Construction of 1H-pyrrol-2-ylphosphonates via [3+2] cycloaddition of phosphate azomethine ylides with ynones

Article abstract of DOI:10.1016/j.tet.2014.12.091

An efficient route for the construction of 1H-pyrrol-2-ylphosphonates via the [3+2] cycloaddition of phosphonate azomethine ylides with ynones is described. This transformation proceeds with good functional group tolerance under mild conditions with good

Full text of DOI:10.1016/j.tet.2014.12.091

Tetrahedron 71 (2015) 1074e1079
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Construction of 1H-pyrrol-2-ylphosphonates via [3þ2]
cycloaddition of phosphate azomethine ylides with ynones
*
Jiang Meng, Di Wu, Ying Shi, Xingxin Yu , Wei-Ping Deng
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient route for the construction of 1H-pyrrol-2-ylphosphonates via the [3þ2] cycloaddition of
phosphonate azomethine ylides with ynones is described. This transformation proceeds with good
functional group tolerance under mild conditions with good efficiency and selectivity. And the synthesis
of 1H-pyrrol-2-ylphosphonates could also be achieved via the three-component reaction of benzalde-
hydes, aminomethyl phosphonates and ynones.
Received 18 November 2014
Received in revised form 18 December 2014
Accepted 25 December 2014
Available online 31 December 2014
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
[3þ2] Cycloaddition
Pyrrole
Phosphonate azomethine ylide
Ynone
1H-Pyrrol-2-ylphosphonate
1. Introduction
ring-closing reaction of functionalized aminophosphorus de-
rivatives,9 the multi-component coupling reaction10 and the [3þ2]
Considerable attention has been paid to organophosphorus
compounds1 due to their ubiquity in biological systems2 and their
potential to serve as pharmaceuticals.3 Recent studies have in-
dicated that many phosphorus-containing heterocycle compounds
showed interesting bioactivities.4 For instance, nitrogen-containing
bisphosphonates (N-BPs) are the only clinically validated drugs
targeting hFPPS (human farnesyl pyrophosphate synthase), and
also disease modifying agents induce apoptosis and down-
regulation of ERK (Extracellular Regulated Kinase) phosphoryla-
tion in human multiple myeloma cell lines.4a Meanwhile, pyrroles5
are privileged structural motifs in many natural products and
pharmaceuticals exhibiting remarkable biological activities.6 Be-
cause of the importance of organophosphorus compounds and
pyrroles, our continuous interest in natural product-like com-
pounds prompted us to devote our efforts for the development of
efficient and rapid methods for the synthesis of phosphorus-
containing pyrroles, with a hope of finding more active hits or
leads for our particular biological assays.
cycloaddition.11 Among which, the [3þ2] cycloaddition of phos-
phonate azomethine ylides to both activated alkenes and alkynes as
dipolarophiles has arguably been one of the most ideal and pow-
erful synthetic strategies.12 The catalytic asymmetric [3þ2] cyclo-
addition of azomethine ylides with ynones has been established.13
However, phosphonate azomethine ylides have rarely been
employed for the synthesis of 1H-pyrrol-2-ylphosphonates.14
Recently, we developed a direct and facile synthesis of multi-
substituted pyrroles via AgOAc-catalyzed [3þ2] cycloaddition of
azomethine ylides with ynones, providing the corresponding ad-
ducts in moderate to high yields (up to 89%).15 Herein, we would
like to disclose our latest results for the synthesis of 1H-pyrrol-2-
ylphosphonates via [3þ2] cycloaddition of phosphonate azome-
thine ylides with ynones.
2. Results and discussion
Initial study was performed with phosphonate azomethine ylide
1a and ynone 2a in the presence of base in THF at room tempera-
ture (Table 1). To our delight, the formation of desired 1H-pyrrol-2-
ylphosphonate 3a was observed when t-BuOK was used as the base,
albeit in low yield (17%, Table 1, entry 1). The yield of 3a was further
increased to 34% in the presence of NaH (Table 1, entry 2). In order
to reduce the competitive byproducts, the amounts and ratios of
phosphonate azomethine ylide 1a and ynone 2a were screened
(Table 1, entries 3e5). Using 2 equiv of phosphonate azomethine
Recently, many efforts have been made towards the de-
velopment of novel and highly efficient synthetic protocols for 1H-
pyrrol-2-ylphosphonates synthesis, such as the aromatization of
phosphonate pyrrolidines,7 the phosphorylation of pyrroles,8 the
* Corresponding author. Tel./fax: þ86 21 64252431; e-mail address: xxyu@ecust.
edu.cn (X. Yu).
http://dx.doi.org/10.1016/j.tet.2014.12.091
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

J. Meng et al. / Tetrahedron 71 (2015) 1074e1079
1075
Table 1
Table 3
The [3þ2] cycloaddition of phosphonate azomethine ylide 1a with ynone 2aa
Substrate scope of the [3þ2] cycloaddition of phosphonate azomethine ylide 1 with
ynone 2a
Entry
1a
2a
Base
Yieldb (%)
Entry
R1
R2/R3
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
1.2 equiv
1.2 equiv
1.5 equiv
2 equiv
2.5 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
t-BuOK/1.2 equiv
NaH/1.2 equiv
NaH/1.5 equiv
NaH/2 equiv
NaH/2.5 equiv
t-BuONa/2 equiv
t-BuOK/2 equiv
LDA/2 equiv
17
34
49
64
62
43
47
37
dc
40
1
2
3
4
5
6
7
8
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5/C6H5 (2a)
60 (3a)
65 (3b)
67 (3c)
62 (3d)
43 (3e)
54 (3f)
60 (3g)
57 (3h)
48 (3i)
51 (3j)
63 (3k)
66 (3l)
48 (3m)c
63 (3n)
69 (3o)
55 (3p)
dd
3-ClC6H4/C6H5 (2b)
4-ClC6H4/C6H5 (2c)
4-BrC6H4/C6H5 (2d)
4-MeOC6H4/C6H5 (2e)
2-Naphthyl/C6H5 (2f)
C6H5/4-MeC6H4 (2g)
C6H5/n-C4H9 (2h)
C6H5/Cyclopropyl (2i)
C6H5/C6H5 (2a)
n-BuLi/2 equiv
CH3ONa/2 equiv
9
C6H5 (1a)
10
11
12
13
14
15
16
17
18
19
4-FC6H4 (1b)
4-ClC6H4 (1c)
4-ClC6H4 (1c)
4-ClC6H4 (1c)
4-BrC6H4 (1d)
4-NO2C6H4 (1e)
4-MeC6H4 (1f)
Isopropyl (1g)
C6H5 (1a)
a
Reaction conditions: All reactions were carried out in 0.1 M scale in 1 mL THF at
room temperature. The base was added to a solution of 1a, about 1 min later 2a was
added, and then the solution was stirred about 2 h without other statement.
C6H5/C6H5 (2a)
4-ClC6H4/C6H5 (2c)
4-MeOC6H4/C6H5 (2e)
C6H5/C6H5 (2a)
C6H5/C6H5 (2a)
C6H5/C6H5 (2a)
C6H5/C6H5 (2a)
Methyl/C6H5 (2j)
Methoxy/C6H5 (2k)
b
Isolated yield based on ynone 2a.
The reaction was complicated and no desired product was isolated.
c
dd
dd
ylide 1a led to the generation of 1H-pyrrol-2-ylphosphonate 3a
with 64% yield (Table 1, entry 4). Similar yield was observed when
the amount of 1a was increased to 2.5 equiv (Table 1, entry 5). Base
screening demonstrated that NaH was the best choice. Other bases
such as t-BuONa, t-BuOK, LDA, n-BuLi, CH3ONa gave unsatisfactory
results (Table 1, entries 6e10).
C6H5 (1a)
a
Reaction conditions: All reactions were carried out with 1 (0.4 mmol), 2
(0.2 mmol); NaH (0.4 mmol) in 2 mL THF at 0 ꢀC, once 2 added the temperature was
allowed to rise to room temperature without other statement.
b
Isolated yield based on ynone 2.
14% Dihydropyrrole 4m was isolated.
No desired product.
c
d
Next, solvents and reaction temperatures were investigated in
the presence of 2 equiv of phosphonate azomethine ylide 1a and
2 equiv of NaH (Table 2). THF was found to be optimal for this kind
of transformation (Table 2, entry 1). Carrying out the reactions at
with phosphonate azomethine ylide 1a to afford the corresponding
1H-pyrrol-2-ylphosphonates 3 in moderate to good yields (Table 3,
entries 1e7). For instance, reaction of phosphonate azomethine
ylide 1a and ynone 2c generated the expected product 3c in 67%
yield (Table 3, entry 3). Notably, 2-naphthyl substrate 2f was also
tolerated in this reaction (Table 3, entry 6). In addition to the aro-
matic ring attached to the carbon carbon triple bond, n-butyl and
cyclopropyl groups were found suitable as well to afford the desired
1H-pyrrol-2-ylphosphonates 3 in moderate yields (Table 3, entries
7e9). This [3þ2] cycloaddition was found to be workable for
phosphonate azomethine ylides 1be1f with electron-withdrawing
and -donating substituents on the aromatic backbone, and pro-
ceeded smoothly leading to the desired 1H-pyrrol-2-
ylphosphonates 3 in moderate yields (Table 3, entries 10e16). The
structure of compound 3k was verified by X-ray diffraction analysis
(Fig. 1, CCDC 1040194). Unfortunately, When R1 was replaced with
alkyl group like isopropyl, the reaction did not give the desired
product (Table 3, entry 17). When R2 was replaced with methyl or
0
ꢀC, and then warming up to room temperature naturally had
positive effect on yield.
Table 2
Screening studies of the reaction conditionsa
Entry
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
NaH/2 equiv
NaH/2 equiv
NaH/2 equiv
NaH/2 equiv
NaH/2 equiv
NaH/2 equiv
NaH/2 equiv
NaH/2 equiv
C2H5ONa/2 equiv
NaH/2 equiv
THF
64
33
38
29
44
25
23
30
0
Toluene
2-Me-THF
1,4-Dioxane
CPME
CH3CN
DMF
DCM
C2H5OH
THF
10
54c
a
Reaction conditions: All reactions were carried out with 0.2 mmol of 1a and
0.1 mmol of 2a in 1 mL of solvent at 0 ꢀC, once 2a added the temperature was al-
lowed to rise to room temperature without other statement.
b
Isolated yield based on ynone 2a.
Carried out at ꢁ10 ꢀC, 3 h.
c
The above optimization led to 1a/2a¼2:1, 2 equiv of NaH, THF,
0 ꢀC to room temperature as the optimal reaction conditions for this
[3þ2] cycloaddition. The scope and generality of substrates were
then examined and the results are summarized in Table 3. A wide
array of ynones 2 with electron-neutral, electron-deficient or
electron-rich substituents on the aromatic ring, reacted smoothly
Fig. 1. X-ray ORTEP illustration of compound 3k.

1076
J. Meng et al. / Tetrahedron 71 (2015) 1074e1079
methoxy, the reactions also did not take place under the optimal
reaction conditions (Table 3, entries 18 and 19).
Me-THF, CPME, toluene and ethanol were dried with sodium (Na).
Anhydrous dichloromethane (DCM) and N,N-dimethylformamide
(DMF) were dealt with CaH2. Reactions were monitored by thin
layer chromatography (TLC) carried out on 0.20e0.30 mm silica gel
plates (GF254, Qingdao, China) using UV light as the visualizing
agent. Silica gel (200e300 mesh, Qingdao, China) was used for flash
column chromatography. NMR spectra were recorded on Bruker
AVANCE III 400 M instrument and calibrated using residual
undeuterated solvent as an internal reference (CHCl3 @ 7.26 ppm 1H
NMR, 77.0 ppm 13C NMR). The following abbreviations (or combi-
nations thereof) were used to explain the multiplicities: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet. High-resolution
mass spectra (HRMS) were recorded on Agilent 6520 accurate-
Mass Q-TOF LC/MS system (1200-6520/Agilent). Melting points
were obtained in open capillary tubes using a micro melting point
apparatus.
Due to 14% dihydropyrrole 4m was isolated in the reaction of
phosphonate azomethine ylide 1c and ynone 2e (Table 3, entry 13),
we reason that dihydropyrrole intermediate A was formed first via
the [3þ2] cycloaddition in the presence of base (Scheme 1). In-
termediate A underwent a fast protonation and aromatization16
process to generate the major product 1H-pyrrol-2-
ylphosphonates 3m (path I). Meanwhile, the slow rearrangement
would occur to generate intermediate B. Subsequent tautomerism
and protonation would give rise to the minor product 4m (path II).
4.2. General procedure for the preparation of compounds 3
via the [3D2] cycloaddition of phosphonate azomethine
ylides with ynones
To a solution of phosphonate azomethine ylide (0.4 mmol) in
1.5 mL dry THF at 0 ꢀC was added 0.4 mmol NaH (16 mg, 60%) in
batches. About 1 min later, a solution of ynone (0.2 mmol) in 0.5 mL
dry THF was dropped to the reaction solution. And then the re-
action was allowed to rise to room temperature and monitored
with TLC. The reaction was quenched with saturated NH4Cl when
completed (about 2 h). The mixture was extracted with EtOAc, the
combined organic phases were washed with brine and concen-
trated by reduced pressure to get the crude product, which was
purified by column chromatography on silica gel using PE/EA
(5:1e1:1).
Scheme 1. A plausible route for the [3þ2] cycloaddition.
The three-component reaction of 4-chlorobenzaldehyde 5c,
aminomethyl phosphonate 6 and ynone 2a has been explored. To
our delight, the transformation proceeded smoothly affording the
desired 1H-pyrrol-2-ylphosphonate 3k in 57% yield (Scheme 2).
4.3. Procedure for the preparation of compounds 3k via the
three-component reaction
To a solution of aminomethyl phosphonate 6 (735.3 mg,
4.4 mmol) in 20 mL anhydrous ethanol was added 4-
chlorobenzaldehyde 5c (562.3 mg, 4 mmol), and the mixture was
heated at reflux for 1.5 h. Evaporation of the solvent under reduced
pressure afforded phosphonate azomethine ylide 1c. And then NaH
(160 mg, 4 mmol, 60%) and ynone 2a (412.4 mg, 2 mmol) were
added, respectively, in 25 mL dry THF at 0 ꢀC. The reaction was
allowed to rise to room temperature and stirred overnight. The
reaction was quenched with saturated NH4Cl when completed, and
extracted with EtOAc. The mixture was extracted with EtOAc, the
combined organic phases were washed with brine and concen-
trated by reduced pressure to get the crude product, which was
purified by column chromatography on silica gel using PE/EA
(5:1e1:1) affording the desired 1H-pyrrol-2-ylphosphonate 3k
(560 mg, 57% yield).
Scheme 2. Synthesis of 1H-pyrrol-2-ylphosphonate 3k via the three-component re-
action of 4-chlorobenzaldehyde 5c, aminomethyl phosphonate 6 and ynone 2a.
3. Conclusion
In conclusion, we have developed an efficient route for the
construction of 1H-pyrrol-2-ylphosphonates via the [3þ2] cyclo-
addition of phosphonate azomethine ylides with ynones. This
transformation proceeded with good functional group tolerance
under mild conditions with good efficiency and selectivity. A
plausible reaction pathway was proposed, and the synthesis of 1H-
pyrrol-2-ylphosphonates could also be achieved via the three-
component reaction of benzaldehydes, aminomethyl phospho-
nates and ynones. Currently, the related library construction and
biological activity screening of these pyrrole compounds are still
ongoing, and the results will be reported in due course.
4.4. Characterization data of compounds 3
4.4.1. Diethyl (4-benzoyl-3,5-diphenyl-1H-pyrrol-2-yl)phosphonate
(3a). Yellow solid, 56 mg, 60% yield. Mp: 165e169 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
10.27 (s, 1H), 7.67 (d, J¼7.7 Hz, 2H), 7.47 (d,
4. Experimental section
4.1. General
J¼7.4 Hz, 2H), 7.32 (d, J¼7.5 Hz, 2H), 7.29e7.24 (m, 4H), 7.19e7.13
(m, 5H), 4.03e3.93 (m, 2H), 3.91e3.81 (m, 2H),1.10 (t, J¼7.0 Hz, 6H);
13C NMR (100 MHz, CDCl3)
d
194.2, 138.8 (d, JCP¼12 Hz), 138.4,
3
2
134.9 (d, JCP¼16 Hz), 133.5, 132.4, 130.9, 130.0, 129.9, 128.5, 128.3,
3
All reagents and starting materials were obtained commercially
and used as received unless otherwise stated. All reactions were
carried out with dry solvents. Anhydrous tetrahydrofuran (THF), 2-
128.2, 127.8, 127.5, 127.1, 122.5 (d, JCP¼12 Hz), 115.4 (d,
1
~
JCP¼226 Hz), 62.3, 15.9; IR (KBr):
n
¼3422, 3121, 3081, 2977, 2861,
1649,1596,1549,1491,1463,1395,1286,1245,1220,1050,1020, 977,

J. Meng et al. / Tetrahedron 71 (2015) 1074e1079
1077
904, 783, 733, 696 cmꢁ1; HRMS (EI-TOF): calcd for C27H26NO4P
[M]þ 459.1599, found 459.1597.
1057, 1017, 976, 906, 840, 799, 766, 697, 528 cmꢁ1; HRMS (EI-TOF):
calcd for C31H28NO4P [M]þ 509.1756, found 509.1753.
4.4.2. Diethyl
phosphonate (3b). Yellow solid, 64 mg, 65% yield. Mp: 173e175 ꢀC.
1H NMR (400 MHz, CDCl3)
10.45 (s, 1H), 7.60 (s, 1H), 7.52e7.47 (m,
(4-(3-chlorobenzoyl)-3,5-diphenyl-1H-pyrrol-2-yl)
4.4.7. Diethyl (4-benzoyl-5-phenyl-3-(p-tolyl)-1H-pyrrol-2-yl)phos-
phonate (3g). Yellow solid, 57 mg, 60% yield. Mp: 200e202 ꢀC. 1H
d
NMR (400 MHz, CDCl3)
d
10.28 (s, 1H), 7.68 (d, J¼7.3 Hz, 2H), 7.45
3H), 7.31e7.27 (m, 5H), 7.24e7.17 (m, 4H), 7.04e7.08 (m, 1H),
3.99e3.93 (m, 2H), 3.88e3.82 (m, 2H), 1.10 (t, J¼6.9 Hz, 6H); 13C
(dd, J¼7.5, 1.6 Hz, 2H), 7.29 (t, J¼7.4 Hz, 1H), 7.31e7.28 (m, 5H), 7.15
(t, J¼7.7 Hz, 2H), 6.99 (d, J¼7.9 Hz, 2H), 4.03e3.93 (m, 2H),
NMR (100 MHz, CDCl3)
d
191.3,138.9,138.4 (d, 3JCP¼12 Hz),134.0 (d,
3.91e3.81 (m, 2H), 2.25 (s, 3H), 1.11 (t, J¼7.1 Hz, 6H); 13C NMR
2JCP¼16 Hz), 132.9, 132.3, 131.1, 129.7, 128.9, 128.8, 128.1, 127.7, 127.4,
(100 MHz, CDCl3)
d
194.2, 138.3 (d, JCP¼12 Hz), 138.3, 136.8, 135.1
3
3
127.3, 126.8, 126.5, 126.2, 120.8 (d, JCP¼12 Hz), 114.7 (d,
(d, 2JCP¼16 Hz), 132.4, 130.8, 130.3, 129.9, 129.8, 128.4, 128.3, 128.3,
1
JCP¼227 Hz), 61.3, 14.9; IR (KBr):
n
¼3422, 3122, 3083, 2985, 2924,
128.2, 127.8, 122.5 (d, 3JCP¼12 Hz), 115.3 (d, 1JCP¼226 Hz), 62.4, 21.2,
~
~
1652, 1570, 1549, 1491, 1463, 1242, 1218, 1159, 1049, 1021, 979, 789,
749, 696, 591 cmꢁ1; HRMS (EI-TOF): calcd for C27H25ClNO4P [M]þ
493.1210, found 493.1201.
15.9; IR (KBr):
n
¼3422, 3125, 3080, 2985, 2921, 1654, 1596, 1531,
1492, 1464, 1411, 1391, 1280, 1242, 1222, 1188, 1169, 1057, 1034, 974,
912, 777, 744, 694, 604 cmꢁ1; HRMS (EI-TOF): calcd for C28H28NO4P
[M]þ 473.1756, found 473.1754.
4.4.3. Diethyl
phosphonate (3c). Yellow solid, 66 mg, 67% yield. Mp: 195e198 ꢀC.
1H NMR (400 MHz, CDCl3)
(4-(4-chlorobenzoyl)-3,5-diphenyl-1H-pyrrol-2-yl)
4.4.8. Diethyl (4-benzoyl-3-butyl-5-phenyl-1H-pyrrol-2-yl)phospho-
d
11.34 (s, 1H), 7.60 (d, J¼8.5 Hz, 2H),
nate (3h). Yellow solid, 50 mg, 57% yield. Mp: 120e122 ꢀC. 1H NMR
7.51e7.48 (m, 2H), 7.29e7.31 (m, 2H), 7.26e7.21 (m, 3H), 7.21e7.16
(m, 3H), 7.10 (d, J¼8.5 Hz, 2H), 3.97e3.87 (m, 2H), 3.85e3.75 (m,
(400 MHz, CDCl3)
d
10.45 (s, 1H), 7.66 (d, J¼7.5 Hz, 2H), 7.32 (t,
J¼7.2 Hz, 1H), 7.30e7.24 (m, 2H), 7.19 (t, J¼7.4 Hz, 2H), 7.15e7.10 (m,
3H), 4.09e4.01 (m, 4H), 2.74e2.70 (m, 2H), 1.45e1.43 (m, 2H),
1.35e1.25 (m, 8H), 0.82 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
2H), 1.06 (t, J¼7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 192.9, 139.0
3
2
(d, JCP¼12 Hz), 138.8, 136.9, 135.0 (d, JCP¼16 Hz), 133.4, 131.3,
3
2
130.8, 130.1, 128.6, 128.5, 128.4, 128.2, 127.7, 127.4, 122.2 (d,
d
193.6, 138.6 (d, JCP¼12 Hz), 137.9, 135.8 (d, JCP¼17 Hz), 131.2,
3
1
JCP¼12 Hz), 115.6 (d, JCP¼227 Hz), 62.5, 16.0; IR (KBr):
n
¼3422,
130.1, 128.7, 127.6, 127.5, 127.0, 126.8, 120.8 (d, 2JCP¼12 Hz), 114.2 (d,
~
1JCP¼228 Hz), 61.2, 32.8, 24.1, 21.9, 15.2, 12.8; IR (KBr):
n
¼3422,
~
3124, 3085, 2978, 2923, 2854, 1656, 1584, 1492, 1463, 1399, 1245,
1219, 1159, 1090, 1055, 1018, 904, 793, 697 cmꢁ1; HRMS (EI-TOF):
calcd for C27H25ClNO4P [M]þ 493.1210, found 493.1201.
3132, 3087, 2958, 2929, 2868, 1641, 1596, 1554, 1462, 1431, 1242,
1217, 1169, 1110, 1048, 1022, 965, 908, 772, 740, 694, 658, 602 cmꢁ1
;
HRMS (EI-TOF): calcd for
439.1910.
C
25H30NO4P [M]þ 439.1912, found
4.4.4. Diethyl
phosphonate (3d). Yellow solid, 67 mg, 62% yield. Mp: 180e183 ꢀC.
1H NMR (400 MHz, CDCl3)
11.34 (s, 1H), 7.53e7.48 (m, 4H),
(4-(4-bromobenzoyl)-3,5-diphenyl-1H-pyrrol-2-yl)
d
4.4.9. Diethyl
phosphonate (3i). Yellow solid, 41 mg, 48% yield. Mp: 138e140 ꢀC.
1H NMR (400 MHz, CDCl3)
(4-benzoyl-3-cyclopropyl-5-phenyl-1H-pyrrol-2-yl)
7.36e7.23 (m, 7H), 7.21e7.14 (m, 3H), 3.96e3.86 (m, 2H), 3.84e3.74
(m, 2H), 1.09 (t, J¼7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
193.1,
d
10.06 (s, 1H), 7.76 (d, J¼7.2 Hz, 2H), 7.41
139.0 (d, 3JCP¼12 Hz), 137.2, 135.0 (d, 2JCP¼16 Hz), 133.4, 131.4, 131.2,
(t, J¼6.8 Hz, 1H), 7.34e7.27 (m, 4H), 7.24e7.13 (m, 3H), 4.14e4.07
130.8, 130.1, 128.6, 128.5, 128.4, 127.7, 127.6, 127.4, 122.1 (d,
(m, 4H), 1.82e1.73 (m, 1H), 1.35e1.24 (m, 6H), 0.65e0.60 (m, 4H);
3
1
3
JCP¼12 Hz), 115.6 (d, JCP¼227 Hz), 62.5, 16.0; IR (KBr):
¼3422,
13C NMR (100 MHz, CDCl3)
d
194.9, 138.9, 137.8 (d, JCP¼12.0 Hz),
~
n
2
3126, 3089, 2980, 2924, 2864, 1656, 1582, 1491, 1464, 1396, 1245,
1222,1169, 1054, 1021, 975, 906, 792, 757, 697, 523 cmꢁ1; HRMS (EI-
TOF): calcd for C27H25BrNO4P [M]þ 537.0705, found 537.0706.
135.9 (d, JCP¼16 Hz), 132.6, 130.9, 129.8, 128.3, 128.2, 128.1, 128.0,
123.2 (d, JCP¼13 Hz), 116.6 (d, 1JCP¼227 Hz), 62.3, 16.3, 7.9, 7.1; IR
3
~
n
(KBr):
¼3422, 3145, 3092, 2985, 2928, 2870, 1646, 1595, 1578,
1465, 1435, 1407, 1319, 1235, 1217, 1168, 1057, 1025, 977, 924, 907,
831, 773, 740, 694, 637, 618 cmꢁ1; HRMS (EI-TOF): calcd for
4.4.5. Diethyl (4-(4-methoxybenzoyl)-3,5-diphenyl-1H-pyrrol-2-yl)
phosphonate (3e). Yellow solid, 42 mg, 43% yield. Mp: 195e190 ꢀC.
C
24H26NO4P [M]þ 423.1599, found 423.1596.
1H NMR (400 MHz, CDCl3)
d
10.14 (s, 1H), 7.69 (d, J¼8.8 Hz, 2H),
7.48e7.46 (m, 2H), 7.36e7.34 (m, 2H), 7.29e7.23 (m, 4H), 7.21e7.15
(m, 2H), 6.66 (d, J¼8.8 Hz, 2H), 4.04e3.94 (m, 2H), 3.92e3.82 (m,
2H), 3.74 (s, 3H), 1.11 (t, J¼7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3)
4.4.10. Diethyl (4-benzoyl-5-(4-fluorophenyl)-3-phenyl-1H-pyrrol-2-
yl)phosphonate (3j). Yellow solid, 49 mg, 51% yield. Mp:
178e182 ꢀC. 1H NMR (400 MHz, CDCl3)
d 11.40 (s, 1H), 7.64 (d,
3
2
d
193.1, 163.1, 137.8 (d, JCP¼12 Hz), 134.6 (d, JCP¼16 Hz), 133.5,
J¼7.4 Hz, 2H), 7.52 (dd, J¼8.6, 5.4 Hz, 2H), 7.31e7.26 (m, 3H),
7.18e7.13 (m, 5H), 6.92 (t, J¼8.6 Hz, 2H), 3.96e3.87 (m, 2H),
3.84e3.76 (m, 2H), 1.06 (t, J¼7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3)
132.3, 131.3, 130.9, 129.9, 128.4, 128.2, 128.1, 127.6, 127.1, 122.7 (d,
3JCP¼12 Hz), 115.1 (d, 1JCP¼226 Hz), 113.2, 62.3, 55.3, 15.9; IR (KBr):
¼3422, 3161, 3085, 2962, 2851, 1639, 1598, 1573, 1490, 1462, 1391,
d
194.1, 162.6 (d, 1JCF¼248 Hz), 138.3, 137.9 (d, 3JCP¼12 Hz), 135.1 (d,
~
n
1262, 1221, 1152, 1026, 904, 797, 696, 648, 593 cmꢁ1; HRMS (EI-
3JCP¼16 Hz), 133.4, 132.5, 130.5 (d, JCF¼8 Hz), 130.0, 129.8, 127.9,
3
TOF): calcd for C28H28NO5P [M]þ 489.1705, found 489.1700.
127.5, 127.2, 127.1, 122.5 (d, 3JCP¼12 Hz), 115.2 (d, 2JCF¼22 Hz), 115.2
1
~
(d, JCP¼227 Hz), 62.4, 15.9; IR (KBr):
n
¼3422, 3126, 3083, 2985,
4.4.6. Diethyl (4-(2-naphthoyl)-3,5-diphenyl-1H-pyrrol-2-yl)phos-
2934, 2867, 1651, 1596, 1500, 1456, 1398, 1242, 1221, 1161, 1052,
1018, 978, 909, 846, 788, 751, 697, 592, 530 cmꢁ1; HRMS (EI-TOF):
calcd for C27H25FNO4P [M]þ 477.1505, found 477.1504.
phonate (3f). Yellow solid, 55 mg, 54% yield. Mp: 197e199 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
9.91 (s, 1H), 8.15 (s, 1H), 7.84 (d, J¼8.5 Hz,
1H), 7.72 (d, J¼8.1 Hz, 2H), 7.65 (d, J¼8.6 Hz, 1H), 7.50e7.48 (m, 3H),
7.42 (d, J¼7.6 Hz, 1H), 7.37 (d, J¼7.5 Hz, 2H), 7.26e7.19 (m, 3H),
7.14e7.10 (m, 2H), 7.09e7.02 (m, 1H), 4.08e4.98 (m, 2H), 3.97e3.87
4.4.11. Diethyl (4-benzoyl-5-(4-chlorophenyl)-3-phenyl-1H-pyrrol-
2-yl)phosphonate (3k). Yellow solid, 62 mg, 63% yield. Mp:
(m, 2H), 1.14 (t, J¼7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
194.1,
206e210 ꢀC. 1H NMR (400 MHz, CDCl3)
d 10.95 (s, 1H), 7.66e7.64
3
2
138.3 (d, JCP¼12 Hz), 135.6, 135.3, 134.9 (d, JCP¼16 Hz), 133.4,
(m, 2H), 7.46 (d, J¼8.6 Hz, 2H), 7.33e7.28 (m, 3H), 7.23e7.21 (m,
132.5, 132.2, 130.8, 129.8, 129.4, 128.5, 128.3, 128.2, 128.2, 127.8,
2H), 7.18e7.13 (m, 5H), 3.99e3.89 (m, 2H), 3.87e3.77 (m, 2H), 1.08
2
127.6, 127.6, 127.2, 126.3, 125.1, 122.7 (d, JCP¼12 Hz), 115.4 (d,
(t, J¼7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 194.1, 138.13, 137.4 (d,
1
2
JCP¼226 Hz), 62.4, 15.9; IR (KBr):
n
¼3422, 3114, 3058, 2974, 2920,
3JCP¼12 Hz), 134.9 (d, JCP¼16 Hz), 134.2, 133.2, 132.6, 129.9, 129.8,
~
1641, 1626, 1550, 1491, 1463, 1437, 1393, 1294, 1246,1221, 1149, 1119,
129.8, 129.3, 128.5, 127.9, 127.6, 127.2, 122.8 (d, 3JCP¼12 Hz), 115.6 (d,

1078
1
J. Meng et al. / Tetrahedron 71 (2015) 1074e1079
1.08 (t, J¼7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 193.3, 137.9 (d,
~
n
JCP¼226 Hz), 62.4, 15.9; IR (KBr):
¼3422, 3134, 3086, 2979, 2927,
2
2862, 1657, 1596, 1578, 1490, 1462, 1394, 1314, 1242, 1223, 1158,
1092, 1050, 1027, 975, 901, 785, 742, 698, 588 cmꢁ1; HRMS (EI-TOF):
calcd for C27H25ClNO4P [M]þ 493.1210, found 493.1194.
3JCP¼12 Hz), 137.3, 137.1, 133.9 (d, JCP¼16 Hz), 132.5, 131.3, 128.9,
3
128.8, 127.9, 127.3, 126.9, 126.8, 126.5, 126.1, 121.2 (d, JCP¼12 Hz),
113.8 (d, 1JCP¼226 Hz), 61.3, 20.2, 14.9; IR (KBr):
¼3422, 3127, 3101,
~
n
2978, 2926, 2859, 1650, 1596, 1503, 1462, 1395, 1242, 1225, 1157,
1049, 1025, 973, 902, 816, 777, 743, 699, 585 cmꢁ1; HRMS (EI-TOF):
calcd for C28H28NO4P [M]þ 473.1756, found 473.1754.
4.4.12. Diethyl (4-(4-chlorobenzoyl)-5-(4-chlorophenyl)-3-phenyl-
1H-pyrrol-2-yl)phosphonate (3l). Yellow solid, 70 mg, 66% yield.
Mp: 198e202 ꢀC. 1H NMR (400 MHz, CDCl3)
d 10.76 (s, 1H), 7.58 (d,
J¼7.8 Hz, 2H), 7.46 (d, J¼8.0 Hz, 2H), 7.27e7.25 (m, 4H), 7.16e7.12
4.5. Characterization data of compound 4m
(m, 5H), 4.00e3.90 (m, 2H), 3.88e3.78 (m, 2H), 1.09 (t, J¼7.0 Hz,
6H); 13C NMR (100 MHz, CDCl3)
d 192.7, 138.95, 137.5 (d,
4.5.1. Diethyl (5-(4-chlorophenyl)-4-(4-methoxybenzoyl)-3-phenyl-
2
3JCP¼12 Hz), 136.5, 134.8 (d, JCP¼16 Hz), 134.5, 133.1, 131.2, 129.9,
3,4-dihydro-2H-pyrrol-2-yl)-phosphonate (4m). Light yellow oil,
3
15 mg, 14% yield. 1H NMR (400 MHz, CDCl3)
d 7.65e7.69 (m, 4H),
129.8, 129.2, 128.6, 128.2, 127.7, 127.4, 122.3 (d, JCP¼12 Hz), 115.7
1
~
(d, JCP¼226 Hz), 62.5, 15.9; IR (KBr):
n
¼3448, 3125, 3074, 2980,
7.36e7.30 (m, 5H), 7.21 (d, J¼7.0 Hz, 2H), 6.84 (d, J¼8.0 Hz, 2H),
5.18e5.16 (m, 1H), 4.75 (dd, J¼21.0, 4.8 Hz, 1H), 4.22e4.09 (m, 4H),
3.91e3.82 (m, 1H), 3.85 (s, 3H), 1.31 (t, J¼7.1 Hz, 3H), 1.23 (t,
2936, 1646, 1585, 1545, 1488, 1460, 1438, 1390, 1286, 1243, 1219,
1166, 1086, 1056, 1012, 902, 826, 792, 742, 695, 589, 535 cmꢁ1
;
HRMS (EI-TOF): calcd for C27H24Cl2NO4P [M]þ 527.0820, found
527.0796.
J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 194.3, 170.8, 163.1, 141.9,
135.9, 130.7, 130.3, 128.5, 128.3, 127.8, 127.3, 126.6, 126.2, 112.9, 78.5
1
(d, JCP¼157 Hz), 64.9, 62.2, 61.7, 54.5, 50.2, 15.5, 15.3; IR (KBr):
4.4.13. Diethyl (5-(4-chlorophenyl)-4-(4-methoxybenzoyl)-3-phenyl-
~
n
¼3225, 3062, 2963, 2927, 2853, 1708, 1666, 1598, 1572, 1510, 1492,
1H-pyrrol-2-yl)phosphonate (3m). Yellow solid, 50 mg, 48% yield.
1456, 1400, 1311, 1257, 1172, 1092, 1026, 972, 836, 799, 748, 699,
595 cmꢁ1; LRMS (EI-TOF): calcd for C28H29ClNO5P [M]þ 525.1,
found 526.1 [MþH]þ.
Mp: 202e206 ꢀC. 1H NMR (400 MHz, CDCl3)
d 10.66 (s, 1H), 7.66 (d,
J¼8.0 Hz, 2H), 7.45 (d, J¼7.8 Hz, 2H), 7.32 (d, J¼6.7 Hz, 2H),
7.26e7.22 (m, 3H), 7.18e7.16 (m, 2H), 6.66 (d, J¼8.1 Hz, 2H),
4.01e3.91 (m, 2H), 3.89e3.79 (m, 2H), 3.75 (s, 3H), 1.09 (t,
Acknowledgements
J¼6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 191.9, 162.2, 135.6 (d,
2
3JCP¼12 Hz), 133.6 (d, JCP¼16 Hz), 132.9, 132.3, 131.2, 130.1, 128.8,
This research is sponsored by Shanghai Pujiang Program
(14PJD013), Shanghai Yangfan Program (14YF1404600) and Fun-
damental Research Funds for the Central Universities
(WY1414023).
3
128.6, 128.4, 127.4, 126.5, 126.2, 121.9 (d, JCP¼12 Hz), 114.3 (d,
1
~
JCP¼226 Hz), 112.2, 61.3, 54.3, 14.9; IR (KBr):
n
¼3422, 3141, 3085,
2980, 2928, 2861, 1645, 1594, 1508, 1491, 1462, 1395, 1314, 1261,
1221, 1154, 1052, 1021, 976, 908, 831, 802, 698, 630, 518 cmꢁ1
;
HRMS (EI-TOF): calcd for C28H27ClNO5P [M]þ 523.1315, found
523.1311.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.12.091.
4.4.14. Diethyl (4-benzoyl-5-(4-bromophenyl)-3-phenyl-1H-pyrrol-
2-yl)phosphonate (3n). Yellow solid, 68 mg, 63% yield. Mp:
193e195 ꢀC. 1H NMR (400 MHz, CDCl3)
d 10.81 (s, 1H), 7.65 (d,
References and notes
J¼7.3 Hz, 2H), 7.41e7.36 (m, 4H), 7.33e7.29 (m, 3H), 7.14e7.13 (m,
5H), 4.00e3.91 (m, 2H), 3.89e3.79 (m, 2H), 1.09 (t, J¼7.1 Hz, 6H);
1. For reviews, see: (a) Van der Jeught, K.; Stevens, C. V. Chem. Rev. 2009, 109,
2672; (b) Moneen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104, 6177.
2. (a) Seto, H.; Kuzuyama, T. Nat. Prod. Rep. 1999, 16, 589; (b) Westheimer, F. H.
Science 1987, 235, 1173.
13C NMR (100 MHz, CDCl3)
d
194.1,138.2,137.5 (d, 3JCP¼12 Hz),135.0
2
(d, JCP¼16 Hz), 133.3, 132.6, 132.6, 131.4, 130.1, 129.9, 129.8, 127.9,
127.5,127.2,122.8 (d, 3JCP¼12 Hz),122.4,115.6 (d, 1JCP¼227 Hz), 62.4,
3. For examples of phosphorus compounds as pharmaceuticals, see: (a) Dunford,
J. E. Curr. Pharm. Des. 2010, 16, 2961; (b) Rondeau, J.-M.; Bitsch, F.; ourgier, E.;
Geiser, M.; Hemmig, R.; Kroemer, M.; Lehmann, S.; Ramage, P.; Rieffel, S.;
Strauss, A.; Green, J. R.; Jahnke, W. ChemMedChem 2006, 1, 267; (c) Kavanagh,
K. L.; Guo, K.; Dunford, J. E.; Wu, X.; Knapp, S.; Ebetino, F. H.; Rogers, M. J.;
Russell, R. G. G.; Oppermann, U. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 7829.
4. Recent examples, see: (a) Lin, Y.-S.; Park, J.; De Schutter, J. W.; Huang, X. F.;
Berghuis, A. M.; Sebag, M.; Tsantrizos, Y. S. J. Med. Chem. 2012, 55, 3201; (b)
Deng, L.; Diao, J.; Chen, P.; Pujari, V.; Yao, Y.; Cheng, G.; Crick, D. C.; Prasad, B. V.;
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zewski, R. M.; Robinson, E. D.; van Poelje, P. D.; Reddy, M. R.; Erion, M. D. J. Med.
Chem. 2009, 52, 2880.
5. For reviews, see: (a) Russel, J. S.; Pelkey, E. T.; Yoon-Miller, S. J. P. Prog. Heter-
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Sobenina, L. N. Adv. Heterocycl. Chem. 2010, 99, 209; (c) Balme, G. Angew. Chem.,
Int. Ed. 2004, 43, 6238; (d) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell
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C.; Alfonso, S.; de Logu, A.; Manetti, F.; Botta, M. ChemMedChem 2011, 6, 593; (b)
Rivero, M. R.; Buchwald, S. L. Org. Lett. 2007, 9, 973; (c) Butler, M. S. J. Nat. Prod.
2004, 67, 2141; (d) Tao, H.; Hwang, I.; Boger, D. L. Bioorg. Med. Chem. Lett. 2004,
14, 5979.
7. Davis, F. A.; Bowen, K. A.; He, X.; Velvadapu, V. Tetrahedron 2008, 64, 4174.
8. (a) Kim, S. H.; Kim, K. H.; Lim, J. W.; Kim, J. N. Tetrahedron Lett. 2014, 55, 531; (b)
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9. (a) Buksnaitiene, R.; Urbanaite, A.; Cikotiene, I. J. Org. Chem. 2014, 79, 6532; (b)
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~
15.9; IR (KBr):
n
¼3422, 3129, 3084, 2976, 2926, 2860, 1656, 1595,
1488, 1462, 1393, 1314, 1260, 1241, 1223, 1157, 1049, 1027, 974, 900,
815, 783, 744, 697, 588 cmꢁ1
HRMS (EI-TOF): calcd for
27H25BrNO4P [M]þ 537.0705, found 537.0708.
;
C
4.4.15. Diethyl (4-benzoyl-5-(4-nitrophenyl)-3-phenyl-1H-pyrrol-2-
yl)phosphonate (3o). Brown orange solid, 70 mg, 69% yield. Mp:
202e204 ꢀC. 1H NMR (400 MHz, CDCl3)
d 11.99 (s, 1H), 8.09 (d,
J¼8.8 Hz, 2H), 7.76 (d, J¼8.8 Hz, 2H), 7.66 (d, J¼7.5 Hz, 2H), 7.33 (t,
J¼7.4 Hz, 1H), 7.29e7.26 (m, 2H), 7.20e7.11 (m, 5H), 3.97e3.88 (m,
2H), 3.86e3.78 (m, 2H), 1.07 (t, J¼7.1 Hz, 6H); 13C NMR (100 MHz,
3
CDCl3)
d
194.0, 146.9, 137.9, 137.1, 135.8 (d, JCP¼12 Hz), 135.3 (d,
2JCP¼16 Hz), 132.9, 132.9,129.9,129.8,129.1, 128.1, 127.6, 127.5, 124.2
3
1
(d, JCP¼12 Hz), 123.4, 117.0 (d, JCP¼226 Hz), 62.6, 15.9; IR (KBr):
~
n
¼3423, 3123, 3086, 2979, 2929, 2862, 1656, 1597, 1550, 1518, 1461,
1393, 1337, 1244, 1223, 1156, 1051, 1029, 978, 901, 852, 784, 736,
696, 587 cmꢁ1; HRMS (EI-TOF): calcd for C27H25N2O6P [M]þ
504.1450, found 504.1453.
4.4.16. Diethyl
phosphonate (3p). Yellow solid, 55 mg, 55% yield. Mp: 155e158 ꢀC.
1H NMR (400 MHz, CDCl3)
(4-benzoyl-3-phenyl-5-(p-tolyl)-1H-pyrrol-2-yl)
d
10.76 (s, 1H), 7.67 (d, J¼7.5 Hz, 2H), 7.38
(d, J¼7.1 Hz, 2H), 7.32e7.27 (m, 3H), 7.17e7.15 (m, 5H), 7.05 (d,
J¼7.0 Hz, 2H), 3.98e3.96 (m, 2H), 3.86e3.84 (m, 2H), 2.27 (s, 3H),
10. (a) Yu, X.; Ding, Q.; Wu, J. J. Comb. Chem. 2010, 12, 743; (b) Ding, Q.; Wang, B.;
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