16 h. bIsolated yield of 3a. DBU=1,8-
Diazabicycloundec-7-ene, DABCO=1,4-Diazabicyclo[2.2.2]octane,
TMG=1,1,3,3-Tetramethylguanidine.
O
O
O
O
P(OEt)2
Ph
O
P(OEt)2
Ph
O
P(OEt)2
Ph
O
P(OEt)2
iPr
Ph
CH3
3l
, 57%
O
S
O
O
O
O
3m
, 91%
3j
3k,
, 98%
84%
OMe
S
O
O
O
heterocycle, (ii) multistep preparation of complex advanced
substrates, (iii) transition-metal catalyzed, and (iv) require
directing group on the ring. To our knowledge, the literature is
elusive of any general method suitable for the preparation of 3-
phosphorylated-pyrroles, -furans, and -thiophenes. In addition,
the synthesis of 4-phosphorylated 2,5-dihydropyridazines is yet
to be achieved.
O
O
Cl
O
P(OEt)2
O
Ph
P(OEt)2
O
Ph
3n
Ph
P(OEt)2
O
3o
3p
, 89%
, 83%
, 92%
aStandard reaction condition as in entry 1, Table1. Yields are
the isolated yields after column chromatography.
We hypothesized that all these challenging heterocycles could
be obtained from a common α-phosphorylated 1,4-diketone
intermediate 3 (Scheme 1). Our literature survey did not lead to
any precedence, either metal- or organo-catalyzed, on the
synthesis of 3. Consequently, developing an effective synthetic
method for 3, possibly metal-free and organocatalytic, was key
to the success of this study. With a long interest in metal-free
catalysis, we were interested to develop the first N-heterocyclic
harbene (NHC)-catalyzed method for the preparation of 3
through Stetter reaction of aldehyde 1 with vinylphosphonate
2.6,7
reaction using different aldehydes and vinylphosphonates under
the standard condition. As demonstrated in Scheme 2,
arylaldehydes substituted with electron-donating groups
(EDG), such as methyl, at ortho, meta or para-position reacted
well to give the desired product in 81-89% yield (3b-3d).
Likewise, the electron-withdrawing groups (EWG) on
arylaldehydes were well tolerated giving the diketones in 87-
97% yield (3e-3h). The substitution pattern (ortho/meta/para)
on the aryl rings did not show any general effect on the
reactivity. Next, polyaromatic and heteroaromatic aldehydes
were efficiently converted to produce 3i-3k in excellent yields.
Notably, an aliphatic aldehyde also reacted smoothly to afford
the phosphorylated diketone 3l in a descent yield. We next
examined the substitution effect on vinylphosphonates 2 in
reaction with 1a. The reactions tolerated well aliphatic, both
electron-rich as well as electron-deficient aryl, and heteroaryl-
derived 2 to produce the desired products in excellent yields
(3m-3p). β-phenyl-substituted vinylphosphonate (a derivative
of 2a) under this reaction condition remained largely
unconsumed. Performing the reaction on 2.24 mmol scale (0.60
g) of vinylphosphonate 2a produced the desired product 3a in
91% isolated yield.
Our study commenced using aldehyde 1a and
vinylphosphonate 2a. The key results of reaction condition
optimization are enlisted in Table 1. Precatalyst H in CHCl3 in
o
the presence of DBU base at 50 C produced 3a in 48% yield
(entry 2). The N-Ph- as well as N-Mes-protected pyrrolidinone-
based triazolium salts were not suitable for this reaction (I and
J, entry 3). The use of thiazolium salt K improved the yield to
64% (entry 4). Switching to salt L gratifyingly produced 3a in
an excellent yield of 95% (entry 5). Screening of several other
solvents and bases under a condition similar to entry 5
generated the desired product with a diminished yield (entries
6-10).
Further expanding the scope of the reaction, we used different
enals 4 (Scheme 3). These α,β-unsaturated aldehydes have
We next sought to examine the generality of this Stetter
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Page 3 of 11
The Journal of Organic Chemistry
O
remained comparatively challenging substrates for Stetter-type
reaction due to a competing
O
P(OEt)2
1
2
3
O
P(OEt)2
Ph
NH4OAc, AcOH
100 oC, 10 h
Ph
N
H
6
Scheme 3. Scope of Enals and Vinylphosphonatesa
O
R
R
3
4
5
6
7
8
9
O
O
O
O
O
O
L
cat (20 mol %)
P(OEt)2
R2
P(OEt)2
Ph
P(OEt)2
P(OEt)2
P(OEt)2
R2
O
DBU (40 mol %)
R1
H
O
R1
CHCl3, 50 oC, 16 h
Ph
Ph
N
H
O
N
N
O
5
4
2
H
H
Br
H3C
O
O
O
6a,
6b,
6c,
91%
93%
95%
O
O
P(OEt)2
Ph
O
P(OEt)2
Ph
P(OEt)2
Ph
O
O
10
11
12
13
14
15
16
17
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19
20
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46
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50
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54
55
56
57
58
59
60
P(OEt)2
P(OEt)2
Ph
P(OEt)2
O
O
O
MeO
Ph
Ph
N
N
H
89%
N
5a
5b
5c
, 59%
, 81%
O
, 68%
O
OMe
H
H
S
6d,
6e,
6f,
86%
78%
O
O
P(OEt)2
Ph
O
P(OEt)2
O
P(OEt)2
Ph
Scheme 5. Preparation of 3-Phosphorylated Furans
Ph
O
O
O
F
O
O
OMe
5d
O
Cl
P(OEt)2
Ph
P(OEt)2
5e
5f
, 80%
, 86%
O
, 84%
pTSA, toluene
Ph
O
O
O
O
O
100 oC, 10 h
R
R
P(OEt)2
Ph
3
O
P(OEt)2
Ph
P(OEt)2
Ph
7
O
O
O
O
P(OEt)2
P(OEt)2
P(OEt)2
O
O
O
Br
NO2
5h
NO2
H3C
Ph
O
Ph
Ph
5g
5i
, 73%
, 82%
O
, 51%
O
O
7a,
O
Br
H3C
O
O
O
7b,
7c,
79%
85%
83%
O
P(OEt)2
Ph
P(OEt)2
Ph
P(OEt)2
Ph
O
O
O
P(OEt)2
P(OEt)2
P(OEt)2
O
O
O
S
5j
5k
5l
, 67%
, 66%
, 76%
Ph
Ph
Ph
O
O
O
S
OMe
7d,
7e,
7f,
79%
S
71%
88%
O
O
O
O
O
O
Cl
Scheme 6. Preparation of 3-Phosphorylated Thiophenes
Ph
P(OEt)2
O
Ph
P(OEt)2
Ph
P(OEt)2
O
P(OEt)2
O
O
O
5m
5n
, 88%
, 85%
5o
, 79%
O
P(OEt)2
Ph
aStandard reaction condition as in entry 1, Table1. Yields are
the isolated yields after column chromatography.
Lawesson reagent
toluene, 70 oC, 10 h
Ph
S
O
R
R
3
8
homoenolate and enolate reaction pathways. In general, both
electron-deficient as well as electron-rich enals underwent this
coupling reaction to afford the Stetter products in good to
excellent yields (5a-5i). As in the case of aryl aldehydes, here
also no generality on the reaction outcome among ortho, meta
and para-substitution was observed. Polyaromatic and
heteroaromatic enals were equally compatible under the
optimized condition and gave the corresponding products in
excellent yields (5j-5k).
O
O
O
P(OEt)2
P(OEt)2
P(OEt)2
Ph
Ph
Ph
S
S
S
Me
Br
8a
8b
8c
, 86%
, 81%
, 88%
Scheme 7. Preparation of 4-Phosphorylated 2,5-
Dihydropyridazines
O
O
P(OEt)2
O
P(OEt)2
Ph
Scheme 4. Preparation of 3-Phosphorylated Pyrroles
PhNHNH2, CHCl3
TFA, rt, 10 h
R
Ph
O
N
N
R
9
3
Ph
O
O
O
P(OEt)2
P(OEt)2
P(OEt)2
Br
Me
Ph
Ph
Ph
Ph
N
N
N
N
N
N
Ph
Ph
9a,
9b,
9c,
95%
93%
98%
β-Methyl-substituted enal was also tolerated to produce 5l in
67% yield. We next examined the scope of vinylphosphonates
2. Electron-rich as well as –deficient aryl, and heteroaryl
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The Journal of Organic Chemistry
Page 4 of 11
substituted vinylphosphonates reacted well with 4a to generate mol %) in CHCl3 (1.0 mL) at room temperature. The reaction
1
2
3
4
5
6
7
8
the desired products in 79-88% yield (5m-5o).
chamber was purged with argon and DBU (40 mol %) was
added. After stirring this reaction mixture at 50 oC in an oil bath
for 16 h, the solvent was evaporated under the reduced pressure.
The crude mass was purified by flash column chromatography
on silica gel using 60% EtOAc in hexane to obtain the pure
desired products 3 or 5.
After successfully developing the catalytic method for the
preparation of a wide range of α-phosphorylated 1,4-diketones,
we next undertook the preparation of different class of 3/4-
phosphorylated heterocycles. For all classes of heterocycles
prepared here, such as 3-phosphorylated-pyrroles, -furans and
thiophenes, and 4-phosphorylated 2,5-dihydropyridazines, we
demonstrated the efficiency of our method using electron-rich,
electron-deficient (hetero)aryl-substituted 1,4-diketones. The
diketones 3a, 3d, 3g, 3i, 3k and 5a smoothly converted to 3-
phosphorylated pyrroles 6a-6f in the presence of NH4OAc in
AcOH at an elevated temperature in 78-95% yield (Scheme 4).8
When this set of diketones were treated with pTSA in toluene,
the 3-phosphorylated furans 7a-7f were obtained in 71-88%
yield (Scheme 5).9 Upon subjecting 3a, 3d and 3g with
Lawesson’s reagent in toluene at 70 oC, 3-phosphorylated
thiophenes 8a-8c were obtained in 81-88% yield (Scheme 6).10
Finally, these diketones could be converted to 4-phosphorylated
2,5-dihydropyridazines 9a-9c using PhNHNH2 in excellent
yields of 93-98% (Scheme 7).11 The observed regioselectivity
may be attributed to the steric hindrance from the phosphoryl
group to the neighbouring carbonyl functionality.
The preparation of 3a on gram scale: The product 3a was
obtained in 91% yield (0.76 g) when the reaction was run using
1a (0.356 g, 3.36 mmol) and 2a (0.60 g, 2.24 mmol) under the
optimized reaction condition.
9
10
11
12
13
14
15
16
17
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19
20
21
22
23
24
25
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60
General procedure for the synthesis of compounds 6, 7, 8
and 9:
Pyrroles 6: To an oven-dried sealed tube equipped with a
magnetic stir bar, was added ketophosphonates 3 or 5 (0.10
mmol), NH4OAc (0.115 g, 1.50 mmol) in AcOH (1.0 mL) and
the reaction chamber was sealed. After stirring at 100 oC in an
oil bath for 10 h, the reaction mixture was quenched with a
saturated aqueous solution of NaHCO3, extracted with CH2Cl2
(2 x 10 ml). The combined organic layers were dried over
anhydrous Na2SO4, evaporated under reduced pressure and the
crude product was purified by flash column chromatography on
silica gel using 60% EtOAc in hexane to obtain the pure desired
product 6.
In summary, we have developed the first general method for
the preparation of highly functionalised 3-phosphorylated-
pyrroles, -furans and -thiophenes; and 4-phosphorylated 2,5-
dihydropyridazines from vinylphosphonates and aldehydes. To
achieve this, the first NHC-catalyzed Stetter reaction was
developed for the preparation of α-phosphorylated-1,4-
Furans 7: To an oven-dried sealed tube equipped with a
magnetic stir bar, ketophosphonates 3 or 5 (0.10 mmol), p-TSA
(0.028 g, 0.15 mmol) and toluene (1.0 mL) was added and the
reaction chamber was sealed. After stirring the reaction mixture
diketones for
a wide range of aldehydes, enals and
vinylphosphonates. This is the first method to synthesize 4-
phosphorylated 2,5-dihydropyridazines. This two-step method
is metal-free and highly efficient. This study is expected to
further augment the bioactivity evaluation of different class of
phosphorylated heterocycles.
o
at 100 C in an oil bath for 10 h, the solvent was evaporated
under a reduced pressure and the compound was purified by
flash column chromatography on silica gel using 60% EtOAc
in hexane to obtain the pure desired product 7.
Thiophenes 8: To an oven-dried sealed tube equipped with a
magnetic stir bar, was added ketophosphonates 3 (0.10 mmol),
Lawesson’s reagent (0.048 g, 0.12 mmol) and toluene (1.0 mL)
and the reaction chamber was sealed. After being stirred at 70
oC in an oil bath for 10 h, the reaction mixture was cooled to
room temperature and the solvent was evaporated under a
reduced pressure. The crude product was purified by flash
column chromatography on silica gel using 60% EtOAc in
hexane to obtain the pure furans 8.
EXPERIMENTAL SECTION
General Information: Aldehydes and other reagents were
purchased from a commercial supplier and used without further
purification. All reactions were performed in oven-dried
glasswares. The α,β-unsaturated aldehydes
4
and
vinylphosphonates 2 were prepared following literature known
methods.12,13 Solvents were dried and distilled following the
standard procedures; TLC was carried out on pre-coated plates
(Merck silica gel 60, f254), and the spots were visualized with
UV light or by charring the plates dipped in PMA charring
solution. Flash chromatography was performed using silica gel
(230-400 mess) with distilled solvents. 1H, 13C and 31P NMR for
compounds were recorded at 400 MHz, 100 MHz and 162 MHz
instrument respectively using CDCl3 as the solvent. 98% PPh3
was used as an external standard for 31P NMR. Chemical shifts
were recorded in parts per million (ppm, δ) relative to
tetramethylsilane (δ 0.00). 1H NMR splitting patterns are
designated as singlet (s), doublet (d), triplet (t), quartet (q), dd
(doublet of doublets); m (multiplets), etc. High-resolution mass
spectral analysis (HRMS) was performed on Q-TOF Premier
mass spectrometer. The melting points were recorded on Buchi
M-560 melting point apparatus and are uncorrected.
2,5-Dihydropyridazines 9: To an oven-dried sealed tube
equipped with a magnetic stir bar, was added ketophosphonates
3 (0.10 mmol), PhNHNH2 (17.8 µL, 0.15 mmol), CHCl3 (1.0
mL) and TFA (10.0 µL, 0.13 mmol) was added, and the reaction
chamber was sealed. After stirring the reaction mixture for 10 h
at room temperature, the solvent was evaporated under a
reduced pressure. The crude product was purified by flash
column chromatography on silica gel using 60% EtOAc in
hexane to obtain the pure desired product 9.
Characterization of the products:
Diethyl (1,4-dioxo-1,4-diphenylbutan-2-yl)phosphonate (3a):
95% yield (36 mg), pale yellow gummy liquid, eluent: 60%
EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ 1.08 (3H, t, J
= 6.8 Hz), 1.17 (3H, t, J = 6.8 Hz), 3.47-3.64 (1H, m), 3.85-4.22
(5H, m), 4.63-4.87 (1H, m), 7.28-7.56 (6H, m), 7.91 (2H, d, J =
7.2 Hz), 8.04 (2H, d, J = 7.6 Hz); 13C{1H} NMR (100 MHz,
CDCl3): δ 16.1 (q, JC-P = 7.0 Hz), 37.3 (d, JC-P = 1 Hz), 42.3 (d,
General procedure for the NHC-Catalyzed Synthesis of 3
and 5: To an oven-dried Schlenk tube equipped with a magnetic
stir bar, was added aldehyde 1 or 4 (0.15 mmol, 1.5 equiv.),
vinylphosphonate 2 (0.1 mmol, 1.0 equiv.) and catalyst L (20
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The Journal of Organic Chemistry
JC-P = 128.0 Hz), 62.9 (t, JC-P = 7.0 Hz), 128.2, 128.4, 128.6, Hz), 7.41 (2H, t, J = 7.6 Hz), 7.51 (1H, t, J = 7.2 Hz), 7.62 (1H,
1
2
3
4
5
6
7
8
128.9, 133.2, 133.5, 135.9, 137.4, 195.2 (d, JC-P = 5.0 Hz), 196.6
(d, JC-P = 15.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 22.3;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C20H23O5PNa+
397.1176, found: 397.1171.
d, J = 8.0 Hz), 7.83 (1H, d, J = 7.6 Hz), 8.02 (3H, t, J = 5.6 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P = 6.0 Hz),
37.3, 42.4 (d, JC-P = 128.0 Hz), 62.8 (t, JC-P = 6.0 Hz), 122.9,
126.7, 128.4, 128.9, 130.2, 131.2, 133.2, 136.3, 137.3, 137.6,
195.0 (d, JC-P = 5.0 Hz), 195.3 (d, JC-P = 16.0 Hz); 31P{1H} NMR
(162 MHz, CDCl3): δ 21.8; HRMS (ESI-TOF) m/z: [M+Na]+
calcd. for C20H22BrO5PNa+ [M+Na]+: 475.0281, found:
475.0276.
Diethyl (1,4-dioxo-1-phenyl-4-(o-tolyl)butan-2-yl)phosphonate
(3b): 81% yield (32 mg), pale yellow gummy liquid, eluent:
1
60% EtOAc in hexane. H NMR (400 MHz, CDCl3): δ 1.07
(3H, t, J = 7.2 Hz), 1.16 (3H, t, J = 6.8 Hz), 2.34 (3H, s), 3.33-
3.35 (1H, m), 3.85-4.16 (5H, m), 4.61-4.84 (1H, m), 7.10-7.26
(2H, m), 7.30 (1H, t, J = 7.2 Hz), 7.41 (2H, t, J = 7.6 Hz), 7.50
(1H, t, J = 7.2 Hz), 7.74 (1H, d, J = 7.6 Hz), 8.04 (2H, d, J = 7.2
Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P = 6.0
Hz), 21.3, 39.6 (q, JC-P = 1.0 Hz), 42.7 (d, JC-P = 127.0 Hz), 62.8
(t, JC-P = 7.0 Hz), 125.7, 128.4, 128.9, 128.9, 131.7, 131.9,
133.2, 136.6, 137.4, 138.5, 195.3 (d, JC-P = 4.0 Hz), 200.1 (d,
JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 22.3;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C21H25O5PNa+
[M+Na]+: 411.1332, found: 411.1329.
Diethyl (4-(4-bromophenyl)-1,4-dioxo-1-phenylbutan-2-yl)ph-
osphonate (3g): 97% yield (45 mg), pale yellow gummy liquid,
eluent: 60% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ
1.08 (3H, t, J = 7.2 Hz), 1.16 (3H, t, J = 7.2 Hz), 3.42-3.55 (1H,
m), 3.88-4.15 (5H, m), 4.60-4.80 (1H, m), 7.41 (2H, t, J = 7.2
Hz), 7.50 (3H, t, J = 7.2 Hz), 7.77 (2H, d, J = 8.4 Hz), 8.02 (2H,
d, J = 7.2 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P
= 6.0 Hz), 37.2, 42.3 (d, JC-P = 128.0 Hz), 62.9 (q, JC-P = 6.0
Hz), 128.4, 128.7, 128.9, 129.7, 131.9, 133.2, 134.5, 137.2,
195.1 (d, JC-P = 5.0 Hz), 200.1 (d, JC-P = 16.0 Hz); 31P{1H} NMR
(162 MHz, CDCl3): δ 21.5; HRMS (ESI-TOF) m/z: [M+Na]+
calcd. for C20H22BrO5PNa+ [M+Na]+: 475.0281, found:
475.0278.
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13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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32
33
34
35
36
37
38
39
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41
42
43
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46
47
48
49
50
51
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53
54
55
56
57
58
59
60
Diethyl (1,4-dioxo-1-phenyl-4-(m-tolyl)butan-2-yl)phosphon-
ate (3c): 89% yield (35 mg), pale yellow gummy liquid, eluent:
1
60% EtOAc in hexane. H NMR (400 MHz, CDCl3): δ 1.09
(3H, t, J = 7.2 Hz), 1.16 (3H, t, J = 7.2 Hz), 2.32 (3H, s), 3.44-
3.62 (1H, m), 3.88-4.20 (5H, m), 4.62-4.82 (1H, m), 7.22-7.35
(2H, m), 7.41 (2H, t, J = 7.2 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.71
(2H, d, J = 6.4 Hz), 8.04 (2H, t, J = 7.2 Hz); 13C{1H} NMR (100
MHz, CDCl3): δ 16.1 (q, JC-P = 6.0 Hz), 21.2, 37.3, 42.4 (d, JC-
P = 128.0 Hz), 62.8 (t, JC-P = 8.0 Hz), 125.4, 128.4, 128.5, 128.8,
128.9, 133.1, 134.2, 135.9, 137.4, 138.4, 195.3 (d, JC-P = 5.0
Hz), 196.7 (d, JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 22.3; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C21H25O5PNa+ [M+Na]+: 411.1332, found: 411.1328.
Diethyl (4-(3-nitrophenyl)-1,4-dioxo-1-phenylbutan-2-yl)pho-
sphonate (3h): 89% yield (38 mg), pale yellow gummy liquid,
eluent: 60% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ
1.10 (3H, t, J = 7.2 Hz), 1.17 (3H, t, J = 7.2 Hz), 3.48-3.63 (1H,
m), 3.90-4.08 (4H, m), 4.08-4.21 (1H, m), 4.65-4.82 (1H, m),
7.43 (2H, t, J = 7.2 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.60 (1H, t, J
= 8.0 Hz), 8.03 (2H, t, J = 7.2 Hz), 8.23 (1H, d, J = 8.0 Hz),
8.35 (1H, dd, J = 1.2 Hz), 8.74 (1H, t, J = 1.6 Hz); 13C{1H}
NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P = 3.0 Hz), 37.5, 42.5
(d, JC-P = 129.0 Hz), 63.1 (t, JC-P = 3.0 Hz), 123.2, 127.8, 128.5,
128.9, 130.0, 133.5, 133.8, 137.2, 148.5, 194.8 (d, JC-P = 6.0
Hz), 195.0 (d, JC-P = 5.0 Hz); 31P{1H} NMR (162 MHz, CDCl3):
Diethyl (1,4-dioxo-1-phenyl-4-(p-tolyl)butan-2-yl)phosphon-
ate (3d): 82% yield (32 mg), pale yellow gummy liquid, eluent:
1
δ
21.5; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C20H22NO7PNa+ [M+Na]+: 442.1027, found: 442.1029.
Diethyl (4-(naphthalen-1-yl)-1,4-dioxo-1-phenylbutan-2-
60% EtOAc in hexane. H NMR (400 MHz, CDCl3): δ 1.08
(3H, t, J = 7.2 Hz), 1.17 (3H, t, J = 6.8 Hz), 2.33 (3H, s), 3.42-
3.62 (1H, m), 3.87-4.17 (5H, m), 4.60-4.83 (1H, m), 7.18 (2H,
d, J = 8.4 Hz), 7.41 (2H, t, J = 7.6 Hz), 7.50 (1H, t, J = 7.2 Hz),
7.81 (2H, d, J = 8.4 Hz), 8.04 (2H, t, J = 7.2 Hz); 13C{1H} NMR
(100 MHz, CDCl3): δ 16.1 (q, JC-P = 6.0 Hz), 21.7, 37.2, 42.3
(d, JC-P = 128.0 Hz), 62.8 (t, JC-P = 7.0 Hz), 128.4, 128.5, 128.9,
129.3, 133.1, 133.5, 137.5, 144.4, 195.3 (d, JC-P = 5.0 Hz), 196.2
(d, JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 22.4;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C21H25O5PNa+
[M+Na]+: 411.1332, found: 411.1330.
yl)phosphonate (3i): 91% yield (39 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.08 (3H, t, J = 7.2 Hz), 1.16 (3H, t, J = 6.8 Hz),
3.49-3.67 (1H, m), 3.91-4.09 (4H, m), 4.14-4.27 (1H, m), 4.76-
4.92 (1H, m), 7.38-7.48 (5H, m), 7.51 (1H, t, J = 7.2 Hz), 7.77
(1H, d, J = 7.2 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.99 (1H, d, J =
4.0 Hz), 8.08 (1H, d, J = 7.6 Hz), 8.45 (2H, d, J = 8.4 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P = 7.0 Hz),
40.1, 42.9 (d, JC-P = 128.0 Hz), 62.8 (t, JC-P = 6.0 Hz), 124.3,
125.7, 126.4, 128.0, 128.3, 128.3, 128.4, 128.9, 130.1, 133.1,
133.2, 133.8, 134.3, 137.5, 195.4 (d, JC-P = 4.0 Hz), 200.3 (d,
JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 22.2;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C24H25O5PNa+
[M+Na]+: 447.1332, found: 447.1335.
Diethyl (4-(2-bromophenyl)-1,4-dioxo-1-phenylbutan-2-yl)ph-
osphonate (3e): 94% yield (43 mg), pale yellow gummy liquid,
eluent: 60% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ
1.08 (3H, t, J = 6.8 Hz), 1.15 (3H, t, J = 6.8 Hz), 3.38-3.53 (1H,
m), 3.86-4.09 (5H, m), 4.61-4.83 (1H, m), 7.15-7.36 (2H, m),
7.37-7.59 (5H, m), 8.02 (2H, d, J = 7.6 Hz); 13C{1H} NMR (100
MHz, CDCl3): δ 16.1 (q, JC-P = 7.0 Hz), 37.2, 42.3 (d, JC-P
=
Diethyl
(4-(furan-2-yl)-1,4-dioxo-1-phenylbutan-2-
128.0 Hz), 62.8 (t, JC-P = 6.0 Hz), 128.4, 128.7, 128.9, 129.7,
131.9, 133.2, 134.6, 137.2, 195.1 (d, JC-P = 5.0 Hz), 195.6 (d,
JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 21.9;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C20H22BrO5PNa+
[M+Na]+: 475.0281, found: 475.0274.
yl)phosphonate (3j): 98% yield (36 mg), pale yellow gummy
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
1
CDCl3): δ 1.08 (3H, t, J = 7.2 Hz), 1.16 (3H, t, J = 7.2 Hz),
3.31-3.48 (1H, m), 3.87-4.12 (5H, m), 4.59-4.79 (1H, m), 6.45
(1H, t, J = 1.6 Hz), 7.15 (1H, d, J = 3.6 Hz), 7.39 (2H, t, J = 7.6
Hz), 7.49 (2H, t, J = 7.2 Hz), 8.01 (2H, d, J = 8.0 Hz); 13C{1H}
NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P = 6.0 Hz), 36.7 (q, JC-
Diethyl (4-(3-bromophenyl)-1,4-dioxo-1-phenylbutan-2-yl)ph-
osphonate (3f): 87% yield (40 mg), pale yellow gummy liquid,
eluent: 60% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ
1.09 (3H, t, J = 6.8 Hz), 1.16 (3H, t, J = 7.2 Hz), 3.39-3.57 (1H,
m), 3.89-4.16 (5H, m), 4.61-4.79 (1H, m), 7.25 (1H, t, J = 8.0
= 2.0 Hz), 41.9 (d, JC-P = 128.0 Hz), 62.8 (t, JC-P = 4.0 Hz),
P
112.3, 117.6, 128.4, 128.9, 133.2, 137.3, 146.6, 151.9, 185.7 (d,
JC-P = 16.0 Hz), 195.2 (d, JC-P = 5.0 Hz); 31P{1H} NMR (162
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Page 6 of 11
MHz, CDCl3): δ 21.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd.
128.2, 128.7, 128.9, 129.7, 133.0, 133.6, 134.7, 135.7, 138.9,
for C18H21O6PNa+ [M+Na]+: 387.0968, found: 387.0970.
194.2 (d, JC-P = 6.0 Hz), 196.5 (d, JC-P = 16.0 Hz); 31P{1H} NMR
(162 MHz, CDCl3): δ 21.7; HRMS (ESI-TOF) m/z: [M+Na]+
calcd. for C20H22ClO5PNa+ [M+Na]+: 431.0786, found:
431.0786.
1
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3
4
5
6
7
8
Diethyl (1,4-dioxo-1-phenyl-4-(thiophen-2-yl)butan-2-yl)pho-
sphonate (3k): 84% yield (32 mg), pale yellow gummy liquid,
eluent: 60% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ
1.09 (3H, t, J = 6.8 Hz), 1.16 (3H, t, J = 7.2 Hz), 3.41-3.57 (1H,
m), 3.89-4.14 (5H, m), 4.64-4.81 (1H, m), 7.06 (1H, t, J = 4.4
Hz), 7.40 (2H, t, J = 7.6 Hz), 7.49 (1H, t, J = 7.2 Hz), 7.57 (1H,
d, J = 4.8 Hz), 7.76 (1H, d, J = 4.0 Hz), 8.01 (2H, d, J = 7.6 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P = 6.0 Hz),
Diethyl
(1,4-dioxo-4-phenyl-1-(thiophen-2-yl)butan-2-
yl)phosphonate (3p): 89% yield (33 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.21-1.31 (6H, m), 3.51-3.66 (1H, m), 4.05-4.22 (5H,
m), 4.53-4.67 (1H, m), 7.19 (1H, t, J = 4.4 Hz), 7.45 (1H, d, J =
7.6 Hz), 7.57 (1H, t, J = 7.6 Hz), 7.69 (1H, d, J = 5.2 Hz), 7.99
(3H, t, J = 8.0 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 16.2
(t, JC-P = 6.0 Hz), 36.8 (d, JC-P = 2.0 Hz), 43.9 (d, JC-P = 127.0
Hz), 62.9 (t, JC-P = 7.0 Hz), 128.1, 128.2, 128.6, 133.5, 133.6,
9
37.5 (d, JC-P = 1.0 Hz), 42.3 (d, JC-P = 128.0 Hz), 62.8 (t, JC-P
=
10
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21
22
23
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26
27
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29
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32
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6.0 Hz), 128.2, 128.4, 128.9, 132.6, 133.2, 134.1, 137.3, 142.7,
189.5 (d, JC-P = 17.0 Hz), 195.1 (d, JC-P = 5.0 Hz); 31P{1H} NMR
(162 MHz, CDCl3): δ 21.8; HRMS (ESI-TOF) m/z: [M+Na]+
calcd. for C18H21O5PSNa+ [M+Na]+: 403.0740, found:
403.0743.
134.4, 135.8, 144.0, 187.1 (d, JC-P = 5.0 Hz), 196.4 (d, JC-P
=
15.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 21.9; HRMS
(ESI-TOF) m/z: [M+Na]+ calcd. for C18H21O5PNa+ [M+Na]+:
403.0740, found: 403.0739.
Diethyl (1,4-dioxo-1-phenyloctan-2-yl)phosphonate (3l): 57%
yield (20 mg), pale yellow gummy liquid, eluent: 60% EtOAc
in hexane. 1H NMR (400 MHz, CDCl3): δ 0.80 (3H, t, J = 7.2
Hz), 1.05 (3H, t, J = 6.8 Hz), 1.13-1.27 (5H, m), 1.40-1.52 (2H,
m), 2.33-2.46 (2H, m), 2.84-3.03 (1H, m), 3.44-3.59 (1H, m),
3.86-4.08 (4H, m), 4.46-4.62 (1H, m), 7.39 (2H, t, J = 7.6 Hz),
7.49 (1H, t, J = 7.2 Hz), 7.96 (2H, d, J = 8.0 Hz); 13C{1H} NMR
(100 MHz, CDCl3): δ 13.8, 16.1 (q, JC-P = 6.0 Hz), 22.2, 25.7,
40.5 (d, JC-P = 2.0 Hz), 41.6, 42.2 (d, JC-P = 128.0 Hz), 62.7 (q,
JC-P = 6.0 Hz), 128.0, 128.4, 128.7, 128.9, 133.2, 137.4, 195.4
(d, JC-P = 5.0 Hz), 207.6 (d, JC-P = 16.0 Hz); 31P{1H} NMR (162
MHz, CDCl3): δ 22.1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd.
for C18H27O5PNa+ [M+Na]+: 377.1489, found: 377.1492.
Diethyl (E)-(1,4-dioxo-1,6-diphenylhex-5-en-2-yl)phosphona-
te (5a): 81% yield (33 mg), pale yellow gummy liquid, eluent:
1
60% EtOAc in hexane. H NMR (400 MHz, CDCl3): δ 1.16
(3H, t, J = 6.8 Hz), 1.24 (3H, t, J = 6.8 Hz), 3.23-3.41 (1H, m),
3.78-3.96 (1H, m), 3.97-4.18 (4H, m), 4.63-4.86 (1H, m), 6.74
(1H, d, J = 16.4 Hz), 7.33-7.44 (3H, m), 7.45-7.67 (6H, m), 8.09
(2H, d, J = 7.6 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 16.0
(q, JC-P = 6.0 Hz), 38.8, 42.2 (d, JC-P = 128.0 Hz), 62.7 (t, JC-P
=
8.0 Hz), 124.9, 128.2, 128.3, 128.8, 128.9, 130.6, 133.1, 134.1,
137.3, 143.6, 195.2 (d, JC-P = 5.0 Hz), 196.2 (d, JC-P = 16.0 Hz);
31P{1H} NMR (162 MHz, CDCl3): δ 22.2; HRMS (ESI-TOF)
m/z: [M+Na]+ calcd. for C22H25O5P Na+ [M+Na]+: 423.1332,
found: 423.1329.
Diethyl (5-methyl-1,4-dioxo-1-phenylhexan-3-yl)phosphonate
(3m): 91% yield (31 mg), colorless gummy liquid, eluent: 60%
EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ 1.13 (3H, d,
J = 6.8 Hz), 1.27-1.40 (9H, m), 3.13-3.38 (2H, m), 3.87-4.03
(1H, m), 4.04-4.24 (5H, m), 7.45 (2H, t, J = 8.0 Hz), 7.56 (1H,
t, J = 7.2 Hz), 7.98 (2H, d, J = 7.6 Hz); 13C{1H} NMR (100
MHz, CDCl3): δ 16.3 (q, JC-P = 5.0 Hz), 17.6, 19.5, 35.7 (d, JC-
P = 1.0 Hz), 41.4, 45.7 (d, JC-P = 126.0 Hz), 62.7 (dd, JC-P = 6.0
Hz, 7.0 Hz), 128.1, 128.5, 133.3, 136.1, 196.6 (d, JC-P = 16.0
Hz), 208.8 (d, JC-P = 4.0 Hz); 31P{1H} NMR (162 MHz, CDCl3):
Diethyl (E)-(6-(4-methoxyphenyl)-1,4-dioxo-1-phenylhex-5-en-
2-yl)phosphonate (5b): 68% yield (30 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.09 (3H, t, J = 7.2 Hz), 1.17 (3H, t, J = 6.8 Hz),
3.16-3.28 (1H, m), 3.71-3.84 (1H, m), 3.77 (3H, s), 3.91-4.08
(4H, m), 4.58-4.73 (1H, m), 6.56 (1H, d, J = 16.0 Hz), 6.84 (2H,
d, J = 8.8 Hz), 7.41 (4H, t, J = 7.2 Hz), 7.50 (2H, t, J = 6.0 Hz),
8.02 (2H, d, J = 7.2 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ
16.1 (q, JC-P = 6.0 Hz), 38.8, 42.3 (d, JC-P = 128.0 Hz), 55.4, 62.8
(t, JC-P = 9.0 Hz), 114.4, 122.9, 126.9, 128.4, 128.9, 130.1,
133.1, 137.5, 143.5, 161.8, 195.4 (d, JC-P = 5.0 Hz), 196.2 (d,
JC-P = 15.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 22.4;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C23H27O6PNa+
[M+Na]+: 453.1437, found: 453.1434.
δ
22.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C17H25O5PH+ [M+H]+: 341.1513, found: 341.1511.
Diethyl (1-(4-methoxyphenyl)-1,4-dioxo-4-phenylbutan-2-
yl)phosphonate (3n): 83% yield (34 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.21 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 6.8 Hz), 3.52-
3.65 (1H, m), 3.89 (3H, s), 3.98-4.27 (5H, m), 4.69-4.85 (1H,
m), 6.98 (2H, d, J = 8.8 Hz), 7.45 (2H, t, J = 7.6 Hz), 7.57 (1H,
t, J = 7.6 Hz), 8.0 (2H, d, J = 8.0 Hz), 8.12 (2H, d, J = 8.8 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 16.2 (t, JC-P = 6.0 Hz),
37.2, 41.8 (d, JC-P = 128.0 Hz), 55.5, 62.8 (q, JC-P = 7.0 Hz),
113.6, 128.2, 128.6, 130.2, 133.4, 133.5, 135.9, 163.7, 193.3 (d,
JC-P = 5.0 Hz), 196.7 (d, JC-P = 16.0 Hz); 31P{1H} NMR (162
MHz, CDCl3): δ 22.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd.
for C21H25O5PNa+ [M+Na]+: 427.1281, found: 427.1267.
Diethyl (E)-(6-(3-methoxyphenyl)-1,4-dioxo-1-phenylhex-5-en-
2-yl)phosphonate (5c): 59% yield (25 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.09 (3H, t, J = 6.8 Hz), 1.16 (3H, t, J = 7.2 Hz),
3.16-3.32 (1H, m), 3.76 (3H, s), 3.72-3.88 (1H, m), 3.90-4.10
(4H, m), 4.58-4.74 (1H, m), 6.65 (1H, d, J = 16.0 Hz), 6.87 (1H,
dd, J = 8 Hz), 6.98 (1H, s), 7.05 (1H, d, J = 7.6 Hz), 7.16-7.31
(1H, m), 7.34-7.59 (4H, m), 8.0 (2H, t, J = 1.2 Hz); 13C{1H}
NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P = 6.0 Hz), 38.9 (d, JC-
= 2.0 Hz), 42.3 (d, JC-P = 128.0 Hz), 55.3, 62.8 (t, JC-P = 8.0
P
Diethyl
(1-(3-chlorophenyl)-1,4-dioxo-4-phenylbutan-2-
Hz), 113.1, 116.6, 121.1, 125.4, 128.4, 128.9, 129.9, 133.1,
135.6, 137.4, 143.6, 159.9, 195.3 (d, JC-P = 5.0 Hz), 196.3 (d,
JC-P = 15.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 21.2;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C23H27O6PNa+
[M+Na]+: 453.1437, found: 453.1436.
yl)phosphonate (3o): 92% yield (37 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.20 (3H, t, J = 6.8 Hz), 1.27 (3H, t, J = 7.2 Hz), 3.56-
3.70 (1H, m), 4.01-4.23 (5H, m), 4.60-4.79 (1H, m), 7.41-7.51
(3H, m), 7.54-7.62 (2H, m), 7.94-8.05 (2H, m), 8.07 (1H, s);
13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P = 7.0 Hz),
37.4, 42.7 (d, JC-P = 128.0 Hz), 63.0 (d, JC-P = 7.0 Hz), 127.1,
Diethyl (E)-(6-(2-methoxyphenyl)-1,4-dioxo-1-phenylhex-5-en-
2-yl)phosphonate (5d): 80% yield (35 mg), pale yellow gummy
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.09 (3H, t, J = 6.16 Hz), 1.17 (3H, t, J = 6.8 Hz),
3.19-3.34 (1H, m), 3.73-3.89 (1H, m), 3.82 (3H, s), 3.90-4.09
(4H, m), 4.58-4.75 (1H, m), 6.73 (1H, d, J = 16.0 Hz), 6.80-6.95
(2H, m), 7.25-7.35 (1H, m), 7.36-7.57 (4H, m), 7.89 (1H, d, J =
16.8 Hz), 8.01 (2H, t, J = 1.6 Hz); 13C{1H} NMR (100 MHz,
CDCl3): δ 16.1 (q, JC-P = 7.0 Hz), 38.8, 42.3 (d, JC-P = 128.0 Hz),
55.4, 62.8 (q, JC-P = 7.0 Hz), 111.2, 120.7, 123.2, 125.6, 128.4,
8.0 Hz), 125.1, 128.4, 128.9, 129.2, 129.8, 130.6, 130.7, 133.3,
133.7, 137.3, 139.1, 148.4, 195.2 (d, JC-P = 5.0 Hz), 196.0 (d,
JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 21.8;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C22H24NO7PNa+
[M+Na]+: 468.1183, found: 468.1179.
1
2
3
4
5
6
7
8
Diethyl (E)-(6-(3-nitrophenyl)-1,4-dioxo-1-phenylhex-5-en-2-
yl)phosphonate (5i): 73% yield (33 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
128.7, 128.9, 131.9, 133.1, 137.5, 139.1, 158.6, 195.4 (d, JC-P
=
CDCl3): δ 1.09 (3H, t, J = 7.2 Hz), 1.17 (3H, t, J = 6.8 Hz), 3.18-
3.33 (1H, m), 3.74-3.9 (1H, m) 3.91-4.09 (4H, m), 4.58-4.73
(1H, m), 6.79 (1H, d, J = 16.4 Hz), 7.36-7.63 (5H, m), 7.76 (1H,
d, J = 7.6 Hz), 7.9 (2H, dd, J = 1.2 Hz), 8.16 (1H, dd, J = 1.2
Hz), 8.32 (1H, s); 13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (q,
JC-P = 6.0 Hz), 39.3 (d, JC-P = 2.0 Hz), 42.4 (d, JC-P = 128.0 Hz),
62.9 (q, JC-P = 7.0 Hz), 122.6, 124.8, 127.5, 128.4, 128.9, 130.0,
133.3, 133.9, 136.1, 137.3, 140.5, 148.7, 195.9 (d, JC-P = 5.0
Hz), 195.8 (d, JC-P = 15.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 21.8; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C22H24NO7PNa+ [M+Na]+: 468.1183, found: 468.1177.
5.0 Hz), 196.8 (d, JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 22.4; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C23H27O6PNa+ [M+Na]+: 453.1437, found: 453.1434.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Diethyl (E)-(6-(4-fluorophenyl)-1,4-dioxo-1-phenylhex-5-en-2-
yl)phosphonate (5e): 86% yield (36 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.09 (3H, t, J = 6.8 Hz), 1.16 (3H, t, J = 6.8 Hz),
3.15-3.31 (1H, m), 3.71-3.87 (1H, m), 3.89-4.11 (4H, m), 4.57-
4.74 (1H, m), 6.64 (1H, d, J = 16.4 Hz), 7.28 (2H, d, J = 8.4
Hz), 7.34-7.56 (6H, m), 8.01 (2H, d, J = 7.6 Hz); 13C{1H} NMR
(100 MHz, CDCl3): δ 16.1 (q, JC-P = 7.0 Hz), 38.9 (d, JC-P = 2.0
Hz), 42.3 (d, JC-P = 128.0 Hz), 62.8 (q, JC-P = 7.0 Hz), 116.1 (d,
JC-F = 22.0 Hz), 124.8 (d, JC-F = 2.0 Hz), 128.4, 128.9, 130.3 (d,
JC-F = 8.0 Hz), 130.5 (d, JC-F = 3.5 Hz), 133.2, 137.4, 142.3,
164.1 (d, JC-F = 250.0 Hz), 195.2 (d, JC-P = 5.0 Hz), 196.1 (d,
JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 22.2;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C22H24FO5PNa+
[M+Na]+: 441.1238, found: 441.1229.
Diethyl (E)-(6-(naphthalen-1-yl)-1,4-dioxo-1-phenylhex-5-en-
2-yl)phosphonate (5j): 66% yield (30 mg) pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.1 (3H, t, J = 7.2 Hz), 1.19 (3H, t, J = 4.8 Hz), 3.24-
3.39 (1H, m), 3.80-3.93 (1H, m), 3.94-4.11 (4H, m), 4.62-4.78
(1H, m), 6.78 (1H, d, J = 15.6 Hz), 7.34-7.58 (6H, m), 7.70 (1H,
d, J = 7.2 Hz), 7.76-7.87 (2H, m), 7.99-8.14 (3H, m), 8.38 (2H,
d, J = 16.0 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (q,
JC-P = 6.0 Hz), 39.5 (d, JC-P = 2.0 Hz), 42.4 (d, JC-P = 128.0 Hz),
62.8 (t, JC-P = 8.0 Hz), 123.2, 125.2, 125.4, 126.2, 126.9, 127.3,
128.5, 128.8, 128.9, 130.9, 131.5, 131.6, 133.2, 133.6, 137.4,
140.4, 195.3 (d, JC-P = 5.0 Hz), 196.2 (d, JC-P = 15.0 Hz);
31P{1H} NMR (162 MHz, CDCl3): δ 22.2; HRMS (ESI-TOF)
m/z: [M+Na]+ calcd for C26H27O5PNa+ [M+Na]+: 473.1489,
found: 473.1483.
Diethyl (E)-(6-(4-chlorophenyl)-1,4-dioxo-1-phenylhex-5-en-
2-yl)phosphonate (5f): 84% yield (37 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.09 (3H, t, J = 7.2 Hz), 1.16 (3H, t, J = 6.8 Hz),
3.14-3.30 (1H, m), 3.71-3.87 (1H, m), 3.89-4.10 (4H, m), 4.56-
4.76 (1H, m), 6.60 (1H, d, J = 16.4 Hz), 7.29 (2H, d, J = 8.4
Hz), 7.33-7.61 (6H, m), 8.01 (2H, d, J = 7.6 Hz); 13C{1H} NMR
(100 MHz, CDCl3): δ 16.1 (d, JC-P = 6.0 Hz), 39.0 (d, JC-P = 2.0
Hz), 42.9 (d, JC-P = 118.0 Hz), 62.8 (t, JC-P = 8.0 Hz), 125.5,
128.4, 128.9, 129.2, 129.5, 132.7, 133.2, 136.6, 137.3, 142.1,
195.2 (d, JC-P = 5.0 Hz), 196.1 (d, JC-P = 15.0 Hz); 31P{1H} NMR
(162 MHz, CDCl3): δ 22.1; HRMS (ESI-TOF) m/z: [M+Na]+
calcd. for C22H24ClO5PNa+ [M+Na]+: 457.0943, found:
457.0945.
Diethyl (E)-(1,4-dioxo-1-phenyl-6-(thiophen-2-yl)hex-5-en-2-
yl)phosphonate (5k): 76% yield (31 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.09 (3H, t, J = 7.2 Hz), 1.16 (3H, t, J = 7.2 Hz),
3.11-3.27 (1H, m), 3.66-3.83 (1H, m), 3.88-4.11 (4H, m), 4.56-
4.74 (1H, m), 6.48 (1H, d, J = 15.6 Hz), 6.95-7.04 (1H, m), 7.22
(1H, d, J = 4.8 Hz), 7.31-7.56 (4H, m), 7.64 (1H d, J = 16.0 Hz),
7.99 (2H, t, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ
Diethyl (E)-(6-(4-bromophenyl)-1,4-dioxo-1-phenylhex-5-en-
2-yl)phosphonate (5g): 82% yield (40 mg), pale yellow gummy
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.09 (3H, t, J = 7.2 Hz), 1.16 (3H, t, J = 7.2 Hz), 3.16-
3.28 (1H, m), 3.71-3.86 (1H, m), 3.88-4.11 (4H, m), 4.56-4.74
(1H, m), 6.65 (1H, d, J = 16.0 Hz), ), 7.32 (1H, d, J = 8.8 Hz),
7.37-7.55 (6H, m), 8.0 (2H, d, J = 7.2 Hz); 13C{1H} NMR (100
16.1 (q, JC-P = 6.0 Hz), 39.0 (d, JC-P = 2.0 Hz), 42.3 (d, JC-P =
1
128.0 Hz), 62.8 (t, JC-P = 7.0 Hz), 123.7, 128.3, 128.4, 128.9,
129.2, 131.9, 133.1, 136.0, 137.4, 139.6, 195.3 (d, JC-P = 5.0
Hz), 195.7 (d, JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 22.2; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C20H23O5PSNa+ [M+Na]+: 429.0897, found: 429.0893.
MHz, CDCl3): δ 16.1 (q, JC-P = 6.0 Hz), 39.0, 42.23 (d, JC-P
=
Diethyl
(E)-(1,4-dioxo-1-phenylhept-5-en-2-yl)phosphonate
128.0 Hz), 62.8 (t, JC-P = 8.0 Hz), 124.9, 125.5, 128.4, 128.9,
129.7, 132.2, 133.1, 133.2, 137.3, 142.2, 195.2 (d, JC-P = 5.0
Hz), 196.2 (d, JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 22.1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C22H24BrO5PNa+ [M+Na]+: 501.0437, found: 501.0439.
(5l): 67% yield (23 mg), pale yellow gummy liquid, eluent: 60%
EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ 1.07 (3H, t, J
= 6.4 Hz), 1.15 (3H, t, J = 6.8 Hz), 1.84 (3H, d, J = 6.8 Hz),
3.01-3.18 (1H, m), 3.56-3.75 (1H, m), 3.85-4.13 (4H, m), 4.49-
4.70 (1H, m), 6.06 (1H, d, J = 16.0 Hz), 6.77-6.99 (1H, m), 7.39
(3H, t, J = 7.6 Hz), 7.48 (2H, t, J = 7.2 Hz), 7.98 (2H, d, J = 7.6
Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (q, JC-P = 6.0
Hz), 38.1 (d, JC-P = 2.0 Hz), 42.2 (d, JC-P = 128.0 Hz), 62.8 (t,
JC-P = 7.0 Hz), 128.4, 128.9, 130.9, 133.1, 137.4, 144.1, 195.4
(d, JC-P = 5.0 Hz), 196.3 (d, JC-P = 16.0 Hz); 31P{1H} NMR (162
MHz, CDCl3): δ 22.3; HRMS (ESI-TOF) m/z: [M+Na]+ calcd.
for C17H23O5PNa+ [M+Na]+: 361.1176, found: 361.1172.
Diethyl (E)-(6-(2-nitrophenyl)-1,4-dioxo-1-phenylhex-5-en-2-
yl)phosphonate (5h): 51% yield (23 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.09 (3H, t, J = 6.8 Hz), 1.18 (3H, t, J = 6.8 Hz),
3.18-3.35 (1H, m), 3.72-3.89 (1H, m), 3.90-4.11 (4H, m), 4.56-
4.72 (1H, m), 6.54 (1H, d, J = 16.0 Hz), 7.33-7.66 (7H, m),
7.92-8.10 (4H, m); 13C{1H} NMR (100 MHz, CDCl3): δ 16.1
(q, JC-P = 7.0 Hz), 38.8, 42.3 (d, JC-P = 128.0 Hz), 62.9 (d, JC-P
=
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
Diethyl (E)-(1-(4-methoxyphenyl)-1,4-dioxo-6-phenylhex-5-en- (d, JC-P = 12.6 Hz), 124.3, 127.8, 128.1, 128.4, 128.8, 129.4,
1
2
3
4
5
6
7
8
2-yl)phosphonate (5m): 88% yield (38 mg), pale yellow
gummy liquid, eluent: 60% EtOAc in hexane. H NMR (400
131.8, 133.2 (d, JC-P = 16.0 Hz), 136.4, 138.3 (d, JC-P = 22.0 Hz);
31P{1H} NMR (162 MHz, CDCl3): δ 17.9; HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C21H24NO3PH+ 370.1567, found:
370.1566.
1
MHz, CDCl3): δ 1.21 (3H, t, J = 6.8 Hz), 1.25 (3H, t, J = 7.2
Hz), 3.21-3.36 (1H, m), 3.80-3.94 (4H, m), 3.99-4.18 (4H, m),
4.62-4.78 (1H, m), 6.74 (1H, d, J = 16.4 Hz), 6.97 (2H, d, J =
8.8 Hz), 7.39 (3H, t, J = 3.6 Hz), 7.53 (2H, t, J = 3.6 Hz), 7.61
(1H, d, J = 16.0 Hz), 8.09 (2H, d, J = 8.4 Hz); 13C{1H} NMR
(100 MHz, CDCl3): δ 16.2 (t, JC-P = 7.0 Hz), 38.8, 41.8 (d, JC-P
= 128.0 Hz), 55.5, 62.8 (t, JC-P = 6.0 Hz), 113.6, 125.1, 128.3,
Diethyl
(5-(4-bromophenyl)-2-phenyl-1H-pyrrol-3-
yl)phosphonate (6c): 95% yield (41 mg), pale yellow gummy
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.11 (6H, t, J = 7.2 Hz), 3.78-4.01 (4H, m), 6.78 (1H,
q, J = 4.0 Hz), 7.15-7.31 (3H, m), 7.46 (4H, q, J = 4.8 Hz), 7.67
(2H, d, J = 7.6 Hz), 10.27 (1H, s); 13C{1H} NMR (100 MHz,
CDCl3): δ 16.0 (d, JC-P = 7 Hz), 61.7 (d, JC-P = 6.0 Hz), 107.0 (d,
JC-P = 214.0 Hz), 112.8 (d, JC-P = 12.5 Hz), 120.4, 125.9, 128.1,
128.2, 128.4, 130.6, 131.6, 131.8, 131.9 (d, JC-P = 15.0 Hz),
139.1 (d, JC-P = 23.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ
9
128.9, 130.1, 130.6, 131.4, 134.2, 143.6, 163.6, 193.3 (d, JC-P
=
4.0 Hz), 196.5 (d, JC-P = 15.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 22.7; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C23H27O6PNa+ [M+Na]+: 453.1438, found: 453.1435.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Diethyl (E)-(1-(3-chlorophenyl)-1,4-dioxo-6-phenylhex-5-en-
2-yl)phosphonate (5n): 85% yield (37 mg), pale yellow gummy
17.4; HRMS (ESI-TOF) m/z: [M+H]+
C20H21BrNO3PH+ 434.0516, found: 434.0518.
calcd. for
1
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.2 (3H, t, J = 6.8 Hz), 1.27 (3H, t, J = 7.2 Hz), 3.26-
3.42 (1H, m), 3.79-3.93 (1H, m), 3.99-4.17 (4H, m), 4.55-4.68
(1H, m), 6.74 (1H, d, J = 16.0 Hz), 7.37-7.43 (3H, m), 7.45 (1H,
d, J = 7.6 Hz), 7.50-7.58 (3H, m), 7.62 (1H, d, J = 16.4 Hz),
7.98 (1H, d, J = 8.0 Hz), 8.04 (1H, s); 13C{1H} NMR (100 MHz,
CDCl3): δ 16.2 (q, JC-P = 7.0 Hz), 39.1, 42.6 (d, JC-P = 129.0 Hz),
62.9 (t, JC-P = 4.0 Hz), 124.9, 127.0, 128.4, 128.9, 129.0, 129.7,
130.8, 133.0, 134.1, 134.7, 138.9, 143.9, 194.2 (d, JC-P = 5.0
Hz), 196.2 (d, JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 21.6; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C22H24ClO5PNa+ [M+Na]+: 457.0943, found: 457.0944.
Diethyl
(E)-(2-phenyl-5-styryl-1H-pyrrol-3-yl)phosphonate
(6d): 78% yield (30 mg), pale yellow gummy liquid, eluent:
60% EtOAc in hexane. H NMR (400 MHz, CDCl3): δ 1.10
1
(6H, t, J = 7.2 Hz), 3.84-4.01 (4H, m), 6.66 (1H, s), 6.91 (2H,
s), 7.18 (1H, t, J = 7.2), 7.24-7.34 (5H, m), 7.39 (2H, d, J = 8.0
Hz), 7.68 (2H, d, J = 7.6 Hz), 10.09 (1H, s); 13C{1H} NMR (100
MHz, CDCl3): δ 16.0 (d, JC-P = 7.0 Hz), 61.7 (d, JC-P = 5.0 Hz),
106.3 (d, JC-P = 215.0 Hz), 115.1 (d, JC-P = 12.0 Hz), 117.9,
125.5, 125.9, 127.1, 127.9, 128.1, 128.2, 128.6, 131.6, 131.8 (d,
JC-P = 16.0 Hz), 137.3, 138.7 (d, JC-P = 23.0 Hz); 31P{1H} NMR
(162 MHz, CDCl3): δ 17.7; HRMS (ESI-TOF) m/z: [M+H]+
calcd. for C22H24NO3PH+: 382.1567, found: 382.1567.
Diethyl (E)-(1,4-dioxo-6-phenyl-1-(thiophen-2-yl)hex-5-en-2-
yl)phosphonate (5o): 79% yield (32 mg), pale yellow gummy
liquid, eluent: 60% EtOAc in hexane. H NMR (400 MHz,
Diethyl
(2-(naphthalen-1-yl)-5-phenyl-1H-pyrrol-3-
1
yl)phosphonate (6e): 89% yield (36 mg), brown gummy liquid,
eluent: 60% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ
1.11 (6H, t, J = 6.8 Hz), 3.82-4.05 (4H, m), 6.79 (1H, s), 7.21-
7.41 (3H, m), 7.41-7.60 (4H, m), 7.68-7.90 (4H, m), 8.21-8.33
(1H, m), 9.55 (1H, s); 13C{1H} NMR (100 MHz, CDCl3): δ 16.0
(d, JC-P = 7.0 Hz), 61.6 (d, JC-P = 10.0 Hz), 106.4 (d, JC-P = 215.0
Hz), 115.8 (d, JC-P = 12.0 Hz), 122.2, 125.4, 126.0, 126.5, 128.0
(d, JC-P = 8.0 Hz), 128.1, 128.2, 128.3, 129.9, 131.2, 131.2 (d,
JC-P = 16.0 Hz), 131.7, 133.8, 138.2 (d, JC-P = 23.0 Hz); 31P{1H}
NMR (162 MHz, CDCl3): δ 17.8; HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for C24H24NO3PH+: 406.1567, found: 406.1563.
CDCl3): δ 1.17-1.36 (6H, m), 3.21-3.37 (1H, m), 3.73-3.91 (1H,
m), 4.01-4.24 (4H, m), 4.45-4.63 (1H, m), 6.74 (1H, d, J = 16.0
Hz), 7.17 (1H, t, J = 4.4 Hz), 7.40 (3H, t, J = 3.6 Hz), 7.53 (2H,
t, J = 3.6 Hz), 7.62 (1H, d, J = 16.0 Hz), 7.68 (1H, d, J = 4.8
Hz), 7.97 (1H, d, J = 3.6 Hz); 13C{1H} NMR (100 MHz,
CDCl3): δ 16.2 (t, JC-P = 5.0 Hz), 38.4, 43.7 (d, JC-P = 129.0 Hz),
62.9 (t, JC-P = 7.0 Hz), 125.0, 128.1, 128.3, 128.9, 130.7, 133.7,
134.1, 134.4, 143.7, 144.0, 187.2 (d, JC-P = 5.0 Hz), 196.2 (d,
JC-P = 16.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 21.9;
HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for C20H23O5PNa+
[M+Na]+: 429.0897, found: 429.0901.
Diethyl
(5-phenyl-2-(thiophen-2-yl)-1H-pyrrol-3-
Diethyl (2,5-diphenyl-1H-pyrrol-3-yl)phosphonate (6a): 91%
yield (32 mg), pale yellow gummy liquid, eluent: 60% EtOAc
in hexane. 1H NMR (400 MHz, CDCl3): δ 1.14 (6H, t, J = 7.2
Hz), 3.85-4.01 (4H, m), 6.86 (1H, q, J = 2.8 Hz), 7.20-7.43 (6H,
m), 7.61 (2H, d, J = 8.0 Hz), 7.72 (2H, d, J = 7.2 Hz), 9.78 (1H,
s); 13C{1H} NMR (100 MHz, CDCl3): δ 16.04 (d, JC-P = 6.7 Hz),
61.6 (d, JC-P = 5.2 Hz), 106.8 (d, JC-P = 214.2 Hz), 112.4 (d, JC-
P = 12.5 Hz), 124.3, 126.8, 128.0, 128.2, 128.3, 128.8, 131.5 (d,
yl)phosphonate (6f): 86% yield (31 mg), brown gummy liquid,
eluent: 60% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ
1.13 (6H, t, J = 6.8 Hz), 3.84-4.08 (4H, m), 6.75 (1H, s), 7.01
(1H, t, J = 4.0 Hz), 7.19 (2H, d, J = 4.4), 7.28-7.42 (3H, m),
7.68 (2H, d, J = 7.6 Hz), 9.37 (1H, s); 13C{1H} NMR (100 MHz,
CDCl3): δ 16.0 (d, J C-P = 7.0 Hz), 61.7 (d, JC-P = 5.0 Hz), 106.6
(d, JC-P = 214.0 Hz), 112.9 (d, JC-P = 13.0 Hz), 122.2, 123.4,
127.6, 127.6 (d, JC-P = 16.0 Hz), 128.0, 128.2, 128.3, 131.4,
134.6, 138.3 (d, JC-P = 23.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 17.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C18H20NO3PSH+: 362.0975, found: 362.0970.
JC-P = 0.9 Hz), 131.8, 132.9 (d, JC-P = 15.5 Hz), 138.6 (d, JC-P
=
22.7 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 17.7; HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for C20H22NO3PH+: 356.1411,
found: 356.1414.
Diethyl (2,5-diphenylfuran-3-yl)phosphonate (7a): 79% yield
(28 mg), pale yellow gummy liquid, eluent: 60% EtOAc in
hexane. 1H NMR (400 MHz, CDCl3): δ 1.19 (6H, t, J = 7.2 Hz),
3.92-4.18 (4H, m), 6.93 (1H, d, J = 3.6 Hz), 7.24 (1H, d, J = 7.6
Hz), 7.29-7.43 (5H, m), 7.67 (2H, d, J = 7.6 Hz), 7.98 (2H, d, J
Diethyl
(2-phenyl-5-(p-tolyl)-1H-pyrrol-3-yl)phosphonate
(6b): 93% yield (34 mg), pale yellow gummy liquid, eluent:
1
60% EtOAc in hexane. H NMR (400 MHz, CDCl3): δ 1.01
(6H, t, J = 6.8 Hz), 2.25 (3H, s) 3.70-3.92 (4H, m), 6.71 (1H, q,
J = 2.8 Hz), 7.07 (2H, d, J = 8.0 Hz), 7.13-7.32 (3H, m), 7.43
(2H, d, J = 8.0 Hz), 7.61 (2H, d, J = 7.2 Hz), 9.93 (1H, s);
13C{1H} NMR (100 MHz, CDCl3): δ 16.0 (d, JC-P = 7.0 Hz),
21.1, 61.5 (d, JC-P = 5.2 Hz), 106.4 (d, JC-P = 214.0 Hz), 111.9
= 7.6 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 16.2 (d, JC-P
=
6.7 Hz), 62.3 (d, JC-P = 5.3 Hz), 109.5 (d, JC-P = 210.1 Hz),
110.8, 110.9, 124.0, 127.4, 128.1, 128.4, 128.8, 129.2, 129.6,
152.9 (d, JC-P = 15.2 Hz), 157.3 (d, JC-P = 24.3 Hz); 31P{1H}
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NMR (162 MHz, CDCl3): δ 14.0; HRMS (ESI-TOF) m/z:
MHz, CDCl3): δ 13.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd.
[M+H]+ calcd. for C20H21O4PH+ 357.1251, found: 357.1257.
for C18H19O4PH+: 363.0815, found: 363.0810.
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4
5
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7
8
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Diethyl (2-phenyl-5-(p-tolyl)-furan-3-yl)phosphonate (7b):
85% yield (32 mg), pale yellow gummy liquid, eluent: 60%
EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ 1.17 (6H, t, J
= 7.2 Hz), 2.29 (3H, s), 3.91-4.20 (4H, m), 6.87 (1H, d, J = 4.0
Hz), 7.14 (2H, d, J = 7.6 Hz), 7.29 (1H, t, J = 7.2 Hz), 7.36 (2H,
t, J = 8.0 Hz), 7.54 (2H, d, J = 8.0 Hz), 7.96 (2H, d, J = 7.6 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (d, JC-P = 6.0 Hz),
21.3, 62.2 (d, JC-P = 5.0 Hz), 109.2 (d, JC-P = 211.0 Hz), 110.0
(d, JC-P = 11.3 Hz), 123.9, 126.8, 127.3, 128.3, 129.0, 129.4,
129.6, 138.1, 153.2 (d, JC-P = 15.0 Hz), 156.9 (d, JC-P = 24.0 Hz);
31P{1H} NMR (162 MHz, CDCl3): δ 14.3; HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C21H23O4PH+ 371.1407, found:
371.1406.
Diethyl (2,5-diphenylthiophen-3-yl)phosphonate (8a): 81%
yield (30 mg), pale yellow gummy liquid, eluent: 60% EtOAc
in hexane. 1H NMR (400 MHz, CDCl3): δ 1.07 (6H, t, J = 6.8
Hz), 3.82-4.05 (4H, m), 7.20 (1H, d, J = 14.4 Hz), 7.28-7.38
(5H, m), 7.53 (3H, t, J = 6.8 Hz), 7.61 (2H, t, J = 2.4 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 16.0 (d, JC-P = 6.8 Hz),
62.1 (d, JC-P = 5.6 Hz), 125.7 (d, JC-P = 192.5 Hz), 125.8, 128.0,
128.1, 128.2 (d, JC-P = 16.0 Hz), 128.8, 129.0, 129.6, 133.1,
133.2 (d, JC-P = 2.0 Hz), 143.7 (d, JC-P = 19.0 Hz), 151.5 (d, JC-
P = 16.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 12.8; HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for C20H21O3PSH+ 373.1022,
found: 373.1023.
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Diethyl (2-phenyl-5-(p-tolyl)-thiophen-3-yl)phosphonate (8b):
88% yield (34 mg), pale yellow gummy liquid, eluent: 60%
EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ 1.15 (6H, t, J
= 6.8 Hz), 2.38 (3H, s), 3.90-4.11 (4H, m), 7.21 (2H, d, J = 8.0
Hz), 7.41 (3H, d, J = 6.8 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.57 (1H,
d, J = 4.4 Hz), 7.67 (2H, t, J = 5.6 Hz); 13C{1H} NMR (100
Diethyl (5-(4-bromophenyl)-2-phenylfuran-3-yl)phosphonate
(7c): 83% yield (36 mg), pale yellow gummy liquid, eluent:
1
60% EtOAc in hexane. H NMR (400 MHz, CDCl3): δ 1.25
(6H, t, J = 7.2 Hz), 3.98-4.25 (4H, m), 7.0 (1H, d, J = 4.0 Hz),
7.34-7.63 (7H, m), 8.02 (2H, d, J = 8.0 Hz); 13C{1H} NMR (100
MHz, CDCl3): δ 16.1 (d, JC-P = 7.0 Hz), 62.3 (d, JC-P = 6.0 Hz),
109.7 (d, JC-P = 211.0 Hz), 111.3 (d, JC-P = 11.0 Hz), 121.9,
MHz, CDCl3): δ 16.1 (d, JC-P = 7.0 Hz), 21.21, 62.1 (d, JC-P
=
6.0 Hz), 125.7 (d, JC-P = 192.0 Hz), 125.8, 127.7 (d, JC-P = 16.0
Hz), 128.1, 128.7, 129.6, 129.7, 130.5, 133.3 (d, JC-P = 2.0 Hz),
138.1, 143.9 (d, JC-P = 19.0 Hz), 151.0 (d, JC-P = 16.0 Hz);
31P{1H} NMR (162 MHz, CDCl3): δ 12.9; HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for C21H23O3PSH+ 387.1178, found:
387.1178.
125.4, 127.4, 128.3, 128.5, 129.2, 129.3, 131.9, 151.8 (d, JC-P
=
16.0 Hz), 157.5 (d, JC-P = 24.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 13.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C20H20BrO4PH+ 435.0356, found: 435.0359.
Diethyl (E)-(2-phenyl-5-styrylfuran-3-yl)phosphonate (7d):
71% yield (27 mg), pale yellow gummy liquid, eluent: 60%
EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ 1.25 (6H, t, J
= 6.8 Hz), 3.99-4.21 (4H, m), 6.70 (1H, d, J = 4.0 Hz), 6.89 (1H,
d, J = 16.4 Hz), 7.15 (1H, d, J = 16.4 Hz), 7.28 (1H, d, J = 7.2
Hz), 7.33-7.42 (3H, m), 7.43-7.52 (4H, m), 8.04 (2H, d, J = 7.6
Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 16.1 (d, JC-P = 6.0
Hz), 62.3 (d, JC-P = 6.0 Hz), 109.4 (d, JC-P = 211.0 Hz), 114.1
(d, JC-P = 11.0 Hz), 115.2, 126.4, 127.4, 128.0, 128.3, 128.7,
128.8, 129.2, 129.4, 136.5, 152.2 (d, JC-P = 15.0 Hz), 157.3 (d,
JC-P = 24.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 13.9;
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C22H23O4PH+
383.1407, found: 383.1406.
Diethyl
(5-(4-bromophenyl)-2-phenylthiophen-3-yl)
phosphonate (8c): 86% yield (39 mg), pale yellow gummy
1
liquid eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.14 (6H, t, J = 7.2 Hz), 3.88-4.15 (4H, m), 7.36-7.55
(7H, m), 7.61 (1H, d, J = 4.8 Hz), 7.66 (2H, t, J = 3.6 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 16.0 (d, JC-P = 7.0 Hz),
62.1 (d, JC-P = 8.0 Hz), 121.9, 126.2 (d, JC-P = 193.0 Hz), 127.3,
128.2, 128.6 (d, JC-P = 17.0 Hz), 128.9, 129.6, 132.1, 132.2,
133.0 (d, JC-P = 3.0 Hz), 142.3 (d, JC-P = 19.0 Hz), 151.8 (d, JC-
P = 16.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 12.4; HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for C20H20BrO3PSH+ 451.0127,
found: 451.0129.
Diethyl (2-(naphthalen-1-yl)-5-phenylfuran-3-yl)phosphonate
Diethyl
(2,3,6-triphenyl-2,5-dihydropyridazin-4-
(7e): 88% yield (36 mg), pale yellow gummy liquid, eluent:
yl)phosphonate (9a): 93% yield (41 mg), yellow solid (mp 158-
1
o
1
60% EtOAc in hexane. H NMR (400 MHz, CDCl3): δ 1.29
160 C), eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 0.98 (6H, t, J = 7.2 Hz), 3.45 (2H, d, J = 9.2 Hz),
3.59-3.70 (2H, m), 3.71-3.82 (2H, m), 6.85 (1H, t, J = 7.2 Hz),
7.03 (2H, t, J = 8.0 Hz), 7.07-7.25 (7H, m), 7.31-7.42 (3H, m),
7.90 (2H, d, J = 6.4 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ
(6H, t, J = 6.8 Hz), 4.06-4.28 (4H, m), 7.09 (1H, d, J = 3.6 Hz),
7.34-7.64 (6H, m), 7.81 (1H, d, J = 7.2 Hz), 7.87 (2H, t, J = 9.2
Hz), 8.10 (2H, d, J = 8.0 Hz), 8.44 (1H, d, J = 8.0 Hz); 13C{1H}
NMR (100 MHz, CDCl3): δ 16.2 (d, JC-P = 7.0 Hz), 62.3 (d, JC-
P = 6.0 Hz), 109.3 (d, JC-P = 211.0 Hz), 114.8 (d, JC-P = 11.0 Hz),
125.1, 125.2, 126.0, 126.4, 126.9, 127.1, 127.4, 128.4, 128.6,
16.0 (d, JC-P = 6.8 Hz), δ 26.0 (d, JC-P = 8.7 Hz), 61.3 (d, JC-P
=
5.7 Hz), 90.3 (d, JC-P = 206.5 Hz), 123.5, 124.2, 126.9, 127.4,
128.1, 128.5, 128.7, 129.6, 130.9, 133.5 (d, JC-P = 3.1 Hz),
135.1, 143.7 (d, JC-P = 2.5 Hz), 144.0 (d, JC-P = 4.3 Hz), 150.2
(d, JC-P = 21.9 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 19.17;
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for C26H27N2O3PH+
447.1833, found: 447.1838.
129.2 (d, JC-P = 5.0 Hz), 129.6, 130.1, 133.9, 152.5 (d, JC-P
=
16.0 Hz), 157.7 (d, JC-P = 24.0 Hz); 31P{1H} NMR (162 MHz,
CDCl3): δ 14.1; HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
C24H23O4PH+: 407.1407, found: 407.1405.
Diethyl
(5-phenyl-2-(thiophen-2-yl)furan-3-yl)phosphonate
(7f): 79% yield (29 mg), pale yellow gummy liquid, eluent:
Diethyl
(2,3-diphenyl-6-(p-tolyl)-2,5-dihydropyridazin-4-
1
60% EtOAc in hexane. H NMR (400 MHz, CDCl3): δ 1.26
yl)phosphonate (9b): 98% yield (45 mg), yellow solid (mp 160-
o
1
(6H, t, J = 7.2 Hz), 4.01-4.22 (4H, m), 6.85 (1H, d, J = 4.0 Hz),
7.07 (1H, t, J = 4.4 Hz), 7.29 (1H, d, J = 5.2 Hz), 7.35 (1H, d, J
= 4.0 Hz) 7.36-7.52 (3H, m), 8.02 (2H, d, J = 7.6 Hz); 13C{1H}
NMR (100 MHz, CDCl3): δ 16.1 (d, JC-P = 7.0 Hz), 62.3 (d, JC-
P = 5.0 Hz), 109.4 (d, JC-P = 212.0 Hz), 110.6 (d, JC-P = 11.0 Hz),
123.6, 125.1, 127.3, 127.7, 128.3, 129.2, 129.3, 132.2, 148.6 (d,
JC-P = 16.0 Hz), 156.8 (d, JC-P = 24.0 Hz); 31P{1H} NMR (162
162 C), eluent: 60% EtOAc in hexane. H NMR (400 MHz,
CDCl3): δ 1.08 (6H, t, J = 7.2 Hz), 2.43 (3H, s), 3.52 (2H, d, J
= 9.2 Hz), 3.68-3.79 (2H, m), 3.80-3.91 (2H, m), 6.94 (1H, t, J
= 7.2 Hz), 7.12 (2H, t, J = 8.0 Hz), 7.16-7.34 (9H, m), 7.89 (2H,
d, J = 8.0 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 16.0 (d, JC-P
= 7.0 Hz), 21.4, 26.0 (d, JC-P = 8.0 Hz), 61.3 (d, JC-P = 6.0 Hz),
90.2 (d, JC-P = 206.0 Hz), 123.5, 124.1, 126.8, 127.4, 128.1,
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2.
For selected examples, see: (a) Guo, C.; Sun, S.; He, Q.;
128.7, 129.3, 131.0, 132.3, 133.6 (d, JC-P = 3.0 Hz), 139.8, 143.8
(d, JC-P = 2.0 Hz), 144.1 (d, JC-P = 5.0 Hz), 150.3 (d, JC-P = 22.0
Hz); 31P{1H} NMR (162 MHz, CDCl3): δ 19.3; HRMS (ESI-
TOF) m/z: [M+H]+ calcd. for C27H29N2O3PH+ 461.1989, found:
461.1986.
Lynch, V. M.; Sessler, J. L. Pyrene-linked formylated
bis(dipyrromethane): A fluorescent probe for dihydrogen phosphate.
Org. Lett. 2018, 20, 5414–5417. (b) Jiang, H.; Paixão, M. W.; Monge,
D.; Jørgensen, K. A. Acyl phosphonates: Good hydrogen bond
acceptors and ester/amide equivalents in asymmetric organocatalysis.
J. Am. Chem. Soc. 2010, 132, 2775–2783.
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Diethyl (6-(4-bromophenyl)-2,3-diphenyl-2,5-dihydrpyridazin-
5
4-yl)phosphonate (9c): 95% yield (50 mg), yellow solid (mp
6
7
8
9
3.
(a) Mishra, A.; Deb, I. Palladium‐catalyzed oxidative
o
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179-182 C), eluent: 60% EtOAc in hexane. H NMR (400
MHz, CDCl3): δ 1.08 (6H, t, J = 7.2 Hz), 3.51 (2H, d, J = 8.8
Hz), 3.67-3.79 (2H, m), 3.80-3.92 (2H, m), 6.96 (1H, t, J = 7.2
Hz), 7.13 (2H, t, J = 8.0 Hz), 7.17-7.33 (7H, m), 7.59 (2H, d, J
= 8.4 Hz), 7.86 (2H, d, J = 8.0 Hz); 13C{1H} NMR (100 MHz,
CDCl3): δ 16.0 (d, JC-P = 7.0 Hz), δ 25.7 (d, JC-P = 9.0 Hz), 61.3
(d, JC-P = 6.0 Hz), 90.3 (d, JC-P = 206.0 Hz), 123.5, 123.9, 124.4,
127.4, 128.1, 128.3, 128.8, 130.9, 131.7, 133.3 (d, JC-P = 3.0
Hz), 134.0, 142.7 (d, JC-P = 4.0 Hz), 143.5 (d, JC-P = 2.0 Hz),
150.1 (d, JC-P = 22.0 Hz); 31P{1H} NMR (162 MHz, CDCl3): δ
19.02; HRMS (ESI-TOF) m/z: [M+Na]+ calcd. for
C26H26BrN2O3PNa+ 547.0757, found: 547.0756
cyclization for the synthesis of indolyl/pyrrolyl 3‐phosphonates. Adv.
Synth. Catal. 2016, 358, 2267–2272. (b) Debrouwer, W.; Heugebaert,
T. S. A.; Stevens, C. V. Preparation of tetrasubstituted 3-
phosphonopyrroles through hydroamination: scope and limitations. J.
Org. Chem. 2014, 79, 4322–4331. (c) Lonzi, G.; Lõpez, L. A.
Regioselective synthesis of functionalized pyrroles via gold
(I)‐catalyzed [3+ 2] cycloaddition of stabilized vinyl diazo derivatives
and nitriles. Adv. Synth. Catal. 2013, 355, 1948–1954.
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Supporting Information
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The Supporting Information is available free of charge on the ACS
Publications website.
1H, 13C{1H} and 31P{1H} NMR Spectra
AUTHOR INFORMATION
6.
(a) Bhaumik, A.; Azaz, T.; Singh, V.; Khatana, A. K.; Tiwari
B. Carbene/base-mediated redox alkenylation of isatins using β-
substituted organoselenones and aldehydes. J. Org. Chem.
2019, 84, 14898-14903. (b) Verma, R. S.; Pandey, C. B.; Kumar, S.;
Tiwari, B. Carbene-catalyzed tandem [1,2]-phospha-Brook/[1,4]-
phosphonate rearrangement: Access to α-ketophosphates via controlled
cross-acyloin condensation. J. Org. Chem. 2018, 83, 9478−9483. (c)
Bhaumik, A.; Verma, R. S.; Tiwari, B. Direct construction of 2,3-
Corresponding Author
E-mail: btiwari@cbmr.res.in
Ram Subhawan Verma and Monika Mishra have made equal
contribution to this manuscript.
ACKNOWLEDGMENT
dihydroxy-2,
3-diaryltetrahydrofurans
via
N-heterocyclic
R.S.V. thanks the University Grants Commission (UGC), India and
M. M. thanks the Council of Scientific and Industrial Research
(CSIR), India for the fellowships. Financial support
(CRG/2018/004424) by SERB, New Delhi, India, is gratefully
acknowledged.
carbene/base-mediated domino reactions of aromatic aldehydes and
vinylselenone. Org. Lett. 2017, 19, 444−447.
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Catalytic activation of carbohydrates as formaldehyde equivalents for
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