Preparation of tetrasubstituted 3-phosphonopyrroles through hydroamination: Scope and limitations

Article abstract of DOI:10.1021/jo500139z

Phosphonylated pyrroles were obtained by a ZnCl₂-catalyzed 5-exo-dig hydroamination of propargylic enamines. These starting compounds were obtained in two steps from commercially available β-ketophosphonates. The method tolerates a wide variety of substituents at the 1,2- and 5-position of the pyrrole, while further derivatization allows for the introduction of substituents at the 4-position via lithiation or halogenation.

Full text of DOI:10.1021/jo500139z

Article
pubs.acs.org/joc
Preparation of Tetrasubstituted 3‑Phosphonopyrroles through
Hydroamination: Scope and Limitations
Wouter Debrouwer, Thomas S. A. Heugebaert, and Christian V. Stevens*
SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent
University, Coupure Links 653, B-9000 Gent, Belgium
S
* Supporting Information
ABSTRACT: Phosphonylated pyrroles were obtained by a ZnCl2-catalyzed 5-
exo-dig hydroamination of propargylic enamines. These starting compounds were
obtained in two steps from commercially available β-ketophosphonates. The
method tolerates a wide variety of substituents at the 1,2- and 5-position of the
pyrrole, while further derivatization allows for the introduction of substituents at
the 4-position via lithiation or halogenation.
enamines 2a−g while the imines 3a−g are present in both
their (E) and (Z) forms, with the majority in the (E)-
configuration due to steric hindrance between the R2 substituent
and the bulky phosphonate group.
INTRODUCTION
■
Next to the classical Knorr, Paal−Knorr, and Hantschz pyrrole
syntheses and some less prevailing name reactions such as the
Barton−Zard or van Leusen transformations, multicomponent
reactions as well as cycloadditions have been intensively utilized
for the preparation of a range of polysubstituted pyrrole cores.
Another frequently applied method is the hydroamination of
alkynes in order to furnish polysubstituted pyrroles using, among
others,1 gold,2−4 silver,5−7 titanium,8,9 and platinum cata-
lysts.10−15 Only in some cases were 3-pyrrolyl phosphonates
obtained.16−20 Beller and co-workers recently published a
versatile Ru-catalyzed three-component reaction involving
ketones, amines and vicinal diols, which is applicable to
phosphonates.21 Larionov and de Meijere reported on the
formal cycloaddition of α-metalated isocyanides to acetylenes
leading to pyrroles,22,23 and Demir and Tural transformed α-
cyanomethyl-β-ketoesters into pyrrole-3-phosphonates.24
Phosphonylated pyrroles are of interest because of their
presence in bioactive molecules. Analgesic properties have been
ascribed to 2-phosphonopyrroles,25 and 2-phosphonoindoles
display thyromimetic,26 anti-inflammatory,27 and plant growth
regulating properties.28 Furthermore, 3-carboxylpyrroles, of
which the phosphonates are bioisosteres, have been reported
as cyclic AMP-specific phosphodiesterase inhibitors.29 Retro-
synthetically, we envisioned a Lewis acid catalyzed cyclo-
isomerization-type pyrrole assembly, starting from phosphony-
lated propargylic imines, which themselves could be obtained
from β-ketophosphonates (Scheme 1).
The introduction of an alkyne moiety was achieved by treating
the enamine/imine mixture with LiHMDS at −78 °C, leading to
the formation of the corresponding aza-enolate, followed by the
addition of propargyl bromide 4 and allowing the reaction
mixture to warm to room temperature (Table 2). Other strong
bases such as n-BuLi, LDA, or NaH could be employed as well.
The reaction progress was monitored using 31P NMR spectros-
copy, which indicated it was difficult to obtain complete
conversion. Therefore, additional base and electrophile were
consecutively added until complete conversion was achieved.
However, formation of bis-propargylated products was inevi-
table, and these compounds have retention factors that are
similar to those of the desired products 5a−j, accounting for
diminished yields after purification via column chromatography.
In order to simplify the reaction sequence, we evaluated first
propargylating the β-ketophosphonates 1 before performing the
iminations. Unfortunately, the subsequent imination reaction
failed, resulting in full recovery of starting material 1. This was
probably due to increased steric hindrance upon introduction of
the propargyl moiety, blocking amine attack across the carbonyl
bond. Having produced terminal alkynes 5a−g, nonterminal
alkynes could also be synthesized and evaluated toward
hydroamination. This could be done by performing a
Sonogashira coupling using terminal alkynes 5a−g as substrates,
but this would require an extra step in the sequence. The
alternative was to use nonterminal propargyl bromides 4 and add
these to the aza-enolates obtained from 2 and 3. However, in this
manner one is limited to the commercially available propargylic
bromides. A few nonterminal alkynes were produced this way
(R3 = CH3, 1-naphthyl, SiMe3). For R1 = Me though (Table 2,
entry g), introduction of the propargyl moiety proved a lot more
RESULTS AND DISCUSSION
■
The imination of β-ketophosphonates 1a,e−g under Dean−
Stark conditions proceeded in excellent yields.30,31 Several
amines were used in combination with various substrates to
explore the scope of the subsequent reactions (Table 1).
Electron-donating (entry f) as well as electron-withdrawing
aromatic moieties (entry e) were tolerated as R1, while aliphatic
groups could also be used (entry g). While conversion was clean
and quantitative, the obtained crude product consists of
Received: January 20, 2014
Published: April 18, 2014
© 2014 American Chemical Society
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Scheme 1. Retrosynthetic Approach to 3-Phosphonopyrroles
Table 1. Preparation of Diverse Phosphonylated Enamines 2a−g and Imines 3a−g: Reaction Yields and Ratios of Conformations
Based on 1H and 31P NMR
entry
R1
R2
2 + 3 (%)
2/3
3E/Z
a
b
c
d
e
f
Ph
Ph
Ph
Ph
benzyl
allyl
95
98
87
96
92
83
94
60/40
83/17
77/23
69/31
57/43
70/30
63/37
83/17
76/24
85/15
85/15
55/45
63/37
n-butyl
phenyl
benzyl
benzyl
benzyl
4-F-C6H4
4-OCH3-C6H4
CH3
a
g
63 /37
a
The enamine is present in both the (E)- and (Z)-form in a ratio of 2/1, respectively.
Table 2. Introduction of the Propargylic Moiety onto Products 2 and 3
entry
R1
R2
R3
5 (%)
a
b
c
d
e
f
Ph
Ph
Ph
Ph
benzyl
allyl
H
H
H
H
H
H
H
41
21
48
31
37
43
94
46
38
45
n-butyl
phenyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
4-F-C6H4
4-OCH3-C6H4
a
g
h
i
CH3
Ph
CH3
Ph
1-naphthyl
SiMe3
j
Ph
a
Crude yield, as 5g is unstable and degrades during column chromatography.
challenging than for the other substrates, probably due to the
acidic methyl group. Attempted purification through column
chromatography led to severe degradation, so the next step was
performed using the crude product.
The obtained α-propargyl phosphonates 5a−j were mostly
present in the (Z)-enamine form based on the coupling constants
3JCP of ca. 18 Hz,32 although some (E)-isomer was also present.
For both terminal alkynes 5a−g and internal alkynes 5i−j the E/
Z ratio is around 1/9 while for the internal alkyne 5h the ratio is
1/4.
With propargylated enamines 5a−j in hand, we next
envisioned a regioselective 5-exo-dig hydroamination reaction
leading to phosphonylated pyrroles. A literature search resulted
in a copious amounts of references regarding hydroamination
catalysts, solvents, and the substrate scope for the synthesis of
pyrroles.33−45 Based on our own work regarding transition-
metal-catalyzed cyclization reactions,46−48 several Au catalysts
were evaluated at first with 5a, albeit with mediocre results
(Table 3, entries a−c). Hydrolysis of the enamine took place
along with some formation of the desired pyrrole 6a. Application
of gold chlorides under nonanhydrous conditions leads to in situ
hydrochloric acid formation which could account for the
observed hydrolysis. Indeed, 0.2 equiv of aqueous hydrochloric
acid only led to hydrolysis of the starting material and
precipitation, probably due to salt formation (entry d). Other
acids such as TFA also induced hydrolysis instead of hydro-
amination (entry e). Application of ZnCl2 yielded the desired
pyrrole in quantitative yield after 1 day, while AgNO3 did the job
in merely 1 h (entries f and i). Both Pd- and Cu-acetates were less
suitable (entries l, m). Next, the catalyst loading was diminished
to 5 and 1 mol % for both ZnCl2 and AgNO3, and the reaction
times were compared (entries g, h, j, k). For ZnCl2 there was no
difference between a catalyst loading of 20 and 5 mol %. Further
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Zn salts have often been applied for the hydroamination of
alkynes.49−61
Table 3. Catalyst Screening for Pyrrole Synthesis through
Hydroamination
Having identified a suitable catalyst, further optimization of
the reaction conditions indicated that the transformation also
proceeded cleanly in CH2Cl2, THF, and toluene but at a slower
rate. Therefore, CH3CN remained the solvent of choice.
Application of these optimized hydroamination conditions to
the propargylic enamines 5 led to the desired pyrroles in good to
excellent yields (Table 4). The choice of R1 and/or R2 does not
seem to significantly influence the reaction. However, the
nonterminal alkynes 5h−j did not furnish the pyrroles 6h−j
under these conditions, and only starting material was recovered
after 24 h. The reaction was therefore continued at reflux
temperature (82 °C), and this did deliver the aspired pyrroles
6h−j along with hydrolysis of the starting enamines 5h−j.
Consequently, these substrates were transformed using 20 mol %
of dried ZnCl2 in dry CH3CN in order to speed up pyrrole
formation and counteract hydrolysis. For R3 = SiMe3 though
(entry j), no pyrrole was detected even after 7 days reaction at
reflux temperature. This may be attributed to electronic effects,
as Si is more electropositive than sp3- and sp2-hybridized C and
accordingly deactivates the alkyne bond for hydroamination.
Thus, a general method for the preparation of 1,2,5-substituted
3-phosphonopyrroles was developed. Retrosynthetically, the
introduction of substituents at the 4-position would require the
use of branched propargyl halides 4 or the obtained pyrroles 6
had to be derivatized. The first option proved to be troublesome,
since branched propargyl halides are not commercially available
and the introduction of the propargyl group is the most difficult
step in our synthesis. Therefore, we opted for the development of
a general method for derivatization at the 4-position of the
obtained pyrroles 6.
entry
catalyst
AuCl
amt (mol %)
reaction time (h)
6a (%)
a
a
b
c
d
e
f
20
20
20
20
20
20
5
4
5
50
a
AuCl3
41
a
HAuCl4
HCl
4
73
24
24
24
24
144
1
0
0
TFA
ZnCl2
99
99
99
99
g
h
i
ZnCl2
ZnCl2
1
AgNO3
AgNO3
AgNO3
Pd(OAc)2
Cu(OAc)2
20
5
a
j
2
94
a
k
l
1
48
4
62
a
20
20
23
a
m
24
32
a
After column chromatography.
lowering to 1 mol % resulted in a severe rate decrease, prolonging
the reaction to 144 h (entries f−h). Upon application of 5 mol %
AgNO3 the reaction time doubled, while use of 1 mol % required
48 h for the reaction to complete. However, longer exposure to
AgNO3 led to some slight degradation, resulting in lower yields
(entries j, k). Furthermore, we noticed that refluxing the enamine
5a in toluene with a catalytic amount of p-TsOH also yielded the
desired pyrrole 6a, but given pyrrole’s tendency to polymerize
the room temperature catalytic approach was preferred. Due to
these observations and as AgNO3 is a factor of 25 more expensive
than ZnCl2 (ca. 2000 €/kg vs 80 €/kg), the latter was chosen at a
loading of 5 mol % for the further elaboration of the reaction
scope in spite of the discrepancy in reaction rate. In the literature,
The most straightforward possibility was deprotonating the
pyrrole C−H using a strong base followed by subsequent
quenching with a suitable electrophile (Table 5, method A).
While a benzylic proton is present in 6c which can potentially be
deprotonated, literature examples prove the feasability of this
approach.62 Initial attempts to deprotonate the pyrrole using n-
Table 4. Isolated Yields and Reaction Times for the Hydroamination of Enamines 5a−j with Formation of the Corresponding
a
Pyrroles 6a−i
entry
R1
R2
R3
time
24 h
6 (%)
a
b
c
d
e
f
Ph
Ph
Ph
Ph
benzyl
allyl
H
H
H
H
H
H
H
99
89
94
91
97
20 h
20 h
20 h
24 h
24 h
45 min
7 d
n-butyl
phenyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
4-F-C6H4
b
4-OCH3-C6H4
72
b
b
b
,c
g
h
i
CH3
Ph
10
46
37
CH3
Ph
1-naphthyl
SiMe3
24 h
3 d
j
Ph
a
Conditions for terminal alkynes 5a−g: 5 mol % of ZnCl2, CH3CN, rt, air. Nonterminal alkynes 5h−j: 20 mol % of dried ZnCl2, dry CH3CN, Δ, N2.
b
c
After column chromatography. Yield over two steps. Crude starting material 5g was used and catalyst was added based on this weight, so more
than 5 mol % of catalyst was added which accounts for the shorter reaction time.
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Table 5. Derivatization at the 4-Position of Pyrrole 6c
product ratio
entry
method
base
electrophile (equiv)
additive (equiv)
6c (%)
9 (%)
a
b
c
d
e
f
A
A
A
A
A
A
B
B
B
B
B
B
B
n-BuLi
n-BuLi
n-BuLi
s-BuLi
s-BuLi
t-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
D2O (excess)
MeI (1.1)
40
79
60
21
0
benzaldehyde (1.1)
D2O (excess)
MeI (1.1)
100
0
100
62
0
38
MeI (1.1)
100
40
g
h
i
MeI (1.1)
60
69
64
60
74
trace
0
MeI (10)
31
MeI (10)
AgF (1.2)
36
j
MeI (10)
12-crown-4 (1.2)
40
k
l
MeI-d3 (1.1)
TMSCl (1.1)
benzaldehyde (1.1)
26
98
m
100
Scheme 2. Quench with Iodomethane-d3 To Verify the Hypothesis of Intermolecular Deprotonation after Li−Br Exchange and
Addition of Iodomethane
BuLi were only partly successful as no complete conversion could
be attained after the addition of several electrophiles. Reaction
with D2O resulted in 60% deuteration, and with the somewhat
bulkier iodomethane only 21% 9b was obtained (entries a, b).
Using benzaldehyde as an electrophile did not lead to any
alkylation (entry c). Benzaldehyde is most likely too large to
approach the lithiated anion which is in the plane of the pyrrole
ring and is shielded by the phosphonate group. Application of
stronger bases such as s-BuLi led to full deuteration, proving
complete deprotonation of product 6c (entry d). Use of
iodomethane for alkylation only led to 62% of product, as a
result of steric hindrance (entry e). Interestingly, t-BuLi did not
deprotonate the pyrrole 6c which is again attributed to steric
hindrance (entry f). It is noteworthy that under these conditions
no deprotonation of the methyl group on the 5-position of 6c
occurs at all, not even when using t-BuLi.
Another effort to functionalize the pyrroles involved
bromination and subsequent lithium−bromine exchange
(Table 5, method B).63 The introduction of the bromine atom
proceeded smoothly, but attempted methylation proved just as
difficult as after direct deprotonation, although method B gave
cleaner results (entry g). Even a large excess of iodomethane
(entry h) did not improve conversion, nor did the addition of
AgF to precipitate AgI or the addition of 12-crown-4 to scavenge
the lithium ions (entries i, j). Iodomethane-d3 was used in entry k
to investigate whether the newly introduced methyl group at the
4-position of 9e was acidic enough to quench the remainder of
the starting material 10, but this was not the case (Scheme 2).
Introducing larger electrophiles also failed (entries l and m).
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Table 6. Transition Metal-Catalyzed Coupling of Pyrrole 8 to sp, sp2, and sp3 Carbon Atoms
a
b
Based on 31P NMR. Isolated yield.
An alternative to lithiation followed by alkylation is transition
metal-catalyzed cross-coupling. The 4-bromopyrrole 8 was
subjected to standard cross-coupling procedures in order to
join the pyrrole core to an sp-, sp2-, and sp3-hybridized carbon
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atom.64 The results are depicted in Table 6. Attempted
Sonogashira coupling yielded unreacted starting material under
both classical and microwave heating (entries a−d). As an
alternative, Suzuki coupling with 2-phenyl-1-ethynylboronic acid
pinacol ester was evaluated. After 1 h at 130 °C under microwave
irradiation (entry e), mainly debrominated product 6c was
recovered, indicating that oxidative addition had taken place but
the transmetalation or reductive elimination steps did not
proceed. Prolonging the reaction time to 2 h (entry f) resulted in
the formation of some coupled product and complete
consumption of the starting material, along with product
degradation. However, increasing the amount of boronic ester
(entry g) or further prolonging the reaction time (entry h) did
not lead to better results. Next, Stille coupling with tributyl-
(phenylethynyl)tin was assessed. After 2 h of microwave
irradiation (entry i), 60% of coupled product was observed and
after 4 h reaction the conversion to 11 was increased to 75%
(entry j). Longer reaction times did not lead to full conversion of
8, which was chromatographically inseparable from the coupled
product.
(1 mL/mmol) in a round-bottom flask equipped with a Dean−Stark
apparatus. An appropriate primary amine (1.2 equiv) and p-TsOH
monohydrate (0.05 equiv) were added, and the reaction mixture was
heated to reflux temperature and left overnight. The reaction progress
was monitored using gas chromatography. After all starting material had
been consumed, the solvent was removed in vacuo and the residue was
redissolved in diethyl ether and washed with aqueous NaHCO3. The
organic phase was extracted with diethyl ether (3 × 20 mL), dried over
MgSO4, and concentrated in vacuo.
Synthesis of Propargylic Enaminophosphonates 5a−j. In a
flame-dried round-bottom flask, enaminophosphonates 2a−g were
dissolved in dry THF (0.5 mmol/mL) and put under an inert N2-
atmosphere. The solution was cooled to −78 °C before adding
LiHMDS (1.2 equiv) and was kept stirring at −78 °C for 1 h. Next, a
propargyl bromide solution in toluene (1.2 equiv) was added in a
dropwise fashion and the reaction mixture was allowed to warm to 20
°C. Reaction progress was monitored using HPLC. If no further
conversion took place, additional LiHMDS and propargyl bromide were
added until no more starting material was present. Water was added and
the solution was extracted using diethyl ether (3x 20 mL). After drying
the combined organic layers over MgSO4, the solvent was removed in
vacuo and the residue was purified using column chromatography. E/Z
mixtures were obtained but only the peaks of the major isomers were
assigned.
Diethyl (Z)-(1-(Benzylamino)-1-phenylpent-1-en-4-yn-2-yl)phos-
phonate (5a). 317 mg (0.92 mmol) of 2a/3a was converted into 5a.
After column chromatography, 144 mg of 5a was obtained (0.38 mmol,
41% yield, brown oil). 1H NMR (300 MHz, CDCl3) δ: 1.36 (6H, t, J =
7.1 Hz), 1.84 (1H, t, J = 2.2 Hz), 2.62 (2H, dd, 3JHP = 16.5 Hz, J = 2.2
Hz), 3.91 (2H, d, J = 6.5 Hz), 4.11 (4H, dq, 3JHP = 8.3 Hz, J = 7.2 Hz),
7.08−7.10 (2H, m), 7.19−7.26 (4H, m), 7.36−7.43 (4H, m), 8.30 (1H,
t, J = 6.5 Hz). 13C NMR (75 MHz, CDCl3) δ: 16.4 (d, 3JCP = 6.9 Hz),
18.6 (d, 2JCP = 10.4 Hz), 48.6, 61.3 (d, 2JCP = 4.6 Hz), 67.0, 81.8 (d, 1JCP
= 184.6 Hz), 84.8, 126.9, 127.1, 128.4, 128.5, 128.9, 134.8 (d, 3JCP = 17.3
Hz), 140.1, 165.0 (d, 2JCP = 13.9 Hz). 31P NMR (121 MHz, CDCl3) δ:
24.35 (m), 27.31 (M). IR (cm−1) νmax: 1021 (P−O), 1050 (P−O), 1205
(PO), 1589, 1606, 2113, 2980, 3288. MS (ESI, pos) m/z: 384.2/
385.2 (M + H+, 100/25). HRMS: m/z calcd for C22H27NO3P (M + H)+
384.1723, found 384.1734. Chromatography: hexanes/EtOAc 7/3, Rf =
0.26.
Diethyl (Z)-(1-(Allylamino)-1-phenylpent-1-en-4-yn-2-yl)phos-
phonate (5b). 300 mg (1.02 mmol) of 2b/3b was converted into 5b.
After column chromatography, 71 mg of 5b was obtained (0.21 mmol,
21% yield, brown oil). 1H NMR (300 MHz, CDCl3) δ: 1.37 (6H, t, J =
7.2 Hz), 1.86 (1H, t, J = 2.3 Hz), 2.61 (2H, dd, 3JHP = 16.5 Hz, J = 2.3
Hz), 3.32 (2H, dd, J = 6.1 Hz, J = 5.0 Hz), 4.14 (4H, dq, 3JHP = 7.2 Hz, J =
7.2 Hz), 5.03 (1H, dd, JZ = 9.9 Hz, J = 1.1 Hz), 5.13 (1H, dd, JE = 17.1
Hz, J = 1.4 Hz), 5.68 (1H, ddt, JE = 17.1 Hz, JZ = 9.9 Hz, J = 5.0 Hz),
7.29−7.33 (2H, m), 7.40−7.41 (3H, m), 7.96 (1H, t, J = 6.1 Hz). 13C
NMR (75 MHz, CDCl3) δ: 16.3 (d, 3JCP = 6.9 Hz), 18.5 (d, 2JCP = 10.4
Hz), 46.9, 61.3 (d, 2JCP = 4.6 Hz), 66.9, 80.6 (d, 1JCP = 188.0 Hz), 84.9,
115.3, 128.3, 128.5, 128.8, 134.8 (d, 3JCP = 17.3 Hz), 136.1, 165.0 (d, 2JCP
= 12.7 Hz). 31P NMR (121 MHz, CDCl3) δ: 24.41 (m), 27.47 (M). IR
(cm−1) νmax: 1021 (P−O), 1050 (P−O), 1204 (PO), 1587, 1607,
2114, 2981, 3288. MS (ESI, pos) m/z: 334.3/335.3 (M + H+, 100/25).
HRMS: m/z calcd for C18H25NO3P (M + H)+ 334.1567, found
334.1574. Chromatography: hexanes/EtOAc 7/3, Rf = 0.20.
Coupling of the pyrrole core to sp2 carbon atoms was
performed by Stille coupling (entries k, l) and Suzuki coupling
(entry m). The Stille coupling was successful only under
microwave irradiation (48% of 11l), but the coupled product
could not be isolated in analytically pure form. The Suzuki
coupling proceeded cleanly, resulting in the isolation of 63% of
11m. Increasing the reaction time did not lead to improved
conversion to 11m. An sp3 carbon was coupled to the pyrrole
core in 43% isolated yield using allyltributyltin under microwave
irradiation (entry o), whereas conventional heating yielded
exclusively starting material (entry n). Overall, the best results
were obtained using Stille cross-coupling methodology.
CONCLUSION
■
In summary, β-ketophosphonates were subjected to imination
and α-propargylation reactions, the latter being the most difficult
step. Subsequently, the obtained phosphonylated enamines were
transformed into the corresponding pyrroles through a ZnCl2-
catalyzed 5-exo-dig hydroamination which proceeded smoothly
for terminal alkynes. Nonterminal alkynes needed higher catalyst
loading and increased temperatures to effectively undergo
cyclization. Derivatization at the 4-position of the pyrrole via
direct lithiation was feasible but inefficient for larger electro-
philes. Electrophilic bromination with NBS proved efficient, but
subsequent lithium−bromine exchange did not facilitate further
derivatization. Instead, various cross-coupling strategies were
evaluated. High temperatures and microwave irradiation were
required in order to successfully couple the pyrrole core to sp,
sp2, and sp3 carbon atoms.
EXPERIMENTAL SECTION
■
Diethyl (Z)-(1-(Butylamino)-1-phenylpent-1-en-4-yn-2-yl)phos-
phonate (5c). 418 mg (1.34 mmol) of 2c/3c was converted into 5c.
After column chromatography, 224 mg of 5c was obtained (0.64 mmol,
48% yield, brown oil). 1H NMR (300 MHz, CDCl3) δ: 0.71 (3H, t, J =
7.2 Hz), 1.12−1.22 (2H, m), 1.25−1.30 (8H, m), 1.78 (1H, t, J = 2.8
Hz), 2.51 (2H, dd, 3JHP = 16.5 Hz, J = 2.8 Hz), 2.60 (2H, td, J = 6.6 Hz, J
= 6.1 Hz), 4.04 (4H, dq, 3JHP = 8.6 Hz, J = 7.2 Hz), 7.21−7.25 (2H, m),
7.29−7.36 (3H, m), 7.38 (1H, t, J = 6.1 Hz). 13C NMR (75 MHz,
CDCl3) δ: 13.7, 16.3 (d, 3JCP = 6.9 Hz), 18.3 (d, 2JCP = 10.4 Hz), 19.8,
33.0, 44.4, 61.1 (d, 2JCP = 4.6 Hz), 66.8, 79.2 (d, 1JCP = 188.1 Hz), 85.0,
128.2, 128.4, 128.6, 135.2 (d, 3JCP = 17.3 Hz), 165.3 (d, 2JCP = 12.7 Hz).
Commercially available products were used as received without any
purification unless otherwise noted. Column chromatography was
performed in a glass column with silica gel (particle size 70−200 μm,
pore diameter 60 Å) using mixtures of ethyl acetate (EtOAc) and
hexanes. Preparative TLC was executed with 2000 μm 20 × 20 cm TLC
plates. NMR spectra were recorded at 300 and 400 MHz (1H), 121 and
167 MHz (31P), 75 and 100 MHz (13C), and 376 MHz (19F) in CDCl3
unless otherwise noted. Low-resolution mass spectra were obtained with
a single quadrupole mass spectrometer (ESI, 70 eV). High-resolution
mass spectra were obtained with a time-of-flight (TOF) mass
spectrometer (ESI or APCI).
31P NMR (121 MHz, CDCl3) δ: 24.51 (m), 27.88 (M). IR (cm−1) νmax
:
Synthesis of Enamino- and Iminophosphonates 2/3a−g.
Diethyl (2-oxo-2-phenylethyl)phosphonates 1 were dissolved in toluene
1022 (P−O), 1052 (P−O), 1203 (PO), 1588, 1607, 2176, 2932,
4327
dx.doi.org/10.1021/jo500139z | J. Org. Chem. 2014, 79, 4322−4331

The Journal of Organic Chemistry
Article
3283. MS (ESI, pos) m/z: 350.3/351.3 (M + H+, 100/25). HRMS: m/z
calcd for C19H29NO3P (M + H)+ 350.1880, found 350.1878.
Chromatography: hexanes/EtOAc 8/2, Rf = 0.16.
Diethyl (Z)-(1-(Benzylamino)-5-(naphthalen-1-yl)-1-phenylpent-
1-en-4-yn-2-yl)phosphonate (5i). 0.70 g (2.03 mmol) of 2a/3a was
converted into 5i. After column chromatography, 0.39 g of 5i was
obtained (0.77 mmol, 38% yield, pale yellow oil). 1H NMR (400 MHz,
CDCl3) δ: 1.34 (6H, t, J = 7.1 Hz), 3.00 (2H, d, 3JHP = 16.4 Hz), 3.95
(2H, d, J = 6.4 Hz), 4.16 (4H, dq, 3JHP = 7.2 Hz, J = 7.1 Hz), 7.10−7.12
(2H, m), 7.17−7.20 (1H, m), 7.23−7.25 (1H, m), 7.32−7.37 (3H, m),
7.38−7.42 (4H, m), 7.49−7.53 (3H, m), 7.76 (1H, d, J = 8.3 Hz), 7.82−
7.84 (1H, m), 8.21−8.24 (1H, m), 8.36 (1H, t, J = 6.4 Hz). 13C NMR
(100 MHz, CDCl3) δ: 16.5 (d, 3JCP = 7.0 Hz), 19.8 (d, 2JCP = 9.7 Hz),
48.6, 61.5 (d, 2JCP = 4.4 Hz), 77.4, 82.2 (d, 1JCP = 186.1 Hz), 95.8 (d, 3JCP
= 1.6 Hz), 122.1, 125.4, 126.4, 126.5, 126.5, 130.0, 127.1, 127.9, 128.3,
128.5, 128.6, 128.6, 129.0, 129.8, 133.3, 133.7, 134.9 (d, 3JCP = 17.8 Hz),
140.2, 165.2 (d, 2JCP = 12.7 Hz). 31P NMR (162 MHz, CDCl3) δ: 23.88
(m), 26.96 (M). IR (cm−1) νmax: 1022 (P−O), 1049 (P−O), 1205 (P
O), 1588, 1606, 2231, 2924, 3273. MS (ESI, pos) m/z: 510.2/511.2 (M
+ H+, 100/30). HRMS: m/z calcd for C32H33NO3P (M + H)+ 510.2193,
found 510.2182. Chromatography: hexanes/EtOAc 8/2, Rf = 0.16.
Diethyl (Z)-(1-(Benzylamino)-1-phenyl-5-(trimethylsilyl)pent-1-
en-4-yn-2-yl)phosphonate (5j). 0.70 g (2.03 mmol) of 2a/3a was
converted into 5j. After column chromatography, 0.42 g of 5j was
obtained (0.91 mmol, 45% yield, yellow oil). However, 5j and its bis-
propargylated product constitute a chromatographically inseparable
mixture. As a consequence, 20% of bis-propargylated product is present
Diethyl (Z)-(1-Phenyl-1-(phenylamino)pent-1-en-4-yn-2-yl)phos-
phonate (5d). 495 mg (1.50 mmol) of 2d/3d was converted into 5d.
After column chromatography, 172 mg of 5d was obtained (0.47 mmol,
31% yield, yellow oil). 1H NMR (300 MHz, CDCl3) δ: 1.37 (6H, td, J =
7.2 Hz, 4JHP = 1.1 Hz), 2.01 (1H, t, J = 2.8 Hz), 2.85 (2H, dd, 3JHP = 16.5
Hz, J = 2.8 Hz), 4.18 (4H, dq, 3JHP = 8.3 Hz, J = 7.2 Hz), 6.51 (2H, d, J =
8.3 Hz), 6.64 (1H, d, J = 8.8 Hz), 6.73−6.79 (1H, m), 6.96 (2H, dd, J =
7.2 Hz), 7.30−7.33 (2H, m), 7.42−7.45 (2H, m), 9.82 (1H, br s). 13C
NMR (75 MHz, CDCl3) δ: 16.4 (d, 3JCP = 6.9 Hz), 18.8 (d, 2JCP = 8.1
Hz), 61.8 (d, 2JCP = 4.6 Hz), 68.1, 84.5, 88.7 (d, 1JCP = 182.3 Hz), 121.2,
121.9, 128.9, 129.2, 129.5, 134.9 (d, 3JCP = 17.3 Hz), 141.5, 159.0 (d, 2JCP
= 10.4 Hz). 31P NMR (121 MHz, CDCl3) δ: 23.57 (m), 25.65 (M). IR
(cm−1) νmax: 1020 (P−O), 1049 (P−O), 1242 (PO), 1496, 1576,
1595, 2116, 2980, 3283. MS (ESI, pos) m/z: 370.3/371.3 (M + H+, 100/
23). HRMS: m/z calcd for C21H25NO3P (M + H)+ 370.1567, found
370.1566. Chromatography: hexanes/EtOAc 8/2, Rf = 0.22.
Diethyl (Z)-(1-(Benzylamino)-1-(4-fluorophenyl)pent-1-en-4-yn-
2-yl)phosphonate (5e). 1.12 g (3.08 mmol) of 2e/3e was converted
into 5e. After column chromatography, 0.46 g of 5e was obtained (1.14
mmol, 37% yield, yellow oil). 1H NMR (400 MHz, CDCl3) δ: 1.36 (6H,
td, J = 7.1 Hz, 4JHP = 0.4 Hz), 1.85 (1H, t, J = 2.6 Hz), 2.61 (2H, dd, 3JHP
= 16.4 Hz, J = 2.6 Hz), 3.91 (2H, d, J = 6.6 Hz), 4.06−4.15 (4H, m),
7.04−7.09 (4H, m), 7.19−7.26 (5H, m), 8.32 (1H, t, J = 6.6 Hz). 13C
NMR (100 MHz, CDCl3) δ: 16.3 (d, 3JCP = 7.0 Hz), 18.4 (d, 2JCP = 9.5
Hz), 48.4, 61.3 (d, 2JCP = 4.4 Hz), 67.2, 82.7 (d, 1JCP = 186.2 Hz), 84.5
(d, 3JCP = 1.5 Hz), 115.5 (d, 2JCF = 21.7 Hz), 126.9, 126.9, 128.4, 130.4
(d, 3JCF = 8.1 Hz), 130.6 (dd, 3JCP2 = 18.1 Hz, 4JCF = 3.2 Hz), 139.9, 162.8
(d, 1JCF = 248.3 Hz), 163.9 (d, JCP = 12.9 Hz). 19F NMR (376 MHz,
CDCl3) δ: −114.48 to −114.41 (multiplet, m), −112.06 to −111.99
(multiplet, M). 31P NMR (162 MHz, CDCl3) δ: 23.45 (m), 26.23 (M).
IR (cm−1) νmax: 1022 (P−O), 1050 (P−O), 1205 (PO), 1589, 1607,
2113, 2981, 3283. MS (ESI, pos) m/z: 402.1/403.1 (M + H+, 100/23).
HRMS: m/z calcd for C22H26FNO3P (M + H)+ 402.1629, found
402.1628. Chromatography: hexanes/EtOAc 7/3, Rf = 0.29.
1
(31P NMR (162 MHz, CDCl3) δ: 25.61 ppm). H NMR (400 MHz,
CDCl3) δ: 0.10 (9H, s), 1.36 (6H, td, J = 7.1 Hz, 4JHP = 0.3 Hz), 2.63
(2H, d, J = 16.3 Hz), 3.91 (2H, d, J = 6.5 Hz), 4.11 (4H, dq, 3JHP = 7.4
Hz, J = 7.1 Hz), 7.09−7.11 (2H, m), 7.19−7.30 (4H, m), 7.33−7.38
(4H, m), 8.28 (1H, t, J = 6.5 Hz). 13C NMR (100 MHz, CDCl3) δ: 0.1,
16.4 (d, 3JCP = 7.2 Hz), 19.7 (d, 2JCP = 9.7 Hz), 48.5, 61.2 (d, 2JCP = 4.2
Hz), 82.0 (d, 1JCP = 185.7 Hz), 82.7, 87.1 (d, 3JCP = 1.3 Hz), 126.8, 127.0,
127.6, 128.1, 128.3, 128.3, 128.6, 128.8, 134.7 (d, 3JCP = 17.7 Hz), 140.1,
165.1 (d, 2JCP = 12.7 Hz). 31P NMR (162 MHz, CDCl3) δ: 23.74 (m),
26.83 (M). IR (cm−1) νmax: 1024 (P−O), 1051 (P−O), 1248 (PO),
1590, 1607, 2172, 2959, 3267. MS (ESI, pos) m/z: 456.2/457.2 (M +
H+, 100/30). HRMS: m/z calcd for C25H35NO3PSi (M + H)+ 456.2118,
found 456.2121. Chromatography: hexanes/EtOAc 7/3, Rf = 0.19.
Synthesis of Pyrroles 6a−g. Propargylic enaminophosphonates
5a−g were dissolved in CH3CN (0.5 mmol/mL) in a round-bottom
flask, and 5 mol % of ZnCl2 was added. The reaction progress was
monitored using HPLC. When all starting material had been consumed,
the reaction mixture was filtered over a plug of silica (ca. 5 cm) to
remove the catalyst. If necessary, column chromatography was
performed.
Synthesis of Pyrroles 6h−i. Propargylic enaminophosphonates
5h−i were dissolved in dry CH3CN (0.5 mmol/mL) in a round-bottom
flask, and 20 mol % of dried ZnCl2 (2 h at 60 °C under a 1 mbar vacuum)
was added. The mixture was then heated to reflux temperature. The
reaction progress was monitored using HPLC. When all starting
material had been consumed, the reaction mixture was filtered over a
plug of silica (ca. 5 cm) to remove the catalyst. If necessary, column
chromatography was performed.
Diethyl (Z)-(1-(Benzylamino)-1-(4-methoxyphenyl)pent-1-en-4-
yn-2-yl)phosphonate (5f). 1.0 g (2.67 mmol) of 2f/3f was converted
into 5f. After column chromatography, 0.47 g of 5f was obtained (1.14
mmol, 43% yield, yellow oil). 1H NMR (400 MHz, CDCl3) δ: 1.35 (6H,
td, J = 7.1 Hz, 4JHP = 0.4 Hz), 1.86 (1H, t, J = 2.6 Hz), 2.66 (2H, dd, 3JHP
= 16.5 Hz, J = 2.6 Hz), 3.84 (3H, s), 3.93 (2H, d, J = 6.5 Hz), 4.10 (4H,
dq, 3JHP = 9.4 Hz, J = 7.2 Hz), 6.83−6.92 (2H, m), 7.09−7.25 (7H, m),
8.26 (1H, t, J = 6.5 Hz). 13C NMR (100 MHz, CDCl3) δ: 16.3 (d, 3JCP
=
7.1 Hz), 18.6 (d, 2JCP = 9.2 Hz), 48.5, 55.1, 61.1 (d, 2JCP = 4.3 Hz), 67.1,
82.1 (d, 1JCP = 185.6 Hz), 84.9 (d, 3JCP = 1.2 Hz), 113.8, 126.8, 126.8 (d,
3JCP = 17.7 Hz), 127.0, 128.3, 129.8, 140.1, 159.9, 164.9 (d, 2JCP = 12.8
Hz). 31P NMR (162 MHz, CDCl3) δ: 23.91 (m), 26.82 (M). IR (cm−1)
νmax: 1022 (P−O), 1050 (P−O), 1248 (PO), 1592, 1610, 1712, 2116,
2980, 3287. MS (ESI, pos) m/z: 414.2/415.2 (M + H+, 100/23).
HRMS: m/z calcd for C23H29NO4P (M + H)+ 414.1829, found
414.1842. Chromatography: hexanes/EtOAc 7/3, Rf = 0.21.
Diethyl (1-Benzyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)phosphonate
(6a). 51 mg (0.13 mmol) of 5a was converted into 50 mg of 6a (0.13
mmol, 99% yield, yellow oil). 1H NMR (300 MHz, CDCl3) δ: 1.12 (6H,
t, J = 6.9 Hz), 2.11 (3H, s), 3.81−4.03 (4H, m), 4.96 (2H, s), 6.40 (1H, d,
3JHP = 4.4 Hz), 6.83−6.85 (2H, m), 7.19−7.37 (8H, m). 13C NMR (75
Diethyl (Z)-(1-(Benzylamino)-1-phenylhex-1-en-4-yn-2-yl)phos-
phonate (5h). 0.70 g (2.03 mmol) of 2a/3a was converted into 5h.
After column chromatography, 0.37 g of 5h was obtained (0.93 mmol,
46% yield, yellow oil). 1H NMR (400 MHz, CDCl3) δ: 1.36 (6H, td, J =
7.1 Hz, 4JHP = 0.4 Hz), 1.70 (3H, t, J = 2.5 Hz), 2.56 (2H, dq, 3JHP = 16.8
Hz, J = 2.5 Hz), 3.90 (2H, d, J = 6.5 Hz), 4.10 (4H, dq, 3JHP = 10.2 Hz, J =
7.1 Hz), 7.08−7.11 (2H, m), 7.19−7.25 (4H, m), 7.34−7.38 (4H, m),
8.25 (1H, t, J = 6.5 Hz). 13C NMR (100 MHz, CDCl3) δ: 3.6, 16.3 (d,
3JCP = 7.1 Hz), 18.6 (d, 2JCP = 9.5 Hz), 48.5, 61.2 (d, 2JCP = 4.3 Hz), 73.9,
MHz, CDCl3) δ: 12.5, 16.2 (d, 3JCP = 6.9 Hz), 47.9, 61.4 (d, 2JCP = 5.8
Hz), 106.5 (d, 1JCP = 218.1 Hz), 111.7 (d, 2JCP = 11.5 Hz), 125.7, 127.3,
128.0, 128.4, 128.8, 130.0 (d, 3JCP = 15.0 Hz), 130.8, 131.9, 137.9, 139.3
(d, 2JCP = 23.1 Hz). 31P NMR (121 MHz, CDCl3) δ: 18.89. IR (cm−1)
νmax: 1024 (P−O), 1053 (P−O), 1227 (PO), 1400, 1454, 2979. MS
(ESI, pos) m/z: 384.3/385.3 (M + H+, 100/15). HRMS: m/z calcd for
C22H27NO3P (M + H)+ 384.1723, found 384.1719.
79.4 (d, 3JCP = 1.9 Hz), 82.9 (d, 1JCP = 184.3 Hz), 126.8, 127.0, 128.3,
128.5, 128.7, 134.9 (d, 3JCP = 17.9 Hz), 140.1, 164.6 (d, 2JCP = 12.9 Hz).
Diethyl (1-Allyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)phosphonate
(6b). 80 mg (0.24 mmol) of 5b was converted into 71 mg of 6b (0.21
mmol, 89% yield, yellow oil). 1H NMR (300 MHz, CDCl3) δ: 1.10 (6H,
t, J = 7.2 Hz), 2.23 (3H, s), 3.79−4.01 (4H, m), 4.29 (2H, m), 4.76 (1H,
d, JE = 16.8 Hz), 5.15 (1H, d, JZ = 10.6 Hz), 5.80 (1H, ddt, JE = 16.8 Hz,
31P NMR (162 MHz, CDCl3) δ: 24.27 (m), 27.17 (M). IR (cm−1) νmax
:
1022 (P−O), 1051 (P−O), 1204 (PO), 1590, 1606, 2238, 2918,
3266. MS (ESI, pos) m/z: 398.2/399.2 (M + H+, 100/23). HRMS: m/z
calcd for C23H29NO3P (M + H)+ 398.1880, found 398.1887.
Chromatography: hexanes/EtOAc 8/2, Rf = 0.29.
JZ = 10.6 Hz, J = 4.5 Hz), 6.36 (1H, d, 3JHP = 4.4 Hz), 7.38 (5H, s). 13
C
4328
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Article
NMR (75 MHz, CDCl3) δ: 12.2, 16.2 (d, 3JCP = 6.9 Hz), 46.7, 61.5 (d,
127.4, 128.9, 129.1 (d, 3JCP = 15.3 Hz), 136.3 (d, 2JCP = 24.2 Hz), 137.0.
31P NMR (162 MHz, CDCl3) δ: 19.77. IR (cm−1) νmax: 1025 (P−O),
1
2
2JCP = 5.8 Hz), 105.8 (d, JCP = 219.2 Hz), 111.3 (d, JCP = 11.5 Hz),
116.3, 127.9, 128.5, 129.9 (d, 3JCP = 16.1 Hz), 130.7, 131.9, 133.9, 138.9
(d, 2JCP = 24.2 Hz). 31P NMR (121 MHz, CDCl3) δ: 18.99. IR (cm−1)
νmax: 1024 (P−O), 1054 (P−O), 1235 (PO), 1399, 1475, 2979. MS
(ESI, pos) m/z: 334.3/335.3 (M + H+, 100/17). HRMS: m/z calcd for
C18H25NO3P (M + H)+ 334.1567, found 334.1566.
1076 (P−O), 1230 (PO), 1410, 1519, 2980. MS (ESI, pos) m/z:
322.1/323.1 (M + H+, 100/15). HRMS: m/z calcd for C17H25NO3P (M
+ H)+ 322.1567, found 322.1575. Preparative TLC: EtOAc, Rf = 0.47.
Diethyl (1-Benzyl-5-ethyl-2-phenyl-1H-pyrrol-3-yl)phosphonate
(6h). 140 mg (0.35 mmol) of 5h was converted into 6h. After
preparative TLC, 63 mg of 6h was obtained (0.16 mmol, 46% yield,
yellow oil). 1H NMR (400 MHz, CDCl3) δ: 1.11 (6H, td, J = 7.1 Hz, 4JHP
= 0.4 Hz), 1.22 (3H, t, J = 7.5 Hz), 2.40 (2H, q, J = 7.5 Hz), 3.82−4.01
(4H, m), 4.96 (2H, s), 6.44 (1H, dt, 3JHP = 4.7 Hz, J = 1.0 Hz), 6.83 (2H,
d, J = 8.0 Hz), 7.22−7.27 (4H, m), 7.29−7.33 (4H, m). 13C NMR (100
Diethyl (1-Butyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)phosphonate
(6c). 100 mg (0.29 mmol) of 5c was converted into 95 mg of 6c
(0.27 mmol, 94% yield, yellow oil). 1H NMR (300 MHz, CDCl3) δ: 0.74
(3H, t, J = 7.6 Hz), 1.07−1.16 (8H, m), 1.45 (2H, quint, J = 7.6 Hz), 2.27
(3H, s), 3.69 (2H, t, J = 7.6 Hz), 3.78−4.01 (4H, m), 6.32 (1H, d, 3JHP
=
3.9 Hz), 7.38 (5H, s). 13C NMR (75 MHz, CDCl3) δ: 12.5, 13.5, 16.1 (d,
MHz, CDCl3) δ: 12.0, 16.1 (d, 3JCP = 7.1 Hz), 19.7, 47.7, 61.3 (d, 2JCP
=
3JCP = 6.9 Hz), 19.8, 32.9, 44.2, 61.5 (d, 2JCP = 4.6 Hz), 105.4 (d, 1JCP
=
1
2
5.3 Hz), 106.3 (d, JCP = 218.1 Hz), 109.7 (d, JCP = 12.3 Hz), 125.6,
218.1 Hz), 111.3 (d, 2JCP = 12.7 Hz), 128.0, 128.3, 129.3 (d, 3JCP = 16.2
127.2, 127.9, 128.4, 128.7, 130.8, 131.7, 136.1 (d, 3JCP = 15.0 Hz), 137.9,
Hz), 130.9, 132.3, 138.7 (d, JCP = 24.2 Hz). 31P NMR (121 MHz,
139.1 (d, JCP = 23.2 Hz). 31P NMR (162 MHz, CDCl3) δ: 18.53. IR
2
2
CDCl3) δ: 19.21. IR (cm−1) νmax: 1024 (P−O), 1054 (P−O), 1227 (P
O), 1400, 1475, 2931, 2959. MS (ESI, pos) m/z: 350.3/351.3 (M + H+,
100/13). HRMS: m/z calcd for C19H29NO3P (M + H)+ 350.1880,
found 350.1885.
(cm−1) νmax: 1023 (P−O), 1053 (P−O), 1229 (PO), 1390, 2976. MS
(ESI, pos) m/z: 398.2/399.2 (M + H+, 100/25). HRMS: m/z calcd for
C23H29NO3P (M + H)+ 398.1880, found 398.1884. Preparative TLC:
EtOAc, Rf = 0.55.
Diethyl (5-Methyl-1,2-diphenyl-1H-pyrrol-3-yl)phosphonate (6d).
75 mg (0.20 mmol) of 5d was converted into 68 mg of 6d (0.18 mmol,
91% yield, yellow oil). 1H NMR (300 MHz, CDCl3) δ: 1.12 (6H, t, J =
6.9 Hz), 2.10 (3H, s), 3.84−4.06 (4H, m), 6.44 (1H, d, 3JHP = 4.4 Hz),
7.03−7.06 (2H, m), 7.14−7.23 (5H, m), 7.27−7.31 (3H, m). 13C NMR
(75 MHz, CDCl3) δ: 13.1, 16.2 (d, 3JCP = 6.9 Hz), 61.5 (d, 2JCP = 5.8
Hz), 106.9 (d, 1JCP = 218.1 Hz), 111.7 (d, 2JCP = 11.5 Hz), 127.5, 127.5,
128.0, 128.5, 129.0, 130.9, 131.2, 131.8, 138.1, 139.0 (d, 2JCP = 24.2 Hz).
31P NMR (121 MHz, CDCl3) δ: 18.81. IR (cm−1) νmax: 1023 (P−O),
Diethyl (1-Benzyl-5-(naphthalen-1-ylmethyl)-2-phenyl-1H-pyrrol-
3-yl)phosphonate (6i). 0.30 g (0.59 mmol) of 5i was converted into 6i.
After column chromatography, 0.11 g of 6i was obtained (0.22 mmol,
37% yield, yellow oil). 1H NMR (400 MHz, CDCl3) δ: 1.06 (6H, t, J =
6.8 Hz), 3.78−3.96 (4H, m), 4.16 (2H, s), 4.98 (2H, s), 6.17 (1H, d, 3JHP
= 4.5 Hz), 6.87 (2H, d, J = 7.4 Hz), 7.17 (1H, d, J = 7.0 Hz), 7.25−7.47
(11H, m), 7.69 (1H, d, J = 8.4 Hz), 7.75 (1H, d, J = 8.2 Hz), 7.84 (1H, d,
J = 8.1 Hz). 13C NMR (100 MHz, CDCl3) δ: 16.1 (d, 3JCP = 7.0 Hz),
30.3, 48.1, 61.3 (d, 2JCP = 5.4 Hz), 106.9 (d, 1JCP = 218.2 Hz), 113.3 (d,
2JCP = 12.3 Hz), 123.8, 125.6, 125.7, 125.8, 126.0, 126.7, 127.5, 128.0,
1053 (P−O), 1238 (PO), 1391, 1496, 2979. MS (ESI, pos) m/z:
370.1/371.2 (M + H+, 100/18). HRMS: m/z calcd for C21H25NO3P (M
+ H)+ 370.1567, found 370.1570.
128.5, 128.7, 128.8, 130.8, 131.6, 132.0, 132.3 (d, 3JCP = 15.4 Hz), 133.9,
134.1, 137.8, 139.9 (d, 2JCP = 23.4 Hz). 31P NMR (162 MHz, CDCl3) δ:
18.06. IR (cm−1) νmax: 1027 (P−O), 1055 (P−O), 1236 (PO), 1453,
2928. MS (ESI, pos) m/z: 510.2/511.3 (M + H+, 100/35). HRMS: m/z
calcd for C32H33NO3P (M + H)+ 510.2193, found 510.2215.
Chromatography: hexanes/EtOAc 1/1, Rf = 0.41.
Synthesis of Pyrrole 8. In a round-bottom flask, pyrrole 6c was
dissolved in a 2/1 1,4-dioxane/acetic acid mixture (0.5 mmol/mL). N-
Bromosuccinimide (NBS, 1.05 equiv) was added, and the reaction
mixture was stirred for 30 min at 20 °C. The reaction mixture was
poured into a 2 N NaOH solution (10 mL) and extracted with diethyl
ether (3 × 10 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo.
Diethyl (1-Benzyl-2-(4-fluorophenyl)-5-methyl-1H-pyrrol-3-yl)-
phosphonate (6e). 100 mg (0.25 mmol) of 5e was converted into 97
1
mg of 6e (0.24 mmol, 97% yield, yellow oil). H NMR (400 MHz,
CDCl3) δ: 1.15 (6H, t, J = 7.1 Hz), 2.12 (3H, s), 3.87−3.98 (4H, m),
4.92 (2H, s), 6.39 (1H, d, 3JHP = 3.7 Hz), 6.81−6.83 (2H, m), 6.79−7.02
(2H, m), 7.21−7.30 (5H, m). 13C NMR (100 MHz, CDCl3) δ: 12.4,
16.2 (d, 3JCP = 6.9 Hz), 47.8, 61.4, 106.7 (d, 1JCP = 209.0 Hz), 111.5 (d,
2JCP = 12.0 Hz), 114.9 (d, 2JCF = 21.5 Hz), 125.5, 127.3, 127.7 (d, 4JCF
=
3
3
3.44 Hz), 128.8, 130.1 (d, JCP = 15.5 Hz), 132.6 (d, JCF = 8.5 Hz),
137.6, 138.1 (d, 2JCP = 23.4 Hz), 162.8 (d, 1JCF = 248.1 Hz). 19F NMR
(376 MHz, CDCl3) δ: −113.01. 31P NMR (162 MHz, CDCl3) δ: 17.92.
IR (cm−1) νmax: 1025 (P−O), 1053 (P−O), 1223 (PO), 1392, 1480,
1529, 2981. MS (ESI, pos) m/z: 402.2/403.2 (M + H+, 100/25).
HRMS: m/z calcd for C22H26FNO3P (M + H)+ 402.1629, found
402.1635.
Diethyl (4-Bromo-1-butyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)-
phosphonate (8). 100 mg (0.29 mmol) of 6c was converted into 99
1
mg of 8 (0.27 mmol, 92% yield, yellow oil). H NMR (400 MHz,
CDCl3) δ: 0.74 (3H, t, J = 7.3 Hz), 1.06−1.15 (8H, m), 1.39−1.46 (2H,
m), 2.28 (3H, d, 5JHP = 0.4 Hz), 3.60−3.64 (2H, m), 3.78−3.87 (2H, m),
3.92−4.01 (2H, m), 7.30−7.33 (2H, m), 7.38−7.41 (3H, m). 13C NMR
(100 MHz, CDCl3) δ: 11.1, 13.4, 16.1 (d, 3JCP = 7.0 Hz), 19.7, 32.7, 45.0,
61.4 (d, 2JCP = 5.6 Hz), 97.9 (d, 2JCP = 8.4 Hz), 106.3 (d, 1JCP = 223.1
Hz), 127.9, 128.2 (d, 3JCP = 12.6 Hz), 128.6, 131.1, 131.9, 139.7 (d, 2JCP
= 21.0 Hz). 31P NMR (162 MHz, CDCl3) δ: 14.12. IR (cm−1) νmax: 1024
(P−O), 1057 (P−O), 1243 (PO), 1391, 1469, 2960. MS (ESI, pos)
m/z: 428.1/430.1 (M + H+, 98/100). HRMS: m/z calcd for
C19H28BrNO3P (M + H)+ 428.0985, found 428.0991.
Synthesis of Pyrrole 9a. In a round-bottom flask, pyrrole 6c was
dissolved in dry THF (0.5 mmol/mL) under an inert N2 atmosphere
and cooled to −78 °C. A solution of s-BuLi (1.2 equiv) was added in a
dropwise fashion and the reaction mixture kept at −78 °C for 1 h. Next,
an excess of D2O was added, and the mixture was allowed to warm to
room temperature after which it was extracted with diethyl ether (3 × 10
mL). The combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. The crude residue was purified using preparative
TLC.
Diethyl (1-Benzyl-2-(4-methoxyphenyl)-5-methyl-1H-pyrrol-3-yl)-
phosphonate (6f). 98 mg (0.24 mmol) of 5f was converted into 6f. After
preparative TLC, 71 mg of 6f was obtained (0.17 mmol, 72% yield,
yellow oil). 1H NMR (400 MHz, CDCl3) δ: 1.15 (6H, td, J = 7.1 Hz, 4JHP
= 0.4 Hz), 2.10 (3H, s), 3.79 (3H, s), 3.83−4.02 (4H, m), 4.94 (2H, s),
6.37 (1H, dd, 3JHP = 4.5 Hz, J = 0.9 Hz), 6.82−6.85 (4H, m), 7.21−7.28
(5H, m). 13C NMR (100 MHz, CDCl3) δ: 12.4, 16.2 (d, 3JCP = 7.2 Hz),
47.7, 55.2, 61.3 (d, 2JCP = 5.3 Hz), 106.1 (d, 1JCP = 218.0 Hz), 111.4 (d,
2JCP = 11.9 Hz), 113.3, 123.9, 125.6, 127.2, 128.7, 129.7 (d, 3JCP = 15.5
Hz), 131.9, 137.9, 139.2 (d, 2JCP = 23.5 Hz), 159.6. 31P NMR (162 MHz,
CDCl3) δ: 18.45. IR (cm−1) νmax: 1025 (P−O), 1053 (P−O), 1245 (P
O), 1395, 1481, 1531, 2979. MS (ESI, pos) m/z: 414.2/415.2 (M + H+,
100/25). HRMS: m/z calcd for C23H29NO4P (M + H)+ 414.1829,
found 414.1838. Preparative TLC: EtOAc, Rf = 0.50.
Diethyl (1-Benzyl-2,5-dimethyl-1H-pyrrol-3-yl)phosphonate (6g).
100 mg of crude 5g was converted into 6g. After preparative TLC, 10 mg
of 6g was obtained (0.03 mmol, 10% yield over two steps, yellow oil). 1H
NMR (400 MHz, CDCl3) δ: 1.32 (6H, td, J = 7.1 Hz, 4JHP = 0.4 Hz),
2.11 (3H, br s), 2.37 (3H, d, 3JHP = 1.8 Hz), 3.99−4.16 (4H, m), 5.03
(2H, s), 6.14 (1H, dq, 3JHP = 4.2 Hz, J = 1.0 Hz), 6.86−6.88 (2H, m),
7.25−7.33 (3H, m). 13C NMR (100 MHz, CDCl3) δ: 11.6, 12.2 (d, 3JCP
Diethyl (1-Butyl-5-methyl-2-phenyl-1H-pyrrol-3-yl-4-d)phos-
phonate (9a). 127 mg (0.36 mmol) of 6c was converted into 9a.
After preparative TLC, 72 mg of 9a was obtained (0.21 mmol, 57% yield,
1
= 1.0 Hz), 16.4 (d, 3JCP = 6.8 Hz), 47.0 (d, 4JCP = 1.5 Hz), 61.3 (d, 2JCP
=
yellow oil). H NMR (400 MHz, CDCl3) δ: 0.75 (3H, t, J = 7.4 Hz),
2
5.0 Hz), 103.6 (d, 1JCP = 216.9 Hz), 109.6 (d, JCP = 11.9 Hz), 125.6,
1.07−1.16 (8H, m), 1.41−1.49 (2H, m), 2.27 (3H, s), 3.67 (1H, d, J =
4329
dx.doi.org/10.1021/jo500139z | J. Org. Chem. 2014, 79, 4322−4331

The Journal of Organic Chemistry
Article
7.8 Hz), 3.69 (1H, d, J = 7.8 Hz), 3.78−3.97 (4H, m), 7.36−7.40 (5H,
m). 13C NMR (100 MHz, CDCl3) δ: 12.4 (d, 4JCP = 1.1 Hz), 13.5, 16.0
(d, 3JCP = 7.2 Hz), 19.7, 32.8, 44.1, 61.2 (d, 2JCP = 5.5 Hz), 105.6 (d, 1JCP
= 218.6 Hz), 110.9 (td, 1JDC = 25.2 Hz, 2JCP = 13.3 Hz), 127.9, 128.2,
d, J = 6.2 Hz), 3.57−3.61 (2H, m), 3.72−3.79 (2H, m), 3.86−3.92 (2H,
m), 4.95 (1H, ddd, JZ = 10.1 Hz, J = 3.5 Hz, J = 1.6 Hz), 5.00 (1H, ddd, JE
= 17.0 Hz, J = 3.8 Hz, J = 1.6 Hz), 5.99 (1H, ddt, JE = 17.0 Hz, JZ = 10.1
Hz, J = 6.2 Hz), 7.31−7.34 (2H, m), 7.36−7.39 (3H, m). 13C NMR (100
MHz, CDCl3) δ: 10.1 (d, 4JCP 1.5 Hz), 13.5, 16.1 (d, 3JCP = 7.2 Hz), 19.8,
29.9, 32.9, 44.1, 60.8 (d, 2JCP = 5.4 Hz), 104.7 (d, 1JCP = 215.9 Hz), 113.5,
120.3 (d, 2JCP = 13.5 Hz), 126.9 (d, 3JCP = 16.1 Hz), 127.6, 128.1, 131.2,
132.9, 138.4, 138.4 (d, 2JCP = 23.0 Hz). 31P NMR (162 MHz, CDCl3) δ:
18.23. IR (cm−1) νmax: 1028 (P−O), 1056 (P−O), 1225 (PO), 1246,
1395, 1466, 2929. MS (ESI, pos) m/z: 390.2/391.2 (M + H+, 100/22).
HRMS: m/z calcd for C22H33NO3P (M + H)+ 390.2193, found
390.2205.
129.1 (d, 3JCP = 15.7 Hz), 130.9, 132.3, 138.5 (d, 2JCP = 23.3 Hz). 31
P
NMR (162 MHz, CDCl3) δ: 18.45. IR (cm−1) νmax: 1026 (P−O), 1055
(P−O), 1229 (PO), 1392, 1474, 2960. MS (ESI, pos) m/z: 351.3/
352.3 (M + H+, 100/15). HRMS: m/z calcd for C19H28DNO3P (M +
H)+ 351.1942, found 351.1946. Preparative TLC: EtOAc, Rf = 0.41.
Synthesis of Pyrrole 9b. In a round-bottom flask, pyrrole 6c was
dissolved in dry THF (1 mmol/mL) under an inert N2-atmosphere and
cooled to −78 °C. A solution of s-BuLi (1.2 equiv) was added in a
dropwise fashion and the reaction mixture kept at −78 °C for 1 h. Next,
iodomethane (1.1 equiv) was added, and the mixture was allowed to
warm to room temperature after which it was extracted with diethyl
ether (3 × 10 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified
using column chromatography.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, 31P NMR spectra and LC traces of new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Diethyl (1-Butyl-4,5-dimethyl-2-phenyl-1H-pyrrol-3-yl)phos-
phonate (9b). 0.86 g (2.45 mmol) of 6c was converted into 9b. After
column chromatography, 0.23 g of 9b was obtained (0.64 mmol, 26%
yield, yellow oil). 1H NMR (400 MHz, CDCl3) δ: 0.74 (3H, t, J = 7.3
Hz), 1.07−1.13 (8H, m), 1.38−1.46 (2H, m), 2.18 (3H, s), 2.22 (3H, s),
3.57 (1H, d, J = 7.9 Hz), 3.59 (1H, d, J = 7.9 Hz), 3.72−3.82 (2H, m),
3.86−3.95 (2H, m), 7.31−7.38 (5H, m). 13C NMR (100 MHz, CDCl3)
δ: 9.9 (d, 3JCP = 1.4 Hz), 10.8, 13.0, 16.0 (d, 3JCP = 7.1 Hz), 19.7, 32.9,
AUTHOR INFORMATION
Corresponding Author
*E-mail: chris.stevens@ugent.be.
■
Notes
The authors declare no competing financial interest.
44.0, 60.7 (d, 2JCP = 5.3 Hz), 105.1 (d, 1JCP = 215.2 Hz), 117.9 (d, 2JCP
13.0 Hz), 126.0 (d, 3JCP = 16.1 Hz), 127.6, 128.0, 131.1, 132.8, 138.4 (d,
2JCP = 23.6 Hz). 31P NMR (162 MHz, CDCl3) δ: 18.56. IR (cm−1) νmax
=
ACKNOWLEDGMENTS
We thank the Research Foundation Flanders (FWO) for
financial support for pre- and postdoctoral mandates.
■
:
1026 (P−O), 1056 (P−O), 1230 (PO), 1246, 1393, 2930. MS (ESI,
pos) m/z: 364.2/365.2 (M + H+, 100/22). HRMS: m/z calcd for
C20H31NO3P (M + H)+ 364.2036, found 364.2047. Chromatography:
EtOAc/hexanes 3/2, Rf = 0.15.
Synthesis of Pyrrole 11m. In a 10 mL Pyrex microwave vial
equipped with a “snap-cap” and magnetic stirrer, pyrrole 8 was dissolved
in a 3/1 DME/H2O mixture. PhB(OH)2 (1.3 equiv) was added, along
with Na2CO3 (2 equiv) and Pd(PPh3)4 (5 mol %). The vial was inserted
into the microwave, and the reaction was performed at 130 °C during 1
h. Afterward, the reaction mixture was poured into water (10 mL) and
extracted with diethyl ether (3 × 10 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was purified using preparative TLC.
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