A general route to 1,3′-bipyrroles

Article abstract of DOI:10.1021/jo401892t

A general method is described for the synthesis of 1,3′-bipyrroles. The route involves constructing a pyrrole ring on the nitrogen of a substituted 1H-pyrrole, so as to generate the 1,3′-bipyrrole. In this approach the nitrogen of the starting pyrrole was alkylated with a special Michael acceptor having an allylic leaving group, and the product was then modified in such a way that the second pyrrole ring could be formed by a Paal-Knorr reaction. Two variants of this sequence were examined, one of which led to formation of a 3-hydroxypyridine instead of the second pyrrole ring; the other variant used phenacyl bromide instead of the special Michael acceptor.

Full text of DOI:10.1021/jo401892t

Article
pubs.acs.org/joc
A General Route to 1,3′-Bipyrroles
Ping Cheng, Wenjie Shao, and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
S
* Supporting Information
ABSTRACT: A general method is described for the synthesis of
1,3′-bipyrroles. The route involves constructing a pyrrole ring on
the nitrogen of a substituted 1H-pyrrole, so as to generate the 1,3′-
bipyrrole. In this approach the nitrogen of the starting pyrrole was
alkylated with a special Michael acceptor having an allylic leaving
group, and the product was then modified in such a way that the
second pyrrole ring could be formed by a Paal−Knorr reaction. Two
variants of this sequence were examined, one of which led to
formation of a 3-hydroxypyridine instead of the second pyrrole ring; the other variant used phenacyl bromide instead of the
special Michael acceptor.
required for the metal-mediated reaction; unfortunately, such
polyhalo substitution is the conspicuous feature of the
marinopyrroles. A number of 1,3′-bipyrroles, lightly substituted
in both pyrrole rings (3-OR, 4-CN, 4′-CN or 3-OR, 4-CO2R,
4′-CO2R), have been made10 by reaction of p-toluenesulfo-
nylmethyl isocyanide (TOSMIC) with α,β-unsubstituted
ketones and esters.
INTRODUCTION
■
The discovery of marinopyrroles A (1) and B (2)1 and the
observation that they show strong activity against methicillin-
resistant bacteria1−3 have served to identify the 1,3′-bipyrrole
system as a potentially important structural type in medicinal
chemistry. Prior to the isolation of these compounds and the
recognition of their antibacterial properties, few methods had
been reported for the synthesis of 1,3′-bipyrroles, and the
methods available proved to be inappropriate4 for the synthesis
of marinopyrrole B, although they were adequate for the less
highly halogenated marinopyrrole A.2,4,5
Recently, a synthesis of marinopyrrole B was developed in
this laboratory (Scheme 1),11 which was based on the use of a
Scheme 1. Principle of the Method Used for Synthesis of
Marinopyrrole B
One of the established routes to 1,3′-bipyrroles is based on
the standard Clauson−Kaas reaction with a 3-aminopyrrole4c,6
This procedure appears to have been used only where the
newly generated pyrrole is unsubstituted. A variant of the Paal−
Knorr reaction that uses a keto-ketal instead of a diketone has
likewise been applied to 3-aminopyrroles.4a,b Again, the pyrrole
unit that is formed has been unsubstituted. The classical Paal−
Knorr reaction7 itself has been used with 3-aminopyrroles1b,8,9
and a number of 1,4-diketones.
Copper-mediated N-arylation of a pyrrole (Ullmann
coupling) with a 3-bromopyrrole was the key step in a
synthesis of marinopyrrole A.5 While the method was suitable
for making this particular natural product, there are intrinsic
limitations1b,5 on the types of substitution allowed in the
starting pyrroles. In general, metal-mediated coupling processes
would be expected to be incompatible with halogen
substitution in the starting materials beyond the single halogen
Received: August 26, 2013
© XXXX American Chemical Society
A
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a
preformed bromodichloropyrrole (1.1). This substance was
alkylated on nitrogen (Scheme 1) by taking advantage of the
high reactivity of the Michael acceptor 1.2,12 which has a
leaving group in the allylic position. The resulting N-
alkylpyrrole 1.3 was then modified to generate keto aldehyde
1.7, a substance that is correctly constituted to undergo a Paal−
Knorr reaction that generates the second pyrrole ring (1.7 →
1.8). In principle, compounds of type 1.4 should be available by
N-alkylation of 1.1 with an α-bromopyruvate, but experiments
directed to that end in model studies were unsuccessful and
eventually led to the use of 1.2.11 The approach shown in
Scheme 1 avoids the difficulties of introducing bromine at the
1,3′-bipyrrole stage; the available evidence suggests that
tetrachloro- and tetrabromo-1,3′-bipyrroles, at least those that
also carry carbonyl substituents at the C2- and C2′-position-
s,4a,c resist further halogenation, and attempts to perform such
late-stage brominations have been unsuccessful.4a,c As the
biological evaluation of other 1,3′-bipyrroles is worthwhile
because of the very high antibiotic activity of 1 and 2 and some
of their analogues,2 we have examined the generality of the
method that was used to make marinopyrrole B and find that it
is indeed a general approach not only to halogenated 1,3′-
bipyrroles but also to 1,3′-bipyrroles carrying substituents other
than halogens.
Table 1. Preparation of the O-Allyl Ethers
RESULTS AND DISCUSSION
Our starting monopyrroles are compounds 3−10 (Figure 1);
these are all known compounds, except for 9, which was made
■
Figure 1. Starting monopyrroles.
from the known and readily accessible 2,2,2-trichloro-1-(4,5-
diiodo-1H-pyrrol-2-yl)ethanone13 by treatment with MeONa in
MeOH, following a procedure described11 for the dichloro
analogue 8. Each monopyrrole was found to react with the
Michael acceptor 1.2 to give the products listed in Table 1, and
with one exception, the adducts were formed in yields of 78−
100%. Usually, the pyrroles were treated with 1.2 in the
presence of K2CO3 in refluxing MeCN for up to 24 h. The
sensitive 2,5-dimethylpyrrole 10 gave a significantly lower yield
(58%) and also required different conditions (the reaction
worked with NaH/DMF but not with the usual K2CO3/
MeCN). The poor yield was due in part to the fact that the
starting 2,5-dimethylpyrrole undergoes Michael addition to the
initial adduct 10a. In the case of the 5-nitro compound 6,
Na2CO3 and 18-crown-6 (1 equiv) were required to give an
acceptable yield; in the absence of the crown ether, the starting
material was largely recovered, and with K2CO3, starting
a
b
c
d
E = CO2Me. K2CO3, MeCN. Na2CO3, 18-crown-6, MeCN. NaH,
e
f
g
DMF. O3; Me2S. OsO4, NMO; Pb(OAc)4. NaH, DMF, allyl
h
bromide, ca. −40 °C to room temp. K2CO3, DMF, allyl bromide,
i
room temp. K2CO3, 18-crown-6, DMF, allyl bromide, room temp.
j
Corrected for recovered 6.
material was also largely recovered irrespective of whether the
crown ether was present or absent.
Cleavage of the initial double bond (cf. 3a → 3b, Table 1)
was usually done by ozonolysis in CH2Cl2 at −78 °C, using
Sudan Red 7B as an indicator,15 and Me2S as the reductant. In
the case of the dihalo compounds 8a and 9a, much better
results were obtained by a two-step process: dihydroxylation
with OsO4/NMO and diol cleavage with Pb(OAc)4. Our
attempts to cleave the double bond of 10a by ozonolysis
B
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a
without degrading the pyrrole nucleus were unsuccessful, even
when only 1 equiv of O3 was added, using a special apparatus16
to deliver a measured aliquot of CH2Cl2 saturated with O3.
Likewise, experiments based on dihydroxylation (OsO4/NMO
or RuCl3/NaIO4) also failed to generate the desired product,
and we conclude that our approach is unsuitable for pyrroles
having electron-donating substituents, even though double
bond cleavage in a system carrying a 2,5-dimethylpyrrole
subunit has indeed been reported.17
Table 2. 1,3′-Bipyrrole Formation
Alkylation with allyl bromide, using either NaH or K2CO3
(depending on the case) in DMF, gave the O-allyl products
(see Table 1) and, in two examples (1.5 from the
marinopyrrole B synthesis itself11 and 3c from the present
work), the double bond geometry was established by single
crystal X-ray analysis. The depicted Z geometry of the other O-
allylated products is an arbitrary assignment. The nitro
compound 7b required the addition of 18-crown-6 to facilitate
the O-alkylation.
Each of the O-allyl ethers underwent smooth Claisen
rearrangement (Table 2) on heating in refluxing PhMe to
give very clean products that usually did not require
chromatography before the next step. We noticed that 5c and
7c, which are the only examples that do not have two
substituents that flank the nitrogen, showed some tendency to
isomerize to the Claisen products at room temperature during
handling. Formation of the diiodide 9d was slow, but the reflux
period should not be extended beyond 42 h for best results.
The second double bond cleavage (cf. 3d → 3e, Table 2) was
again usually best done by ozonolysis, using Sudan Red 7B as
an indicator. The intermediate keto aldehydes 3e−9e were
sensitive compounds and tended to decompose by loss of the
pyrrole unit; fortunately, this pathway could be adequately
suppressed by proper temperature control: specifically, during
isolation of the keto aldehydes, solvent evaporation must be
done below room temperature, and the product used promptly
without purification. For example, the conversion of 4d to 4f
was improved from 43 to 56% by evaporating solutions of the
intermediate 4e at no higher than 15 °C. Our conditions for the
final (Paal−Knorr) step called for treatment of the keto
aldehyde in AcOH with NH4OAc.18
Double bond cleavage in the case of the two halogenated
examples (8d and 9d) had to be done in two steps
[dihydroxylation at room temperature (OsO4/NMO) and
diol cleavage with Pb(OAc)4], rather than by ozonolysis, as
attempted cleavage with O3 was unsuccessful. In both cases (8e
and 9e) the excess of Pb(OAc)4 must be removed by
quenching with pinacol19 before the Paal−Knorr cyclization.20
The diiodo keto aldehyde 9e is light-sensitive, and as a
precaution, we protected all compounds in the diiodo series
from light.
a
b
E = CO2Me. PhMe, reflux. The products of the thermal
rearrangement were not purified; the reactions were very clean, and
the crude products were suitable for direct use in the next step. O3,
MeOH−CH2Cl2, −78 °C; Ph3P. NH4OAc, AcOH. O3, CH2Cl2,
Sudan Red 7B, CH2Cl2, −78 °C; Me2S. OsO4, NMO; Pb(OAc)4.
c
d
e
f
Although the overall yields for the three steps from the O-
allyl compounds 3c−9c to the 1,3′-bipyrroles 3f−9f were
modest (see Table 2), the products would be difficult to make,
if indeed possible in all cases, by existing methods. We did not
establish the individual yields for the last two steps of the
sequence (the double bond cleavage and the Paal−Knorr
pyrrole formation), except for observing that the yields for the
crude intermediate diols generated from 8d and 9d were no
greater than 50 and 61%, respectively. The 1,3′-bipyrroles we
made are all crystalline; their structures are clear from spectral
data, but in one case (3f) the assignment was also supported by
single crystal X-ray analysis.
All the examples of Table 2 have an ester substituent
(−CO2Me) at C2′ in the newly generated pyrrole ring, and
during the synthesis of marinopyrrole B, the possibility of using
a keto group, instead of an ester, was examined. As reported
previously,11 but without experimental details, the α-diketone
4.3 (see Scheme 4) had been prepared for this purpose. One of
the required subunits for synthesis of this compound was the
keto acetate 2.7, which was made from the known21 Baylis−
Hillman adduct 2.1 by the reactions summarized in Scheme 2.
The only complication met in this sequence was the acetyl
migration leading to 2.6, but fortunately, this minor byproduct
C
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Allylation of 3.5 (NaH, allyl bromide) afforded the O-allyl
derivative 4.1, and this rearranged on heating in PhMe.
Lemieux−Johnson oxidation and ozonolysis were then
examined for the purpose of cleaving the terminal double
bond, but neither of these procedures was successful.
Fortunately, the two-stage process involving dihydroxylation
with OsO4/NMO and cleavage with Pb(OAc)4 afforded the
required aldehyde 4.3 in 57% yield. However, exposure of this
compound to NH4OAc in AcOH did not furnish a 1,3′-
bipyrrole, but gave instead the hydroxypyridine 4.4 (62%)
(Scheme 4). The 3-hydroxypyridine unit is of pharmaceutical
Scheme 2. Preparation of Keto Acetate 2.7
Scheme 4. Formation of the 3-Hydroxypyridine 4.4
could be converted, by the action of DBU, into the desired
primary acetate 2.5, which was then oxidized (2.5 → 2.7).
The other component needed was the known and easily
prepared bromodichloropyrrole 3.1.1b This reacted with 2.7
(Scheme 3) after deprotonation with NaH. Hydrolysis under
Scheme 3. Linking 2.7 and 3.1
a
Z-Geometry is an arbitrary assignment.
interest and, as far as we can determine, has not been generated
this way before.23,24 This sequence leading to 4.4 had actually
been the first approach for implementing the principle
summarized in Scheme 1, and the unexpected outcome
suggested the use of an ester group in the route to
marinopyrrole B that was ultimately successful.
We have also examined the substrate 5.2 (see Scheme 5), in
which a phenyl group is present instead of the CO2Me group at
C2′ of the examples listed in Tables 2. The compound was
readily made by N-alkylation of pyrrole 4, using phenacyl
bromide (5.1). The subsequent allylation afforded the products
of O-allylation (5.3) and C-allylation (5.4),25 in a ratio of ca.
2:1, but the former was easily converted into the latter by
heating the mixture of 5.3 and 5.4 in PhMe, the overall yield of
5.4 from 5.2, then being 36% (53% corrected for recovered
5.2).26 The double bond of 5.4 was easily cleaved by ozonolysis
under our standard conditions, and the resulting keto aldehyde
5.5 underwent a smooth Paal−Knorr reaction to give 5.6 in
71% yield (from 5.4). We formed the impression that keto
aldehyde 5.5 was more stable than the other keto aldehydes we
had generated; the presence of a phenyl group instead of an
acidic conditions1b then served to release phenol 3.3 (75%).
Methylation of the phenolic hydroxyl of 3.3 under classical
conditions and double bond cleavage22 gave diketone 3.5, the
desired substrate for allylation. In the case of 3.4 the double
bond cleavage was best done with RuCl3, NaIO4;22 other
methods [dihydroxylation with OsO4/NMO, followed by diol
cleavage with Pb(OAc)4 or NaIO4−SiO2] were less satisfactory
and ozonolysis failed.
D
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the initial pyrrole subunit. The method is not applicable when
the initial pyrrole carries electron-donating groups (e.g.,
methyl), as the double bond in the allyl substituent could not
then be cleaved without degradation of the pyrrole ring.
The variation described in Schemes 5 and 6 shows that the
second pyrrole ring need not be substituted by an ester group
but can have an aromatic ring. The sequence of Scheme 4 is a
new route to the hydroxypyridine system. The antibacterial
properties of the marinopyrroles suggest that extensive SAR
studies with 1,3′-bipyrroles is warranted, and the present
method should provide opportunities for far more extensive
structure−activity studies than have hitherto been practicable.
Scheme 5. Formation of 5.6
EXPERIMENTAL SECTION
■
General Procedures. Solvents used for chromatography were
distilled before use. Commercial thin layer chromatography plates
(silica gel, Merck 60F-254) were used. Silica gel for flash
chromatography was Merck type 60 (230−400 mesh). Dry solvents
were prepared under an inert atmosphere and transferred by syringe or
cannula. The symbols s, d, t, and q used for 13C NMR spectra indicate
zero, one, two, or three attached hydrogens, respectively, the
assignments being made from APT spectra. Solutions were evaporated
under a water pump vacuum and the residue was then kept under an
oil pump vacuum. High resolution electrospray mass spectrometry
analyses were done on an orthogonal time-of-flight analyzer.
a
b
Combined yield corrected for recovered 5.2. Z-Geometry is an
arbitrary assignment.
ester must lower the tendency for elimination of the pyrrole
subunit.
2,5-Dimethyl 1-(3-methoxy-2-methylidene-3-oxopropyl)-
1H-pyrrole-2,5-dicarboxylate (3a). A solution of 1.212 (529.2
mg, 3.348 mmol) in MeCN (5 mL) was added to a stirred suspension
of K2CO3 (1.25 g, 8.95 mmol) in a solution of 328 (408.6 mg, 2.231
mmol) in MeCN (25 mL). The mixture was refluxed for 12 h, cooled,
diluted with water and extracted with CH2Cl2. The combined organic
extracts were dried (MgSO4) and evaporated. Flash chromatography
of the residue over silica gel (2.8 × 20 cm), using 1:10 EtOAc−
hexanes, gave 3a (621.1 mg, 99%) as a white solid: mp 77−81 °C;
Finally, we have prepared the N-protected 1,3′-bipyrrole 6.5
by the analogous route shown in Scheme 6. Again, both O- and
Scheme 6. Formation of 6.5
1
FTIR (CDCl3, cast) 1728 cm−1; H NMR (CDCl3, 500 MHz) δ 3.78
(s, 3 H), 3.79 (s, 6 H), 4.69 (apparent t, J = 1.5 Hz, 1 H), 5.73
(apparent t, J = 1.5 Hz, 2 H), 6.11 (apparent t, 1 H), 6.93 (s, 2 H); 13C
NMR (CDCl3, 125 MHz) δ 46.8 (t), 51.6 (q), 51.9 (q), 116.9 (d),
122.9 (t), 127.4 (s), 138.2 (s), 160.6 (s), 165.6 (s); exact mass
(electrospray) m/z calcd for C13H15NNaO6 (M + Na)+ 304.0792,
found 304.0788.
2,5-Dimethyl 1-(3-methoxy-2,3-dioxopropyl)-1H-pyrrole-
2,5-dicarboxylate (3b). A stream of ozonized oxygen was bubbled
through a stirred and cooled (−78 °C) solution of 3a (1.17 g, 3.15
mmol) in CH2Cl2 (20 mL). After 18 min, the solution became blue,
and O2 was then bubbled through the solution for 20 min to remove
the excess of O3. Me2S (1.80 mL, 24.2 mmol) was then added, the cold
bath was removed, and stirring was continued for 4 h. Evaporation of
the solvent and flash chromatography of the residue over silica gel (2.8
× 25 cm), using 1:5 to 3:10 EtOAc−hexanes, gave 3b (625.5 mg,
91%) as a white solid: mp 84−87 °C; FTIR (CDCl3, cast) 1761, 1722
cm−1; 1H NMR (CDCl3, 500 MHz) δ 3.79 (s, 6 H), 3.94 (s, 3 H), 6.23
(s, 2 H), 6.96 (s, 2 H); 13C NMR (CDCl3, 125 MHz) δ 51.8 (q), 53.2
(q), 53.5 (t), 117.0 (d), 127.2 (s), 159.9 (s), 161.2 (s), 186.9 (s); exact
mass (electrospray) m/z calcd for C12H13NNaO7 (M + Na)+
306.0584, found 306.0584.
a
Z-Geometry is an arbitrary assignment.
2,5-Dimethyl 1-[(1Z)-3-methoxy-3-oxo-2-(prop-2-en-1-
yloxy)prop-1-en-1-yl]-1H-pyrrole-2,5-dicarboxylate (3c). NaH
(60% w/w in oil, 16.0 mg, 0.400 mmol) was added to a stirred and
cooled (−42 °C) solution of 3b (87.0 mg, 0.307 mmol) in DMF (5
mL). After 20 min, allyl bromide (0.033 mL, 0.38 mmol) was added.
The reaction flask was transferred to a single-walled cold bath at −42
°C, and stirring was continued for 2 h, during which time the reaction
mixture reached room temperature. Stirring was continued for a
further 8 h, saturated aqueous NH4Cl was added, and the mixture was
extracted with Et2O and then with EtOAc. The combined organic
extracts were washed with water, dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (1.8 × 20 cm),
C-allylation products were generated, and the intermediate keto
aldehyde 6.4 proved to be decidedly more stable than the keto
aldehydes in Table 2. The final step was done using BnNH2
and catalysis by I2 with THF as solvent instead of NH4OAc/
AcOH.
27
CONCLUSION
■
Our experiments establish that the approach to 1,3′-bipyrroles
summarized in Scheme 1 represents a general route that
accommodates a range of electron-withdrawing substituents on
E
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using 3:50 to 3:20 EtOAc−hexanes, gave 3c (87.9 mg, 88%) as a white
solid: mp 81−84 °C; FTIR (CDCl3, cast) 1732 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 3.79 (s, 6 H), 3.83 (s, 3 H), 4.17 (apparent dt, J
= 7.0, 1.0 Hz, 2 H), 4.98−5.04 (m, 2 H), 5.45−5.55 (m, 1 H), 6.90 (s,
2 H), 7.89 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 51.8 (q), 52.3
(q), 72.9 (t), 117.0 (d), 118.2 (t), 123.2 (d), 128.8 (s), 132.6 (d),
141.0 (s), 160.5 (s), 163.5 (s); exact mass (electrospray) m/z calcd for
C15H17NNaO7 (M + Na)+ 346.0897, found 346.0895. A sample was
crystallized from i-Pr2O for X-ray analysis.
4a (301 mg, 1.21 mmol) and Sudan Red 7B (1.6 mg) in CH2Cl2 (24
mL). When the color changed from red to light yellow, the O3 flow
was stopped and O2 was bubbled through the solution for 15 min at
−78 °C. Me2S (0.45 mL, 6.1 mmol) was then added. The cold bath
was left in place, but not recharged, and stirring was continued for 5 h,
during which time the reaction mixture reached room temperature.
The mixture was washed with water and brine, and the organic extract
was dried (MgSO4) and evaporated to give 4b (289 mg, 95%) as an
almost white solid that was used directly in the next step: mp 100−105
°C; FTIR (CDCl3, cast) 2229, 1761, 1739, 1713 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 3.81 (s, 3 H), 3.97 (s, 3 H), 5.70 (s, 2 H), 6.85
(d, J = 4.5 Hz, 1 H), 6.98 (d, J = 4.5 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 52.1 (q), 53.5 (q), 54.2 (s), 111.0 (s), 111.8 (s), 117.4 (d),
119.0 (d), 126.5 (s), 159.4 (s), 160.4 (s), 185.1 (s); exact mass
(electrospray) m/z calcd for C11H11N2O5 (M + H)+ 251.0662, found
251.0657.
2,5-Dimethyl ( )-1-(1-methoxy-1,2-dioxohex-5-en-3-yl)-1H-
pyrrole-2,5-dicarboxylate (3d). A solution of 3c (427.8 mg, 1.323
mmol) in PhMe (10 mL) was stirred and refluxed for 21.5 h and then
cooled to room temperature. Evaporation of the solution gave 3d as a
white solid (427.6 mg, 100%), which was used directly in the next
1
step: mp 100−102 °C; FTIR (CDCl3, cast) 1759, 1723 cm−1; H
NMR (CDCl3, 500 MHz) δ 2.59−2.66 (m, 1 H), 3.19−3.24 (m, 1 H),
3.69 (s, 3 H), 3.83 (s, 6 H), 4.83 (dm, J = 7.0 Hz, 1 H), 4.86 (apparent
t, J = 1.0 Hz, 1 H), 5.54−5.63 (m, 1 H), 6.95 (s, 2 H), 7.09 (dd, J =
10.0, 4.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 35.4 (t), 52.0 (q),
52.7 (q), 62.3 (d), 117.6 (d), 118.5 (t), 127.2 (s), 132.6 (d), 161.5 (s),
161.6 (s), 188.1 (s); exact mass (electrospray) m/z calcd for
C15H17NNaO7 (M + Na)+ 346.0897, found 346.089.
Methyl 5-cyano-1-[(1Z)-3-methoxy-3-oxo-2-(prop-2-en-1-
yloxy)prop-1-en-1-yl]-1H-pyrrole-2-carboxylate (4c). A solution
of 4b (780 mg, 3.12 mmol) in DMF (20 mL) was added over 10 min
to a stirred and cooled (−40 °C) mixture of NaH (60% w/w in
mineral oil, 150 mg, 3.76 mmol) and DMF (16 mL). Stirring at −40
°C was continued for 30 min, and allyl bromide (0.35 mL, 4.13 mmol)
was added dropwise over ca. 5 min. The cold bath was left in place, but
not recharged, and stirring was continued overnight. The reaction
mixture was diluted with saturated aqueous NH4Cl and extracted with
EtOAc. The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (3 × 20 cm), using 1:10 EtOAc−hexane to 1:4 EtOAc−
hexane, gave 4c (740 mg, 82%) as a white solid: mp 72−75 °C; FTIR
2,5-Dimethyl ( )-1-(1-methoxy-1,2,5-trioxopentan-3-yl)-1H-
pyrrole-2,5-dicarboxylate (3e) and 2,5-Dimethyl 1-[2-(methox-
ycarbonyl)-1H-pyrrol-3-yl]-1H-pyrrole-2,5-dicarboxylate (3f). A
stream of ozonized oxygen was bubbled through a stirred and cooled
(−78 °C) solution of the above crude keto ester (3d) (427.6 mg,
1.323 mmol) in a mixture of MeOH (7 mL) and CH2Cl2 (7 mL).
After 22 min, the solution became blue and O2 was then bubbled
through the solution for 20 min to remove the excess of O3. Ph3P (702
mg, 2.65 mmol) was added, the cooling bath was left in place but not
recharged, and stirring was continued for 15 h. Evaporation of the
solution gave 3e as a yellow residue, which was used directly in the
next step.
NH4OAc (1.62 g, 21.0 mmol) was added to a stirred solution of the
above crude keto aldehyde 3e in AcOH (9 mL), and stirring was
continued for 30 min. Water was then added, and the mixture was
extracted with CH2Cl2. The combined organic extracts were washed
with saturated aqueous NaHCO3 and brine, dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (2.2 ×
25 cm), using 1:5 to 1:2 EtOAc−hexanes, gave 3f (161.6 mg, 40% over
three steps) as a white solid: mp 143−149 °C; FTIR (CDCl3, cast)
3327, 3139, 1736, 1708 cm−1; 1H NMR (CDCl3, 500 MHz) δ 3.60 (s,
3 H), 3.72 (s, 6 H), 6.29 (apparent t, J = 3.0 Hz, 1 H), 6.92 (apparent
t, J = 3.0 Hz, 1 H), 7.02 (s, 2 H), 9.26 (br, 1 H); 13C NMR (CDCl3,
125 MHz) δ 51.3 (q), 51.5 (q), 110.6 (d), 116.7 (d), 117.6 (s), 120.5
(d), 128.1 (s), 129.1 (s), 159.8 (s), 160.3 (s); exact mass
(electrospray) m/z calcd for C14H14N2NaO6 (M + Na)+ 329.0744,
found 329.0738. A sample was crystallized from CHCl3 for X-ray
analysis.
1
(CDCl3, cast) 3136, 2231, 1776, 1728 cm−1; H NMR (CDCl3, 500
MHz) δ 3.84 (s, 3 H), 3.87 (s, 3 H), 4.48 (ddd, J = 6.0, 1.0, 1.0 Hz, 2
H), 5.12 (ddd, J = 10.0, 2.5, 1.0 Hz, 1 H), 5.17 (ddd, J = 17.0, 3.0, 1.5
Hz, 1 H), 5.73 (ddt, J = 17.5, 10.0, 6.0 Hz, 1 H), 6.87 (d, J = 4.0 Hz, 1
H), 6.96 (d, J = 4.0 Hz, 1 H), 7.55 (s, 1 H); 13C NMR (CDCl3, 125
MHz) δ 52.1 (s), 52.6 (s), 110.8 (s), 112.1 (s), 117.3 (d), 118.7 (t),
119.5 (d), 120.0 (d), 127.5 (s), 132.5 (d), 142.9 (s), 159.7 (s), 162.8
(s); exact mass (electrospray) m/z calcd for C14H15N2O5 (M + H)+
291.0975, found 291.0976.
Methyl ( )-5-cyano-1-(1-methoxy-1,2-dioxohex-5-en-3-yl)-
1H-pyrrole-2-carboxylate (4d). A solution of 4c (494 mg, 1.70
mmol) in PhMe (17 mL) was refluxed for 18 h, cooled and evaporated
to afford 4d (491 mg, ca. 99%) as a thick, light yellow oil: FTIR
(CDCl3, cast) 2227, 1736, 1717 cm−1; 1H NMR (CDCl3, 500 MHz) δ
2.72−2.84 (m, 1 H), 3.19−3.25 (m, 1 H), 3.78 (s, 3 H), 3.85 (s, 3 H),
4.97−5.02 (m, 2 H), 5.59−5.67 (m, 1 H), 5.97 (br, 1 H), 6.82 (d, J =
4.5 Hz, 1 H), 6.97 (d, J = 4.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 34.6 (t), 52.3 (q), 53.2 (q), 64.4 (d), 111.9 (s), 112.4 (s), 118.3 (d),
119.3 (d), 120.0 (t), 125.9 (s), 131.3 (d), 160.6 (s), 160.8 (s), 186.5
(s); exact mass (electrospray) m/z calcd for C14H14N2NaO5 (M +
Na)+ 313.0795, found 313.0788.
Methyl 5-cyano-1-(3-methoxy-2-methylidene-3-oxopropyl)-
1H-pyrrole-2-carboxylate (4a). K2CO3 (1.98 g, 14.3 mmol) was
added to a stirred solution of 429 (537 mg, 3.58 mmol) and ester 1.212
(647 mg, 4.09 mmol) in MeCN (30 mL). The resulting mixture was
stirred and refluxed for 10 h, cooled to room temperature, diluted with
water and extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried (MgSO4) and evaporated. Flash chromatog-
raphy of the residue over silica gel (3 × 20 cm), using 1:6 EtOAc−
hexane, gave 4a (870 mg, 98%) as a white solid: mp 77−80 °C; FTIR
Methyl ( )-5-cyano-1-(1-methoxy-1,2,5-trioxopentan-3-yl)-
1H-pyrrole-2-carboxylate (4e) and Methyl 5-cyano-1-[2-(me-
thoxycarbonyl)-1H-pyrrol-3-yl]-1H-pyrrole-2-carboxylate (4f).
A slow stream of ozonized oxygen was bubbled via a Pasteur pipet
through a stirred and cooled (−78 °C) solution of 4d (159 mg, 0.548
mmol) and Sudan Red 7B (1 mg) in CH2Cl2 (12 mL). When the color
changed from red to light yellow, the O3 flow was stopped and O2 was
bubbled through the solution for 15 min at −78 °C. Me2S (0.12 mL,
1.6 mmol) was then added. The cold bath was left in place, but not
recharged, and stirring was continued for 14 h, during which time the
reaction mixture reached room temperature. The mixture was
evaporated directly at ca. 15 °C to give 4e as a thick, yellow oil,
which was used immediately, as follows.
The method for 3f was followed, using NH4OAc (630 mg, 8.18
mmol), the above crude keto aldehyde 4e in AcOH (6 mL) and a
reaction time of 45 min. In this case extraction was done with EtOAc.
Flash chromatography of the crude product over silica gel (1 × 20
cm), using 1:4 to 1:2 EtOAc−hexane, gave 4f (83.7 mg, 56% over
three steps) as a white solid: mp 149−154 °C; FTIR (CDCl3, cast)
3321, 2229, 1715 cm−1; 1H NMR (CDCl3, 500 MHz) δ 3.67 (s, 3 H),
1
(CDCl3, cast) 2227, 1720 cm−1; H NMR (CDCl3, 500 MHz) δ 3.81
(s, 3 H), 3.83 (s, 3 H), 4.93 (apparent t, J = 2.0 Hz, 1 H), 5.38
(apparent t, J = 2.0 Hz, 2 H), 6.27 (apparent t, J = 2.0 Hz, 1 H), 6.82
(d, J = 4.0 Hz, 1 H), 6.96 (d, J = 4.0 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 47.9 (t), 51.9 (q), 52.2 (q), 110.8 (s), 112.0 (s), 117.5 (d),
118.7 (d), 125.1 (t), 126.7 (s), 136.3 (s), 159.8 (s), 165.1 (s); exact
mass (electrospray) m/z calcd for C12H12N2NaO4 (M + Na)+
271.0689, found 271.0684.
Methyl 5-cyano-1-(3-methoxy-2,3-dioxopropyl)-1H-pyrrole-
2-carboxylate (4b). A slow stream of ozonized oxygen was bubbled
via a Pasteur pipet through a stirred and cooled (−78 °C) solution of
F
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The Journal of Organic Chemistry
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3.75 (s, 3 H), 6.36 (dd, J = 3.0, 3.0 Hz, 1 H), 6.88 (d, J = 4.5 Hz, 1 H),
6.92 (dd, J = 3.0, 3.0 Hz, 1 H), 7.01 (d, J = 4.5 Hz, 1 H), 9.55 (br, 1
H); 13C NMR (CDCl3, 125 MHz) δ 51.6 (q), 51.8 (q), 110.2 (d),
112.3 (s), 112.4 (s), 116.9 (d), 117.7 (s), 119.0 (d), 121.2 (d), 125.7
(s), 128.5 (s), 159.5 (s), 159.7 (s); exact mass (electrospray) m/z
calcd for C13H11N3O4 (M + H)+ 274.0822, found 274.0823.
evaporated directly at ca. 15 °C to give 5e as a thick, yellow oil, which
was used immediately, as follows.
The method for 3f was followed, using NH4OAc (500 mg, 6.49
mmol), the above crude keto aldehyde 5e in AcOH (8 mL) and a
reaction time of 3.5 h. In this case extraction was done with EtOAc.
Flash chromatography of the crude product over silica gel (1 × 20
cm), using 1:1 EtOAc−hexane, gave 5f (72.3 mg, 65% over three
steps) as a white solid: mp 159−165 °C; FTIR (CDCl3, cast) 3320,
3133, 2234, 1715 cm−1; 1H NMR (CDCl3, 500 MHz) δ 3.69 (s, 3 H),
3.73 (s, 3 H), 6.31 (apparent t, J = 3.0 Hz, 1 H), 6.95 (apparent t, J =
3.0 Hz, 1 H), 7.25 (d, J = 2.0 Hz, 1 H), 7.32 (d, J = 2.0 Hz, 1 H), 9.25
(br, 1 H); 13C NMR (CDCl3, 125 MHz) δ 51.6 (q), 51.7 (q), 93.8 (s),
109.8 (d), 115.1 (s), 117.3 (s), 119.8 (d), 120.9 (d), 125.5 (s), 127.5
(s), 135.1 (d), 159.6 (s), 159.7 (s); exact mass (electrospray) m/z
calcd for C13H11N3NaO4 (M + Na)+ 296.0642, found 296.0638.
Methyl 1-(3-methoxy-2-methylidene-3-oxopropyl)-5-nitro-
1H-pyrrole-2-carboxylate (6a). Na2CO3 (242 mg, 2.28 mmol)
was added to a stirred solution of 630 (195 mg, 1.14 mmol), 18-crown-
6 (300 mg, 1.14 mmol) and ester 1.212 (202 mg, 1.28 mmol) in
MeCN (12 mL). The resulting mixture was stirred and refluxed for 36
h, cooled to room temperature, diluted with water and extracted with
Et2O. The combined organic extracts were washed with brine, dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (2 × 20 cm), using 1:6 EtOAc−hexane, gave 6a (240 mg, 78
or 99% corrected for recovered 6) as a colorless oil: FTIR (CDCl3,
Methyl 4-cyano-1-(3-methoxy-2-methylidene-3-oxopropyl)-
1H-pyrrole-2-carboxylate (5a). The method for 4a was followed,
using K2CO3 (2.42 g, 17.5 mmol), 529 (659 mg, 4.39 mmol) and 1.212
(763 mg, 4.83 mmol) in MeCN (40 mL). Flash chromatography of
the crude product over silica gel (3 × 20 cm), using 1:6 EtOAc−
hexane, gave 5a (1.06 g, 98%) as a white solid: mp 92−95 °C; FTIR
(CDCl3, cast) 3129, 2232, 1719 cm−1; 1H NMR (CDCl3, 500 MHz) δ
3.76 (s, 3 H), 3.79 (s, 3 H), 5.20 (apparent t, J = 1.5 Hz, 1 H), 5.43
(apparent t, J = 1.5 Hz, 1 H), 6.29 (s, 2 H), 7.16 (d, J = 2.0 Hz, 1 H),
7.37 (d, J = 2.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 49.4 (t),
51.7 (q), 52.2 (q), 93.3 (s), 115.0 (s), 120.8 (d), 123.2 (t), 127.7 (s),
134.3 (d), 136.1 (s), 160.0 (s), 165.5 (s); exact mass (electrospray) m/
z calcd for C12H13N2O4 (M + H)+ 249.0870, found 249.0872.
Methyl 4-cyano-1-(3-methoxy-2,3-dioxopropyl)-1H-pyrrole-
2-carboxylate (5b). The method for 4b was followed, using 5a (750
mg, 3.02 mmol), Sudan Red 7B (2 mg) in CH2Cl2 (30 mL) and Me2S
(1.33 mL, 18.1 mmol), with a reduction period of 4 h. Evaporation of
the organic extract gave 5b (701 mg, 93%) as an almost white solid
that was used directly in the next step: mp 114−115 °C; FTIR
(CDCl3, cast) 3133, 2233, 1759, 1738, 1712 cm−1; 1H NMR (CDCl3,
500 MHz) δ 3.88 (s, 3 H), 3.97 (s, 3 H), 5.53 (s, 2 H), 7.23 (AB q, J =
1.74 Hz, ΔνAB = 1.73 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 52.0
(q), 53.6 (q), 56.0 (t), 94.2 (s), 114.6 (s), 120.6 (d), 123.1 (s), 134.1
(d), 159.7 (s), 160.6 (s), 185.2 (s); exact mass (electrospray) m/z
calcd for C11H10N2NaO5 (M + Na)+ 273.0482, found 273.0483.
Methyl 4-cyano-1-[(1Z)-3-methoxy-3-oxo-2-(prop-2-en-1-
yloxy)prop-1-en-1-yl]-1H-pyrrole-2-carboxylate (5c). A solution
of 5b (137 mg, 0.55 mmol) in DMF (5 mL) was added over 10 min to
a stirred mixture of K2CO3 (77 mg, 0.55 mmol), allyl bromide (0.19
mL, 2.2 mmol) and DMF (10 mL), and stirring was continued for 5 h.
The reaction mixture was diluted with water and extracted with
EtOAc, and the combined organic extracts were washed with brine,
dried (MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (1 × 20 cm), using 1:10 EtOAc−hexane to 1:5 EtOAc−
hexane, gave 5c (98.1 mg, 58%) as a white solid: mp 107−110 °C;
1
cast) 1722 cm−1; H NMR (CDCl3, 500 MHz) δ 3.75 (s, 3 H), 3.86
(s, 3 H), 4.98 (apparent t, J = 1.5 Hz, 1 H), 5.78 (apparent t, J = 1.5
Hz, 2 H), 6.21 (apparent t, J = 1.5 Hz, 1 H), 6.96 (d, J = 4.5 Hz, 1 H),
7.19 (d, J = 4.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 47.3 (t),
52.1 (q), 52.2 (q), 112.7 (d), 116.2 (d), 124.5 (t), 126.8 (s), 136.5 (s),
140.7 (s), 160.1 (s), 165.2 (s); exact mass (electrospray) m/z calcd for
C11H12N2NaO6 (M + Na)+ 291.0588, found 291.0581.
The aqueous layer was acidified with 1.0 M hydrochloric acid and
extracted with Et2O. The combined organic extracts were washed with
brine, dried (MgSO4) and evaporated to give 6 (41.9 mg).
Methyl 1-(3-methoxy-2,3-dioxopropyl)-5-nitro-1H-pyrrole-
2-carboxylate (6b). The method for 4b was followed, using 6a
(309 mg, 1.15 mmol), Sudan Red 7B (1 mg) in CH2Cl2 (20 mL) and
Me2S (0.5 mL, 7 mmol) and a reduction period of 6 h. In this case,
flash chromatography of the crude product over silica gel (2 × 20 cm),
using 1:3 EtOAc−hexane, gave 6b (280 mg, 90%) as a white solid: mp
1
121−123 °C; FTIR (CDCl3, cast) 1761, 1738, 1717 cm−1; H NMR
1
FTIR (CDCl3, cast) 3137, 2235, 1724 cm−1; H NMR (C6D6, 500
(CDCl3, 500 MHz) δ 3.86 (s, 3 H), 3.98 (s, 3 H), 6.29 (s, 2 H), 7.00
(d, J = 4.5 Hz, 1 H), 7.25 (d, J = 4.5 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 52.4 (q), 53.5 (q), 54.0 (t), 113.0 (d), 116.4 (d), 126.4 (s),
140.5 (s), 159.4 (s), 160.2 (s), 185.6 (s); exact mass (electrospray) m/
z calcd for C10H10N2NaO7 (M + Na)+ 293.0380, found 93.0377.
Methyl 1-[(1Z)-3-methoxy-3-oxo-2-(prop-2-en-1-yloxy)prop-
1-en-1-yl]-5-nitro-1H-pyrrole-2-carboxylate (6c). The method
for 5c was followed, using 6b (249 mg, 0.922 mmol) in DMF (2 mL),
and an addition time of ca. 2 min, allyl bromide (0.16 mL, 1.9 mmol),
K2CO3 (150 mg, 1.09 mmol) and DMF (10 mL), and a reaction time
of 1 h. Flash chromatography of the crude product over silica gel (2 ×
15 cm), using 1:2 EtOAc−hexane, gave 6c (206 mg, 72%) as a white
solid: mp 52−55 °C; FTIR (CDCl3, cast) 3140, 1731 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 3.847 (s, 3 H), 3.863 (s, 3 H), 4.27 (ddd, J = 6.0,
1.0, 1.0 Hz, 2 H), 5.01−5.03 (m, 1 H), 5.04−5.06 (m, 1 H), 5.50 (ddt,
J = 17.5, 10.0, 6.0 Hz, 1 H), 6.93 (d, J = 4.5 Hz, 1 H), 7.12 (d, J = 4.5
Hz, 1 H), 7.73 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 52.3 (q), 52.5
(q), 73.0 (t), 112.3 (d), 116.0 (d), 119.0 (t), 127.8 (s), 132.1 (d),
141.2 (s), 142.3 (s), 159.7 (s), 162.6 (s); exact mass (electrospray) m/
z calcd for C13H14N2NaO7 (M + Na)+ 333.0693, found 333.0686.
Methyl ( )-1-(1-methoxy-1,2-dioxohex-5-en-3-yl)-5-nitro-
1H-pyrrole-2-carboxylate (6d). A solution of 6c (320 mg, 1.03
mmol) in PhMe (10.3 mL) was refluxed for 36 h, cooled and
evaporated to afford 6d (317 mg, ca. 99%) as a thick, light yellow oil:
FTIR (CDCl3, cast) 1733 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.59−
2.66 (m, 1 H), 3.25−3.30 (m, 1 H), 3.76 (s, 3 H), 3.91 (s, 3 H), 4.86−
4.92 (m, 2 H), 5.57−5.65 (m, 1 H), 6.99 (d, J = 5.0 Hz, 1 H), 7.11
(dd, J = 10.0, 4.5 Hz, 1 H), 7.21 (d, J = 4.5 Hz, 1 H); 13C NMR
MHz) δ 3.27 (s, 3 H), 3.28 (s, 3 H), 4.22 (ddd, J = 6.0, 1.5, 1.0 Hz, 2
H), 4.86 (ddd, J = 10.5, 2.5, 1.0 Hz, 1 H), 4.96 (ddd, J = 17.0, 2.5, 1.5
Hz, 1 H), 5.54 (ddt, J = 17.5, 10.0, 6.0 Hz, 1 H), 6.73 (d, J = 1.5 Hz, 1
H), 8.04 (d, J = 1.5 Hz, 1 H), 8.56 (s, 1 H); 13C NMR (C6D6, 125
MHz) δ 50.9 (q), 51.4 (q), 72.7 (t), 95.8 (s), 114.1 (s), 119.1 (t),
119.7 (d), 120.5 (d), 123.5 (s), 132.3 (d), 133.1 (d), 136.2 (s), 163.0
(s); exact mass (electrospray) m/z calcd for C14H14N2NaO5 (M +
Na)+ 313.0795, found 313.0792.
Methyl ( )-4-cyano-1-(1-methoxy-1,2-dioxohex-5-en-3-yl)-
1H-pyrrole-2-carboxylate (5d). A solution of 5c (370 mg, 1.28
mmol) in PhMe (12 mL) was refluxed for 20 h, cooled and evaporated
to afford 5d (367 mg, ca. 99%) as a thick, light yellow oil that was pure
enough for use directly in the next step: FTIR (CDCl3, cast) 2233,
1739, 1709 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.70−2.77 (m, 1 H),
3.01−3.07 (m, 1 H), 3.81 (s, 1 H), 3.92 (s, 3 H), 5.15 (ddd, J = 7.0,
2.5, 1.0 Hz, 1 H), 5.17 (apparent t, J = 2.0 Hz, 1 H), 5.67−5.75 (m, 1
H), 6.47 (dd, J = 10.0, 4.5 Hz, 1 H), 7.20 (d, J = 2.0 Hz, 1 H), 7.46 (d,
J = 2.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 34.2 (t), 52.1 (q),
53.5 (q), 62.4 (d), 94.1 (s), 114.8 (s), 120.2 (t), 120.9 (d), 123.1 (s),
130.8 (d), 132.2 (d), 160.0 (s), 160.7 (s), 187.8 (s); exact mass
(electrospray) m/z calcd for C14H14N2NaO5 (M + Na)+ 313.0795,
found 313.0794.
Methyl ( )-4-cyano-1-(1-methoxy-1,2,5-trioxopentan-3-yl)-
1H-pyrrole-2-carboxylate (5e) and Methyl 4-cyano-1-[2-(me-
thoxycarbonyl)-1H-pyrrol-3-yl]-1H-pyrrole-2-carboxylate (5f).
The procedure for 4e was followed, using, 5d (117 mg, 0.403
mmol), Sudan Red 7B (0.5 mg) in CH2Cl2 (20 mL), Me2S (0.18 mL,
2.5 mmol) and an overnight reduction period. The mixture was
G
dx.doi.org/10.1021/jo401892t | J. Org. Chem. XXXX, XXX, XXX−XXX

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(CDCl3, 125 MHz) δ 35.1 (t), 52.6 (q), 53.1 (q), 62.9 (d), 113.8 (d),
116.9 (d), 119.6 (t), 126.8 (s), 131.6 (d), 140.3 (s), 161.0 (s), 161.1
(s), 186.2 (s); exact mass (electrospray) m/z calcd for C13H14N2NaO7
(M + Na)+ 333.0693, found 333.0686.
Methyl ( )-1-(1-methoxy-1,2,5-trioxopentan-3-yl)-5-nitro-
1H-pyrrole-2-carboxylate (6e) and Methyl 1-[2-(methoxycar-
bonyl)-1H-pyrrol-3-yl]-5-nitro-1H-pyrrole-2-carboxylate (6f).
The method for 4e was followed, using 6d (95.6 mg, 0.308 mmol),
Sudan Red 7B (0.2 mg) in CH2Cl2 (10 mL), Me2S (0.10 mL, 1.4
mmol) and a reduction period of 6 h. The mixture was evaporated
directly at ca. 15 °C to give 6e as a thick, yellow oil, which was used
immediately, as follows.
122.4 (s), 126.4 (d), 132.2 (d), 136.7 (s), 137.2 (s), 159.7 (s), 162.8
(s); exact mass (electrospray) m/z calcd for C13H15N2O7 (M + H)+
311.0874, found 311.0871.
Compound 7c is sensitive to silica gel and acidic solvents (CDCl3),
and it rearranges to a significant extent within several h in solution
(CDCl3) at room temperature.
Methyl ( )-1-(1-methoxy-1,2-dioxohex-5-en-3-yl)-4-nitro-
1H-pyrrole-2-carboxylate (7d). A solution of 7c (110 mg, 0.355
mmol) in PhMe (3.6 mL) was refluxed for an arbitrary period of 24 h,
cooled and evaporated to afford 7d (110.1 mg, ca. 100%) as a thick,
light yellow oil: FTIR (CDCl3, cast) 3148, 1739, 1714 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 2.74−2.81 (m, 1 H), 3.05−3.11 (m, 1 H), 3.83
(s, 3 H), 3.94 (s, 3 H), 5.19 (apparent t, J = 1.5 Hz, 1 H), 5.22 (ddd, J
= 7.0, 2.5, 1.0 Hz, 1 H), 5.72−5.80 (m, 1 H), 6.50 (dd, J = 10.0, 4.5
Hz, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.83 (d, J = 2.0 Hz, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 34.1 (t), 52.2 (q), 53.6 (q), 62.5 (d),
113.4 (d), 120.5 (t), 122.2 (s), 125.7 (d), 130.6 (d), 136.3 (s), 159.9
(s), 160.9 (s), 187.5 (s); exact mass (electrospray) m/z calcd for
C13H14N2NaO7 (M + Na)+ 333.0693, found 333.0685.
Methyl ( )-1-(1-methoxy-1,2,5-trioxopentan-3-yl)-4-nitro-
1H-pyrrole-2-carboxylate (7e) and Methyl 1-[2-(methoxycar-
bonyl)-1H-pyrrol-3-yl]-4-nitro-1H-pyrrole-2-carboxylate (7f).
The method for 4e was followed, using 7d (73.3 mg, 0.236 mmol),
Sudan Red 7B (0.2 mg) in CH2Cl2 (6 mL), Me2S (0.10 mL, 1.4
mmol) and a reduction period of 12 h. The mixture was evaporated
directly at ca. 15 °C to give 7e as a thick, yellow oil, which was used
immediately, as follows.
The method for 3f was followed, using NH4OAc (360 mg, 4.68
mmol), the above crude keto aldehyde 6e in AcOH (6 mL) and a
reaction time of 3.5 h. (The addition of NH4OAc was made within ca.
2 min of dissolving the keto aldehyde in AcOH.) In this case extraction
was done with EtOAc. Flash chromatography of the crude reaction
product over silica gel (1 × 15 cm), using 1:3 EtOAc−hexane to 1:2
EtOAc−hexane, gave 6f (52.2 mg, 58% over three steps) as a white
1
solid: mp 127−132 °C; FTIR (CDCl3, cast) 3332, 1717 cm−1; H
NMR (CDCl3, 125 MHz) δ 3.63 (s, 3 H), 3.75 (s, 3 H), 6.35
(apparent t, J = 3.0 Hz, 1 H), 6.98 (apparent t, J = 3.0 Hz, 1 H), 7.02
(d, J = 4.5 Hz, 1 H), 7.24 (d, J = 4.5 Hz, 1 H), 9.32 (br, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 51.6 (q), 52.0 (q), 110.6 (d), 112.1 (d),
116.0 (d), 117.6 (s), 121.0 (d), 125.7 (s), 128.1 (s), 141.4 (s), 159.5
(s), 159.6 (s); exact mass (electrospray) m/z calcd for C12H11N3NaO6
(M + Na)+ 316.0540, found 316.0533.
The method for 3f was followed, using NH4OAc (180 mg, 2.34
mmol), the above crude keto aldehyde 7e in AcOH (2 mL) and a
reaction time of 3 h. In this case the extraction was done with EtOAc.
Flash chromatography of the crude product over silica gel (1 × 15
cm), using 1:1 EtOAc−hexane, gave 7f (46.9 mg, 68% over three
steps) as a white solid: mp 168−170 °C; FTIR (CDCl3, cast) 3327,
Methyl 1-(3-methoxy-2-methylidene-3-oxopropyl)-4-nitro-
1H-pyrrole-2-carboxylate (7a). The method for 4a was followed,
using K2CO3 (1.98 g, 14.3 mmol), 731 (610 mg, 3.59 mmol) and ester
1.212 (630 mg, 3.99 mmol) in MeCN (36 mL), and a reflux period of
22 h. Flash chromatography of the crude product over silica gel (3 ×
20 cm), using 1:6 EtOAc−hexane, gave 7a (960 mg, 100%) as a white
1
1
solid: mp 100−103 °C; FTIR (CDCl3, cast) 3137, 1721 cm−1; H
3142, 1718 cm−1; H NMR (CDCl3, 500 MHz) δ 3.69 (s, 3 H), 3.76
NMR (CDCl3, 500 MHz) δ 3.80 (s, 3 H), 3.84 (s, 3 H), 5.25 (s, 2 H),
5.58 (s, 1 H), 6.37 (s, 1 H), 7.44 (d, J = 2.0 Hz, 1 H), 7.74 (d, J = 2.0
Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 49.7 (t), 51.9 (q), 52.3 (q),
113.2 (d), 122.2 (t), 127.7 (d), 128.3 (s), 135.7 (s), 135.8 (s), 160.2
(s), 165.4 (s); exact mass (electrospray) m/z calcd for C11H12N2NaO6
(M + Na)+ 291.0588, found 291.0584.
(s, 3 H), 6.33 (apparent t, J = 3.0 Hz, 1 H), 6.94 (apparent t, J = 3.0
Hz, 1 H), 7.51 (d, J = 2.0 Hz, 1 H), 7.69 (d, J = 2.0 Hz, 1 H), 9.54 (br,
1 H); 13C NMR (CDCl3, 125 MHz) δ 51.8 (q), 51.9 (q), 109.5 (d),
112.3 (d), 117.3 (s), 121.2 (d), 124.6 (s), 127.2 (s), 128.6 (d), 136.3
(s), 159.7 (s), 159.8 (s); exact mass (electrospray) m/z calcd for
C12H11N3NaO6 (M + Na)+ 316.0540, found 316.0533.
Methyl 1-(3-methoxy-2,3-dioxopropyl)-4-nitro-1H-pyrrole-
2-carboxylate (7b). The method for 4b was followed, using 7a
(960 mg, 3.58 mmol), Sudan Red 7B (1 mg) in CH2Cl2 (48 mL) and
Me2S (0.7 mL, 10 mmol), with a reduction period of 6 h. In this case,
flash chromatography of the crude product over silica gel (3 × 15 cm),
using 1:2 EtOAc−hexane, gave 7b (940 mg, 97%) as a white solid: mp
Methyl 4,5-dichloro-1-(3-methoxy-2-methylidene-3-oxo-
propyl)-1H-pyrrole-2-carboxylate (8a). The method for 3a was
followed, using 1.212 (515.9 mg, 3.264 mmol) in MeCN (5 mL),
K2CO3 (1.22 g, 8.74 mmol) and 811,32 (422 mg, 2.18 mmol) in MeCN
(15 mL), and a reflux period of 38 h. Flash chromatography of the
crude product over silica gel (2.8 × 20 cm), using first hexane and then
2:25 EtOAc−hexane, gave 8a (618.7 mg, 97%) as a white solid: mp
1
118−121 °C; FTIR (CDCl3, cast) 3140, 1759, 1738, 1716 cm−1; H
1
NMR (CDCl3, 500 MHz) δ 3.81 (s, 3 H), 3.97 (s, 3 H), 5.56 (s, 2 H),
7.47 (d, J = 2.0 Hz, 1 H), 7.61 (d, J = 2.0 Hz, 1 H); 13C NMR (CDCl3,
125 MHz) δ 52.2 (q), 53.6 (q), 56.3 (t), 113.0 (d), 122.2 (s), 127.7
(d), 136.2 (s), 159.6 (s), 160.7 (s), 185.0 (s); exact mass
(electrospray) m/z calcd for C10H10N2NaO7 (M + Na)+ 293.0830,
found 293.0830.
76−79 °C; FTIR (CDCl3, cast) 1719 cm−1; H NMR (CDCl3, 500
MHz) δ 3.77 (s, 3 H), 3.80 (s, 3 H), 4.82 (apparent t, J = 2.0 Hz, 1 H),
5.28 (apparent t, J = 2.0 Hz, 2 H), 6.20 (apparent t, J = 2.0 Hz, 1 H),
6.95 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 46.3 (t), 51.5 (q), 52.1
(q), 110.5 (s), 116.8 (d), 120.5 (s), 121.8 (s), 124.2 (t), 136.0 (s),
159.6 (s), 165.3 (s); exact mass (electrospray) m/z calcd for
C11H11Cl2NNaO4 (M + Na)+ 313.9957, found 313.9951.
Methyl 1-[(1Z)-3-methoxy-3-oxo-2-(prop-2-en-1-yloxy)prop-
1-en-1-yl]-4-nitro-1H-pyrrole-2-carboxylate (7c). A solution of
7b (199 mg, 0.737 mmol) in DMF (5 mL) was added over 10 min to a
stirred mixture of K2CO3 (102 mg, 0.739 mmol), allyl bromide (0.60
mL, 7.1 mmol), 18-crown-6 (195 mg, 0.739 mmol) and DMF (10
mL). Stirring was continued, and the progress of the reaction was
monitored by TLC every 10 min. When all of 7b had been consumed
(ca. 45 min), the reaction mixture was diluted with water and extracted
with EtOAc. The combined organic extracts were washed with brine,
dried (MgSO4), and evaporated. Crystallization of the residue from
Et2O gave 7c (137 mg, 60%) as a white solid: mp 107−110 °C; FTIR
(CDCl3, cast) 3142, 1724 cm−1; 1H NMR (C6D6, 500 MHz) δ 3.25 (s,
3 H), 3.27 (s, 3 H), 4.26 (ddd, J = 6.0, 1.5, 1.0 Hz, 2 H), 4.92 (ddd, J =
10.5, 2.5, 1.0 Hz, 1 H), 5.04 (ddd, J = 17.0, 2.5, 1.5 Hz, 1 H), 5.63
(ddt, J = 17.5, 10.0, 6.0 Hz, 1 H), 7.28 (d, J = 2.0 Hz, 1 H), 8.51 (dd, J
= 2.0, 0.5 Hz, 1 H), 8.60 (d, J = 0.5 Hz, 1 H); 13C NMR (C6D6, 125
MHz) δ 51.0 (q), 51.4 (q), 72.8 (t), 113.2 (d), 119.2 (d), 119.3 (t),
Methyl 4,5-dichloro-1-(3-methoxy-2,3-dioxopropyl)-1H-pyr-
role-2-carboxylate (8b). NMO (921 mg, 7.63 mmol) and OsO4
(0.1 M in PhMe, 4.24 mL, 0.42 mmol) were added successively to a
stirred solution of 8a (619 mg, 2.12 mmol) in a mixture of THF (11
mL) and water (11 mL) (protected from light). After 19 h, the
reaction mixture was diluted with EtOAc, washed with water, dried
(MgSO4) and evaporated to give a yellow residue. A solution of
Pb(OAc)4 (1.22 g, 2.61 mmol) in CH2Cl2 (5 mL) was added to a
stirred solution of the yellow residue in CH2Cl2 (15 mL), and stirring
was continued for 20 min in subdued light. The mixture was then
filtered through a pad of silica gel, using EtOAc as a rinse. Evaporation
of the filtrate and flash chromatography of the residue over silica gel
(2.8 × 25 cm), using 1:10 to 1:5 EtOAc−hexanes, gave 8b (538.2 mg,
86%) as a white solid: mp 63−67 °C; FTIR (CDCl3, cast) 3137, 1762,
1
1738, 1708 cm−1; H NMR (CDCl3, 500 MHz) δ 3.75 (s, 3 H), 3.94
(s, 3 H), 5.63 (s, 2 H), 6.96 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ
H
dx.doi.org/10.1021/jo401892t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
51.7 (q), 52.7 (t), 53.4 (q), 110.9 (s), 116.9 (d), 120.5 (s), 121.9 (s),
159.7 (s), 160.3 (s), 185.5 (s); exact mass (electrospray) m/z calcd for
C10H9Cl2NNaO5 (M + Na)+ 315.9750, found 315.9745.
solution of 2,2,2-trichloro-1-(4,5-diiodo-1H-pyrrol-2-yl)ethan-1-
one13,14 (1.20 g, 2.58 mmol) in MeOH (26 mL). The cold bath
was left in place but not recharged, and stirring was continued for 2 h,
during which time the reaction mixture reached room temperature.
The mixture was evaporated directly, and the residue was acidified
with dilute hydrochloric acid (1.0 M) and extracted with EtOAc. The
combined organic extracts were washed with brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel (4
× 15 cm), using 1:5 EtOAc−hexane, gave 9 (943 mg, 96%) as a white
Methyl 4,5-dichloro-1-[(1Z)-3-methoxy-3-oxo-2-(prop-2-en-
1-yloxy)prop-1-en-1-yl]-1H-pyrrole-2-carboxylate (8c). NaH
(12.7 mg, 60% w/w in oil, 0.322 mmol) was added to a stirred and
cooled (−42 °C) solution of 8b (71.8 mg, 0.244 mmol) in DMF (5
mL). After 20 min, allyl bromide (0.026 mL, 0.30 mmol) was added.
The cold bath was left in place but not recharged, and stirring was
continued for 1.5 h, during which time the reaction mixture reached
room temperature. Stirring was continued for a further 6.5 h, water
was then added, and the mixture was extracted with Et2O. The
combined organic extracts were washed with water, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel
(1.2 × 15 cm), using 1:25 to 1:10 EtOAc−hexanes, gave 8c (59.5 mg,
1
solid: mp 200−204 °C; FTIR (CDCl3, cast) 3235, 1682 cm−1; H
NMR (CDCl3, 500 MHz) δ 3.89 (s, 3 H), 6.93 (d, J = 3.0 Hz, 1 H),
9.83 (br, 1 H); 13C NMR (CDCl3, 125 MHz) δ 52.1 (q), 77.0 (s),
83.3 (s), 123.1 (d), 128.7 (s), 159.7 (s); exact mass (electrospray) m/z
calcd for C6H5I2NNaO2 (M + Na)+ 399.8302, found 399.8301.
Methyl 4,5-diiodo-1-(3-methoxy-2-methylidene-3-oxoprop-
yl)-1H-pyrrole-2-carboxylate (9a). The procedure for 4a was
followed, using K2CO3 (790 mg, 5.72 mmol), 9 (1.08 g, 2.87 mmol)
and ester 1.212 (480 mg, 3.04 mmol) in MeCN (29 mL). At the end of
the reaction the extraction was done with Et2O. Flash chromatography
of the crude product over silica gel (3 × 20 cm), using 1:5 EtOAc−
hexane, gave 9a (1.30 g, 96%) as a white solid: mp 101−104 °C; FTIR
1
73%) as a colorless oil: FTIR (CDCl3, cast) 1732 cm−1; H NMR
(CDCl3, 500 MHz) δ 3.79 (s, 3 H), 3.86 (s, 3 H), 4.31 (ddd, J = 6.0,
1.5, 1.5 Hz, 2 H), 5.08−5.15 (m, 2 H), 5.68 (ddt, J = 17.5, 10.0, 6.0
Hz, 1 H), 6.95 (s, 1 H), 7.31 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ
51.7 (q), 52.6 (q), 72.9 (t), 111.8 (s), 117.0 (d), 118.6 (t), 119.2 (d),
121.8 (s), 122.0 (s), 132.4 (d), 143.5 (s), 159.6 (s), 163.0 (s); exact
mass (electrospray) m/z calcd for C13H13Cl2NNaO5 (M + Na)+
356.0063, found 356.0057.
1
(CDCl3, cast) 1715 cm−1; H NMR (CDCl3, 500 MHz) δ 3.78 (s, 3
H), 3.82 (s, 3 H), 4.73 (apparent t, J = 2.0 Hz, 1 H), 5.39 (apparent t,
2 H), 6.22 (apparent t, J = 2.0 Hz, 1 H), 7.22 (s, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 51.6 (q), 52.1 (t), 52.2 (q), 76.4 (s), 94.5 (s),
124.5 (t), 126.0 (d), 127.5 (s), 136.2 (s), 159.1 (s), 165.4 (s); exact
mass (electrospray) m/z calcd for C11H11I2NNaO4 (M + Na)+
497.8670, found 497.8661.
Methyl ( )-4,5-dichloro-1-(1-methoxy-1,2-dioxohex-5-en-3-
yl)-1H-pyrrole-2-carboxylate (8d). A solution of 8c (257.6 mg,
0.7709 mmol) in PhMe (8 mL) was stirred and refluxed for 20 h and
then cooled to room temperature. Evaporation of the solution gave 8d
as a light yellow solid (257.6 mg, 100%), which was used directly in
the next step: mp 92−96 °C; (crude) FTIR (CDCl3, cast) 3136, 1735,
Methyl 4,5-diiodo-1-(3-methoxy-2,3-dioxopropyl)-1H-pyr-
role-2-carboxylate (9b). NMO (260 mg, 2.22 mmol) and OsO4
(0.05 M in PhMe, 1.2 mL, 0.06 mmol) were added to a stirred solution
of 9a (300 mg, 0.632 mmol) in 1:1 THF−water (7 mL) (protected
from light). The yellow mixture was stirred for 36 h and then
quenched with aqueous NaHSO3 (10% w/v). The aqueous layer was
extracted with EtOAc, and the combined organic extracts were washed
with brine, dried (MgSO4) and evaporated. Pb(OAc)4 (310 mg, 0.699
mmol) was added to a stirred and cooled (0 °C) solution of the
residue in MeCN (7 mL) and stirring at 0 °C was continued. The
reaction was monitored by TLC (silica, 1:1 EtOAc−hexane) and,
when all 9a had been consumed (ca. 5 min), pinacol (8.3 mg, 0.070
mmol) was added. Stirring was continued for ca. 2 min, and the
mixture was diluted with EtOAc and filtered through a sintered disc.
The organic layer was washed with brine, dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (2 ×
20 cm), using 1:4 EtOAc−hexane, gave 9b (290 mg, 96%) as a white
solid: mp 95−98 °C; FTIR (CDCl3, cast) 1758, 1736, 1702 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 3.76 (s, 3 H), 3.97 (s, 3 H), 5.76 (s, 2 H),
7.22 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 51.8 (q), 53.4 (q), 58.7
(t), 76.6 (s), 95.2 (s), 125.9 (d), 127.4 (s), 159.7 (s), 159.8 (s), 185.8
(s); exact mass (electrospray) m/z calcd for C10H9I2NNaO5 (M +
Na)+ 499.8462, found 499.8461.
Methyl 4,5-diiodo-1-[(1Z)-3-methoxy-3-oxo-2-(prop-2-en-1-
yloxy)prop-1-en-1-yl]-1H-pyrrole-2-carboxylate (9c). The meth-
od for 8c was followed, using NaH (60% w/w in mineral oil, 26.2 mg,
0.655 mmol), a reaction temperature of −40 °C, 9b (260 mg, 0.545
mmol), DMF (10 mL), a stirring period of 30 min, allyl bromide (0.06
mL, 0.7 mmol), and a final stirring period of 12 h. In this case the
reaction mixture was quenched with saturated aqueous NH4Cl, and
extracted with EtOAc. Flash chromatography of the crude product
over silica gel (2 × 15 cm), using 1:6 EtOAc−hexane), gave 9c (227
mg, 81%) as a thick, colorless oil: FTIR (CDCl3, cast) 1730 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 3.79 (s, 3 H), 3.88 (s, 3 H), 4.26 (ddd, J =
6.0, 1.5, 1.5 Hz, 2 H), 5.09 (ddd, J = 4.5, 3.0, 1.5 Hz, 1 H), 5.12 (ddd, J
= 6.0, 3.0, 1.5 Hz, 1 H), 5.65 (ddt, J = 17.5, 10.0, 6.0 Hz, 1 H), 7.14 (s,
1 H), 7.31 (s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 51.7 (q), 52.6
(q), 72.9 (t), 77.6 (s), 92.8 (s), 118.6 (t), 123.2 (d), 125.6 (d), 129.5
(s), 132.5 (d), 143.5 (s), 158.9 (s), 163.1 (s); exact mass
(electrospray) m/z calcd for C13H13I2NNaO5 (M + Na)+ 539.8775,
found 539.8776.
1
1708 cm−1; H NMR (CDCl3, 500 MHz) δ 2.66−2.73 (m, 1 H),
3.11−3.16 (m, 1 H), 3.73 (s, 3 H), 3.79 (s, 3 H), 4.94−4.98 (m, 2 H),
5.23−5.61 (m, 1 H), 5.94 (br, 1 H), 6.96 (s, 1 H); 13C NMR (CDCl3,
125 MHz) δ 34.4 (t), 51.9 (q), 53.0 (q), 62.9 (d), 111.3 (s), 117.9 (d),
119.5 (t), 120.2 (s), 131.7 (d), 160.4 (s), 161.3 (s), 187.4 (s); exact
mass (electrospray) m/z calcd for C13H13Cl2NNaO5 (M + Na)+
356.0063, found 356.0058.
Methyl ( )-4,5-dichloro-1-(1-methoxy-1,2,5-trioxopentan-3-
yl)-1H-pyrrole-2-carboxylate (8e) and Methyl 4,5-dichloro-1-
[2-(methoxycarbonyl)-1H-pyrrol-3-yl]-1H-pyrrole-2-carboxy-
late (8f). NMO (580 mg, 4.96 mmol) and OsO4 (0.05 M in PhMe,
2.8 mL, 0.14 mmol) were added to a stirred solution of 8d (471 mg,
1.41 mmol) in 1:1 THF−water (16 mL) (protected from light). The
yellow mixture was stirred for 6 h, quenched with aqueous NaHSO3
(10% w/v) and extracted with EtOAc. The combined organic extracts
were washed with brine, dried (MgSO4) and evaporated to afford a
pale yellow residue (260 mg, 50%). Pb(OAc)4 (320 mg, 0.722 mmol)
was added to a stirred and cooled (0 °C) solution of the residue in
MeCN (10 mL) and stirring at 0 °C was continued. When all the
starting material had reacted (ca. 5 min, TLC control, silica, 1:1
EtOAc−hexane), pinacol solution (0.05 M in MeCN, several drops)
was added dropwise. When the excess of Pb(OAc)4 had reacted (ca. 2
min, TLC control, silica, 1:1 EtOAc−hexane), the mixture was diluted
with EtOAc and filtered while still cold through a sintered disc. The
organic layer was evaporated at 10 °C to give 8e as a thick, yellow oil,
which was used immediately, as follows.
The method for 3f was followed, using NH4OAc (540 mg, 7.01
mmol), the above crude keto aldehyde 8e in AcOH (8 mL) and a
reaction time of 3.5 h. In this case the extraction was done with
EtOAc. Flash chromatography of the crude product over silica gel (2 ×
15 cm), using 1:3 EtOAc−hexane, gave 8f (107 mg, 24% over three
steps) as a white solid: mp 161−165 °C; FTIR (CDCl3, cast) 3308,
1
3137, 1710 cm−1; H NMR (CDCl3, 500 MHz) δ 3.69 (s, 3 H), 3.71
(s, 3 H), 6.29 (apparent t, J = 3.5 Hz, 1 H), 6.98 (apparent t, J = 3.5
Hz, 1 H), 7.01 (s, 1 H), 9.26 (br, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 51.4 (q), 51.7 (q), 110.7 (s), 110.9 (d), 116.6 (d), 118.3 (s), 120.9
(d), 122.6 (s), 123.0 (s), 125.6 (s), 159.4 (s), 159.7 (s); exact mass
(electrospray) m/z calcd for C12H10Cl2N2NaO4 (M + Na)+ 338.9910,
found 338.9908.
Methyl 4,5-diiodo-1H-pyrrole-2-carboxylate (9). MeONa
(167 mg, 3.09 mmol) was added to a stirred and cooled (0 °C)
I
dx.doi.org/10.1021/jo401892t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Methyl ( )-4,5-diiodo-1-(1-methoxy-1,2-dioxohex-5-en-3-
yl)-1H-pyrrole-2-carboxylate (9d). A solution of 9c (210 mg,
0.406 mmol) in PhMe (4.1 mL) was refluxed for 42 h in the dark,
cooled and evaporated to afford 9d (208.2 mg, ca. 99%) as a brown
were dried (MgSO4) and evaporated. Flash chromatography of the
residue over silica gel (3.8 × 20 cm), using 3:50 EtOAc−hexanes, gave
2.2 (2.92 g, 96%) as a colorless oil: FTIR (CDCl3, cast) 1727 cm−1;
1H NMR (CDCl3, 500 MHz) δ −0.07 (s, 3 H), 0.10 (s, 3 H), 0.90 (s,
9 H), 3.72 (s, 3 H), 3.85 (s, 3 H), 5.85 (t, J = 2.0 Hz, 1 H), 6.09 (s, 1
H), 6.25−6.26 (m, 1 H), 6.87 (dd, J = 8.0, 1.0 Hz, 1 H), 6.95 (dt, J =
7.5, 1.0 Hz, 1 H), 7.23−7.27 (m, 1 H), 7.39 (dd, J = 7.5, 2.0 Hz, 1 H);
13C NMR (CDCl3, 125 MHz) δ −5.1 (q), −5.0 (q), 18.2 (s), 25.8 (q),
51.6 (q), 55.4 (q), 66.1 (d), 110.4 (d), 120.4 (d), 124.5 (t), 127.9 (d),
128.4 (d), 131.0 (s), 143.9 (s), 156.2 (s), 166.8 (s); exact mass
(electrospray) m/z calcd for C18H28NaO4Si (M + Na)+ 359.1649,
found 359.1650.
1
solid: FTIR (CDCl3, cast) 1732, 1705 cm−1; H NMR (CDCl3, 500
MHz) δ 2.69−2.76 (m, 1 H), 3.14−3.19 (m, 1 H), 3.73 (s, 3 H), 3.80
(s, 3 H), 4.95−4.99 (m, 2 H), 5.58−5.67 (m, 1 H), 5.72 (br, 1 H),
7.23 (s, 1 H); 13C NMR (CDCl3, 500 MHz) δ 35.0 (t), 52.0 (q), 53.0
(q), 118.6 (s), 119.4 (t), 127.1 (d), 131.9 (d), 132.5 (d), 159.8 (s),
161.5 (s), 187.6 (s), other expected signals were not observed; exact
mass (electrospray) m/z calcd for C13H13I2NNaO5 (M + Na)+
539.8775, found 539.8776. Compound 9d is sensitive to light.
Methyl ( )-4,5-diiodo-1-(1-methoxy-1,2,5-trioxopentan-3-
yl)-1H-pyrrole-2-carboxylate (9e) and Methyl 4,5-diiodo-1-[2-
(methoxycarbonyl)-1H-pyrrol-3-yl]-1H-pyrrole-2-carboxylate
(9f). The method for 8f was followed, using NMO (160 mg, 1.37
mmol) and OsO4 (0.05 M in PhMe, 0.8 mL, 0.04 mmol), 9d (210 mg,
0.406 mmol) in 1:1 THF−water (4 mL) (protected from light). The
yellow mixture was stirred for 6 h and then quenched with aqueous
NaHSO3 (10% w/v). Pb(OAc)4 (180 mg, 0.406 mmol) was added to a
stirred and cooled (0 °C) solution of the crude product, which is
sensitive to light, in MeCN (5 mL). The reaction was monitored by
TLC (silica, 1:1 EtOAc−hexane) and when all of the diol had been
consumed (ca. 5 min), pinacol solution (0.05 M in MeCN, 5 drops)
was added dropwise. When the excess of Pb(OAc)4 had reacted (ca. 2
min), the mixture was diluted with EtOAc, and the cold reaction
mixture was filtered through a sintered disc. The organic layer was
quickly washed with saturated aqueous NaHCO3 and brine, dried
(MgSO4) and evaporated at 15 °C to give 9e as a thick, yellow oil,
which is sensitive to light and was used immediately, as follows.
With the exception that the reaction flask was protected from light,
the method for 3f was followed, using NH4OAc (460 mg, 5.98 mmol),
the above crude keto aldehyde 9e in AcOH (4 mL) and a reaction
time of 5 h (protected from light). In this case the extraction was done
with EtOAc. The combined organic extracts were washed with
saturated aqueous NaHCO3 and brine, dried (MgSO4) and
evaporated. Flash chromatography of the crude product over silica
gel (1 × 20 cm), using 1:3 EtOAc−hexane, gave 9f (60.7 mg, 30% over
three steps) as a white solid: mp 177−182 °C; FTIR (CDCl3, cast)
(
)-2-{[(tert-Butyldimethylsilyl)oxy](2-methoxyphenyl)-
methyl}prop-2-en-1-ol (2.3). DIBAL-H (1.0 M in PhMe, 22 mL, 22
mmol) was added dropwise to a stirred and cooled (−78 °C) solution
of 2.2 (2.92 g, 8.69 mmol) in CH2Cl2 (40 mL). Stirring at −78 °C was
continued for 2.5 h and then MeOH (2.0 mL) was added. The cooling
bath was removed and a saturated aqueous solution of Rochelle’s salt
(ca. 100 mL) was added. Stirring was continued for 4 h, and the
mixture was then extracted with EtOAc. The combined organic
extracts were washed with brine, dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (3.8 × 20 cm), using
1:10 to 3:25 EtOAc−hexanes, gave 2.3 (2.46 g, 92%) as a colorless oil:
FTIR (CDCl3, cast) 3374 cm−1; 1H NMR (CDCl3, 500 MHz) δ −0.06
(s, 3 H), 0.10 (s, 3 H), 0.93 (s, 9 H), 2.34 (br, 1 H), 3.85 (s, 3 H),
3.98−4.02 (m, 1 H), 4.13 (d, J = 13.5 Hz, 1 H), 5.09−5.11 (m, 1 H),
5.21−5.22 (m, 1 H), 5.78 (s, 1 H), 6.87 (dd, J = 8.0, 1.0 Hz, 1 H),
6.98−7.02 (m, 1 H), 7.23−7.27 (m, 1 H), 7.52 (dd, J = 8.0, 2.0 Hz, 1
H); 13C NMR (CDCl3, 125 MHz) δ −5.2 (q), −5.0 (q), 18.2 (s), 25.8
(q), 55.4 (q), 63.8 (t), 70.2 (d), 110.3 (d), 111.6 (t), 120.8 (d), 127.5
(d), 128.3 (d), 131.1 (s), 149.6 (s), 155.7 (s); exact mass
(electrospray) m/z calcd for C17H28NaO3Si (M + Na)+ 331.1700,
found 331.1696.
(
)-2-{[(tert-Butyldimethylsilyl)oxy](2-methoxyphenyl)-
methyl}prop-2-en-1-yl acetate (2.4). Pyridine (1.30 mL, 16.1
mmol) and AcCl (0.93 mL, 12.8 mmol) were added successively to a
stirred and cooled (0 °C) solution of 2.3 (2.00 g, 9.01 mmol) in
CH2Cl2 (40 mL). After 40 min, the mixture was quenched with
saturated aqueous NaHCO3 and washed with saturated aqueous
CuSO4, water and brine. The organic solution was dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (3.8 ×
20 cm), using 3:50 EtOAc−hexanes, gave 2.4 (2.76 g, 99%) as a
1
3308, 1709 cm−1; H NMR (CDCl3, 500 MHz) δ 3.67 (s, 3 H), 3.69
(s, 3 H), 6.24 (apparent t, J = 3.0 Hz, 1 H), 6.98 (apparent t, J = 3.0
Hz, 1 H), 7.22 (s, 1 H), 9.25 (br, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 51.4 (q), 51.7 (q), 76.0 (s), 96.6 (s), 111.0 (d), 118.3 (s), 120.8 (d),
125.4 (d), 129.5 (s), 130.1 (s), 158.8 (s), 159.7 (s); exact mass
(electrospray) m/z calcd for C12H10I2N2NaO4 (M + Na)+ 522.8622,
found 522.8622.
colorless oil: FTIR (CDCl3, cast) 1745 cm−1; H NMR (CDCl3, 500
1
MHz) δ −0.10 (s, 3 H), 0.05 (s, 3 H), 0.89 (s, 9 H), 1.98 (s, 3 H),
3.80 (s, 3 H), 4.49 (AB q, J = 13.5 Hz, ΔνAB = 9.6 Hz, 2 H), 5.11−5.12
(m, 1 H), 5.31−5.32 (m, 1 H), 5.69 (s, 1 H), 6.82 (dd, J = 8.5, 1.0 Hz,
1 H), 6.94 (td, J = 7.5, 1.0 Hz, 1 H), 7.21 (ddd, J = 8.3, 7.3, 2.0 Hz, 1
H), 7.44 (dd, J = 7.5, 2.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ
−5.2 (q), −5.1 (q), 18.2 (s), 20.8 (q), 25.8 (q), 55.3 (q), 63.9 (t), 68.6
(d), 110.2 (d), 112.3 (t), 120.6 (d), 127.6 (d), 128.2 (d), 131.0 (s),
145.9 (s), 155.9 (s), 170.6 (s); exact mass (electrospray) m/z calcd for
C19H30NaO4Si (M + Na)+ 373.1806, found 373.1806.
Methyl 2-[(2,5-dimethyl-1H-pyrrol-1-yl)methyl]prop-2-
enoate (10a). NaH (60% w/w in mineral oil 34.0 mg, 0.850
mmol) was added to a cold (0 °C) and stirred solution of 1033 (freshly
distilled, 74 mg, 0.78 mmol) in DMF (2 mL) (N2 atmosphere,
exclusion of oxygen is important). The cold bath was left in place but
not recharged, and stirring was continued for 1 h. Ester 1.212 (123 mg,
0.778 mmol) in DMF (2 mL) was added at a fast dropwise rate, and
stirring was continued for 24 h. The mixture was diluted with water
and extracted with Et2O. The combined organic extracts were washed
with brine, dried (MgSO4) and evaporated. Flash chromatography of
the residue over silica gel (1 × 12 cm), using 1:10 EtOAc−hexane,
gave 10a (87.0 mg, 58%) as a colorless oil: FTIR (CDCl3, cast) 1719
cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.16 (s, 6 H), 3.86 (s, 3 H), 4.63
(apparent t, J = 2.0 Hz, 2 H), 4.79 (apparent td, J = 2.0, 1.0 Hz, 1 H),
5.85 (s, 2 H), 6.23 (apparent td, J = 2.0, 1.0 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 12.0 (q), 43.7 (t), 52.0 (q), 105.6 (d), 125.0 (t),
127.6 (s), 137.2 (s), 166.0 (s); exact mass (electrospray) m/z calcd for
C11H16NO2 (M + H)+ 194.1176, found 194.1176.
(
)-3-Hydroxy-3-(2-methoxyphenyl)-2-methylidenepropyl
acetate (2.5) and ( )-3-Hydroxy-1-(2-methoxyphenyl)-2-meth-
ylidenepropyl acetate (2.6). Bu4NF (1.0 M in THF, 3.8 mL, 3.8
mmol) was added dropwise to a stirred solution of 2.4 (1.33 g, 3.79
mmol) in THF (40 mL). Stirring was continued for 3.5 h, and the
mixture was then quenched with saturated aqueous NH4Cl and
extracted with EtOAc. The combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (2.8 × 20 cm), using 3:20 to 3:10 EtOAc−hexanes, gave 2.5
(646.2 mg, 72%) as a colorless oil. Further development of the
column, using 2:5 to 3:5 EtOAc−hexanes, gave 2.6 (135.0 mg, 15%)
as a colorless oil. Compound 2.5: FTIR (CDCl3, cast) 3464, 1739
cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.04 (s, 3 H), 2.98 (s, 1 H), 3.84
(s, 3 H), 4.57 (AB q, J = 13.5 Hz, ΔνAB = 37.7 Hz, 2 H), 5.25−5.26
(m, 1 H), 5.29−5.31 (m, 1 H), 5.52 (s, 1 H), 6.90 (dd, J = 8.5, 1.0 Hz,
1 H), 6.98 (td, J = 7.5, 1.0 Hz, 1 H), 7.28 (ddd, J = 8.3, 7.5, 2.0 Hz, 1
H), 7.33 (dd, J = 7.5, 1.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ
20.9 (q), 55.4 (q), 64.7 (t), 70.5 (d), 110.8 (d), 113.5 (t), 120.9 (d),
Methyl ( )-2-{[(tert-butyldimethylsilyl)oxy](2-methoxy-
phenyl)methyl}prop-2-enoate (2.2). Imidazole (1.55 g, 22.5
mmol) and t-BuMe2SiCl (2.08 g, 13.5 mmol) were added successively
to a stirred solution of 2.121 (2.00 g, 9.01 mmol) in CH2Cl2 (20 mL).
Stirring was continued for 5 h, and the mixture was then quenched
with water and extracted with CH2Cl2. The combined organic extracts
J
dx.doi.org/10.1021/jo401892t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
127.8 (d), 129.0 (d), 129.5 (s), 145.1 (s), 156.9 (s), 170.7 (s); exact
mass (electrospray) m/z calcd for C13H16NaO4 (M + Na)+ 259.0941,
found 259.0937.
164−167 °C; FTIR (CDCl3, cast) 3221, 1768, 1746 cm−1; H NMR
(CDCl3, 500 MHz) δ 2.21 (s, 3 H), 6.66 (d, J = 3.0 Hz, 1 H), 7.20
(dd, J = 8.5, 1.0 Hz, 1 H), 7.33 (td, J = 7.5, 1.0 Hz, 1 H), 7.55 (ddd, J =
8.0, 7.5, 1.5 Hz, 1 H), 7.62 (dd, J = 8.0, 1.5 Hz, 1 H), 10.15 (br, 1 H);
13C NMR (CDCl3, 125 MHz) δ 20.9 (q), 112.3 (s), 119.0 (d), 122.0
1
Compound 2.6: FTIR (CDCl3, cast) 3444, 1739 cm−1; H NMR
(CDCl3, 500 MHz) δ 2.13 (s, 3 H), 2.20 (br, 1 H), 3.86 (s, 3 H), 4.11
(s, 2 H), 5.17 (t, J = 1.0 Hz, 1 H), 5.28 (t, J = 1.0 Hz, 1 H), 6.74 (s, 1
H), 6.91 (dd, J = 8.5, 1.0 Hz, 1 H), 6.99 (td, J = 7.5, 1.0 Hz, 1 H), 7.31
(m, 1 H), 7.38 (dd, J = 7.5, 1.5 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 21.2 (q), 55.7 (q), 63.6 (t), 69.6 (d), 110.8 (d), 112.3 (t),
120.7 (d), 126.7 (s), 127.4 (d), 129.4 (d), 147.1 (s), 156.6 (s), 170.0
(s); exact mass (electrospray) m/z calcd for C13H16NaO4 (M + Na)+
259.0941, found 259.0937.
(s), 123.6 (d), 125.7 (d), 128.5 (s), 129.9 (d), 130.1 (s), 132.4 (d),
148.6 (s), 169.3 (s), 181.4 (s); exact mass (electrospray) m/z calcd for
C13H935Cl2NNaO3 (M + Na)+ 319.9852, found 319.9850.
2-({3-Bromo-4,5-dichloro-1-[3-(2-methoxyphenyl)-2-methyl-
idene-3-oxopropyl]-1H-pyrrol-2-yl}carbonyl)phenyl acetate
(3.2). NaH (60% w/w in oil, 30.5 mg, 0.763 mmol) was added to a
stirred solution of 3.1 (222 mg, 0.592 mmol) in DMF (5 mL). After
20 min, a solution of 2.7 (165 mg, 0.704 mmol) in DMF (6 mL) was
added, and stirring was continued for 84 h. The mixture was quenched
with water and extracted with Et2O, and the combined organic extracts
were washed with water and brine, dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (2.8 × 20 cm),
using 2:25 to 3:20 EtOAc−hexanes, gave 3.2 (267.1 mg, 83%) as a
(
)-3-Hydroxy-3-(2-methoxyphenyl)-2-methylidenepropyl
acetate (2.5) from 2.6. DBU (0.1 mL, 0.7 mmol) was added to a
stirred solution of 2.6 (74.1 mg, 0.314 mmol) in THF (4 mL). After 3
days, water was added, and the mixture was extracted with CH2Cl2.
The combined organic extracts were dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (1.4 × 20 cm),
using 1:10 to 1:5 EtOAc−hexanes, gave 2.5 (46.0 mg, 62%) as a
colorless oil.
white foam: FTIR (CDCl3, cast) 1768 cm−1; H NMR (CDCl3, 500
1
MHz) δ 2.19 (s, 3 H), 3.72 (s, 3 H), 5.40−5.42 (m, 2 H), 5.45
(apparent t, J = 1.5 Hz, 1 H), 5.75 (apparent t, J = 1.5 Hz, 1 H), 6.93
(d, J = 8.5 Hz, 1 H), 6.99 (td, J = 7.5, 1.0 Hz, 1 H), 7.23 (dd, J = 8.0,
1.0 Hz, 1 H), 7.29−7.33 (m, 2 H), 7.43 (ddd, J = 8.3, 7.5, 1.5 Hz, 1
H), 7.53−7.59 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 20.8 (q),
47.0 (t), 55.5 (q), 106.2 (s), 111.4 (d), 113.4 (s), 120.3 (d), 123.5 (d),
123.6 (s), 125.9 (d), 127.4 (t), 128.0 (s), 128.1 (s), 129.4 (d), 130.9
(d), 131.2 (s), 132.1 (d), 132.8 (d), 144.4 (s), 149.0 (s), 157.3 (s),
169.1 (s), 182.9 (s), 196.0 (s); exact mass (electrospray) m/z calcd for
C24H1879Br35Cl2NNaO5 (M + Na)+ 571.9638, found 571.9631.
2-({3-Bromo-4,5-dichloro-2-[(2-hydroxyphenyl)carbonyl]-
1H-pyrrol-1-yl}methyl)-1-(2-methoxyphenyl)prop-2-en-1-one
(3.3). Concentrated hydrochloric acid (36.5−38%, 0.6 mL) was added
dropwise to a stirred solution of 3.2 (552.8 mg, 1.003 mmol) in
MeOH (11 mL). Stirring was continued for 6.5 h, and the solvent was
then evaporated. The residue was dissolved in Et2O, and the solution
was dried (MgSO4) and evaporated. Flash chromatography of the
residue over silica gel (2.8 × 20 cm), using 1:50 to 1:20 EtOAc−
hexanes, gave 3.3 (385.6 mg, 75%) as a yellow oil: FTIR (CDCl3, cast)
3500−3000, 1661 cm−1; 1H NMR (CDCl3, 500 MHz) δ 3.68 (s, 3 H),
5.21 (br, 2 H), 5.51 (apparent t, J = 1.5 Hz, 1 H), 5.74 (apparent t, J =
1.5 Hz, 1 H), 6.90−6.98 (m, 3 H), 7.05−7.08 (m, 1 H), 7.21 (dd, J =
7.5, 1.5 Hz, 1 H), 7.42 (ddd, J = 8.5, 7.5, 2.0 Hz, 1 H), 7.52−7.56 (m,
1 H), 7.66−7.69 (m, 1 H), 11.5 (s, 1 H); 13C NMR (CDCl3, 125
MHz) δ 46.6 (t), 55.4 (q), 102.9 (s), 111.4 (d), 112.8 (s), 118.2 (d),
119.2 (d), 119.3 (s), 120.4 (d), 121.5 (s), 127.71 (s), 127.73 (s), 128.3
(t), 129.3 (d), 132.2 (d), 134.3 (d), 137.1 (d), 144.0 (s), 157.2 (s),
162.8 (s), 189.8 (s), 195.9 (s); exact mass (electrospray) m/z calcd for
C22H1679Br35Cl2NNaO4 (M + Na)+ 529.9532, found 529.9536.
2-({3-Bromo-4,5-dichloro-2-[(2-methoxyphenyl)carbonyl]-
1H-pyrrol-1-yl}methyl)-1-(2-methoxyphenyl)prop-2-en-1-one
(3.4). K2CO3 (131.8 mg, 0.954 mmol), followed by MeI (0.06 mL, 1
mmol), were added to a stirred solution of 3.3 (97 mg, 0.19 mmol) in
dry acetone (3 mL). Stirring was continued for 22 h, and the mixture
was then filtered through a pad of Celite, using Et2O as a rinse. The
filtrate was washed with water, dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (1.4 × 20 cm), using
3:50 to 3:20 EtOAc−hexanes, gave 3.4 (90.1 mg, 90%) as a white
3-(2-Methoxyphenyl)-2-methylidene-3-oxopropyl acetate
(2.7). DMSO (0.77 mL, 11 mmol) in CH2Cl2 (5 mL) was added
dropwise to a stirred and cooled (−78 °C) solution of (COCl)2 (0.47
mL, 5.4 mmol) in CH2Cl2 (10 mL). After 15 min, a solution of 2.5
(629 mg, 2.67 mmol) in CH2Cl2 (10 mL) was added dropwise over 20
min and stirring at −78 °C was continued for 45 min. Then Et3N
(1.20 mL) was added dropwise (ca. 1−2 drop per sec), and stirring
was continued at −78 °C for 5 min. The cooling bath was removed,
stirring was continued for 50 min, and water (10 mL) was added. The
organic layer was separated, and the aqueous phase was extracted with
CH2Cl2. The combined organic extracts were dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (2.8 ×
20 cm), using 2:25 to 1:5 EtOAc−hexanes, gave 2.7 (473.8 mg, 76%)
1
as a colorless oil: FTIR (CDCl3, cast) 1745 cm−1; H NMR (CDCl3,
500 MHz) δ 2.13 (s, 3 H), 3.83 (s, 3 H), 4.99 (t, J = 1.5 Hz, 2 H), 5.84
(d, J = 1.0 Hz, 1 H), 6.07 (td, J = 1.5, 0.5 Hz, 1 H), 6.97 (d, J = 8.5 Hz,
1 H), 7.01 (td, J = 7.5, 1.0 Hz, 1 H), 7.30 (dd, J = 7.5, 1.5 Hz, 1 H),
7.44 (ddd, J = 8.5, 7.5, 1.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ
20.9 (q), 55.7 (q), 62.3 (t), 111.5 (d), 120.4 (d), 128.3 (s), 128.8 (t),
129.3 (d), 131.9 (d), 143.9 (s), 157.2 (s), 170.5 (s), 196.3 (s); exact
mass (electrospray) m/z calcd for C13H14NaO4 (M + Na)+ 257.0784,
found 257.0782.
Preparation of (3.1). The preparation of this compound is
reported in the literature1b but without experimental details for the
following two intermediates:
a. 2-[(1H-Pyrrol-2-yl)carbonyl]phenyl acetate (ii). DMAP (45 mg,
0.37 mmol), pyridine (1.80 mL, 22.3 mmol) and AcCl (1.60 mL, 22.1
mmol) were added successively to a stirred and cooled (0 °C) solution
of 2-[(1H-pyrrol-2-yl)carbonyl]phenol (i)34 (3.13 g, 16.7 mmol) in
CH2Cl2 (60 mL). Stirring was continued for 1 h, and the mixture was
then quenched with water and extracted with CH2Cl2. The combined
organic extracts were dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (3.8 × 20 cm), using
3:10 to 2:5 EtOAc−hexanes, gave 2-[(1H-pyrrol-2-yl)carbonyl]phenyl
acetate (ii) (3.79 g, 99%) as a colorless oil: FTIR (CDCl3, cast) 3293,
1767 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.19 (s, 3 H), 6.32 (dt, J =
4.0, 2.5 Hz, 1 H), 6.75−6.78 (m, 1 H), 7.18−7.21 (m, 1 H), 7.23 (dd, J
= 8.0, 1.0 Hz, 1 H), 7.35 (td, J = 7.5, 1.0 Hz, 1 H), 7.55 (ddd, J = 8.0,
7.5, 2.0 Hz, 1 H), 7.71 (dd, J = 8.0, 2.0 Hz, 1 H), 10.63 (br, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 20.8 (q), 111.1 (d), 120.6 (d), 123.6 (d),
125.6 (d), 126.7 (d), 130.2 (d), 131.62 (s), 131.64 (s), 131.7 (d),
148.6 (s), 169.5 (s), 182.9 (s); exact mass (electrospray) m/z calcd for
C13H11NNaO3 (M + Na)+ 252.0631, found 252.0630.
1
solid: mp 142−145 °C; FTIR (CDCl3, cast) 1661, 1635 cm−1; H
NMR (CDCl3, 500 MHz) δ 3.76 (s, 3 H), 3.77 (s, 3 H), 5.46
(apparent t, J = 1.5 Hz, 1 H), 5.51−5.54 (m, 2 H), 5.77 (apparent t, J
= 1.5 Hz, 1 H), 6.94 (d, J = 3.5 Hz, 1 H), 6.96 (d, J = 4.5 Hz, 1 H),
6.99 (td, J = 7.5, 1.0 Hz, 1 H), 7.06 (td, J = 7.5, 1.0 Hz, 1 H), 7.33 (dd,
J = 7.5, 2.0 Hz, 1 H), 7.40 (dd, J = 7.5, 2.0 Hz, 1 H), 7.43 (ddd, J = 8.3,
7.5, 1.5 Hz, 1 H), 7.50 (ddd, J = 8.3, 7.5, 1.5 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 46.7 (t), 55.6 (q), 55.7 (q), 105.7 (s), 111.3 (d),
111.4 (d), 113.1 (s), 120.3 (d), 120.9 (d), 123.0 (s), 127.3 (t), 128.1
(s), 129.0 (s), 129.5 (d), 130.1 (d), 132.0 (d), 132.9 (d), 144.4 (s),
157.3 (s), 157.9 (s), 184.4 (s), 196.1 (s); exact mass (electrospray) m/
z calcd for C23H1879Br35Cl2NNaO4 (M + Na)+ 543.9688, found
543.9686.
b. 2-[(4,5-Dichloro-1H-pyrrol-2-yl)carbonyl]phenyl acetate (iii).
SO2Cl2 (1.45 mL, 17.5 mmol) was added dropwise to a stirred
solution of 2-[(1H-pyrrol-2-yl)carbonyl]phenyl acetate (ii)1b (1.87 g,
8.15 mmol) in CH2Cl2 (40 mL). After 7 h, the solvent was evaporated,
and flash chromatography of the residue over silica gel (3.8 × 20 cm),
using 2:25 to 3:20 EtOAc−hexanes, gave 2-[(4,5-dichloro-1H-pyrrol-
2-yl)carbonyl]phenyl acetate (iii) (2.20 g, 90%) as a white solid: mp
K
dx.doi.org/10.1021/jo401892t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3-{3-Bromo-4,5-dichloro-2-[(2-methoxyphenyl)carbonyl]-
1H-pyrrol-1-yl}-1-(2-methoxyphenyl)propane-1,2-dione (3.5).
NaIO4 (156 mg, 0.729 mmol) and RuCl3·4H2O (7.5 mg, 0.027
mmol) were added successively to a stirred solution of 3.4 (126.8 mg,
0.24 mmol) in a mixture of MeCN (0.9 mL), CCl4 (0.9 mL) and water
(1.4 mL). After 1.5 h, the mixture changed to dark green-brown. At
that time an additional quantity of NaIO4 (60 mg, 0.28 mmol) was
added, stirring was continued for 1 h, and CH2Cl2 (ca. 6 mL) and
water (ca. 5 mL) were then added. The organic layer was separated,
and the aqueous phase was extracted with CH2Cl2. The combined
organic extracts were washed with water and brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica gel
(1.4 × 20 cm), using 3:50 to 3:25 EtOAc−hexanes, gave 3.5 (71.5 mg,
56%) as a light yellow solid: mp 110−113 °C; FTIR (CDCl3, cast)
residue in CH2Cl2 (1.5 mL), and stirring was continued for 15 min.
The mixture was then filtered through a pad of silica gel, using EtOAc
as a rinse. Evaporation of the filtrate and flash chromatography of the
residue over silica gel (1.2 × 15 cm), using 1:5 to 2:5 EtOAc−hexanes,
gave 4.3 (30.7 mg, 57%) as a yellow oil: FTIR (CDCl3, cast) 2840,
1725 cm−1; 1H NMR (CDCl3, 500 MHz) δ 3.11 (d, J = 16.3 Hz, 1 H),
3.60−4.00 (m, 8 H), 6.90 (d, J = 8.5 Hz, 1 H), 6.94−7.04 (m, 2 H),
7.07 (t, J = 7.5 Hz, 1 H), 7.23 (d, J = 7.0 Hz, 1 H), 7.45−7.50 (m, 1
H), 7.56−7.60 (m, 1 H), 7.88 (br, 1 H), 9.88 (s, 1 H); we were unable
to obtain a satisfactory 13C NMR (CDCl3, 125 MHz) spectrum as
many signals were not detected; exact mass (electrospray) m/z calcd
for C24H1879Br35Cl2NNaO6 (M + Na)+ 587.9587, found 587.9587.
4-{3-Bromo-4,5-dichloro-2-[(2-methoxyphenyl)carbonyl]-
1H-pyrrol-1-yl}-2-(2-methoxyphenyl)pyridin-3-ol (4.4). The
method for 3f was followed, using NH4OAc (119 mg, 1.54 mmol),
4.3 (54.9 mg, 0.0968 mmol) in AcOH (1 mL) and a reaction time of 1
h. Flash chromatography of the crude product over silica gel (1.2 × 15
cm), using 2:5 to 1:2 EtOAc−hexanes, gave 4.4 (33.0 mg, 62%) as a
1
1734 cm−1; H NMR (CDCl3, 500 MHz) δ 3.77 (s, 3 H), 3.79 (s, 3
H), 5.96 (br, 2 H), 6.96 (d, J = 6.0 Hz, 1 H), 6.97 (d, J = 6.0 Hz, 1 H),
7.04 (td, J = 7.5, 1.0 Hz, 1 H), 7.10 (td, J = 7.5, 1.0 Hz, 1 H), 7.40 (dd,
J = 7.5, 2.0 Hz, 1 H), 7.49 (ddd, J = 8.5, 7.5, 2.0 Hz, 1 H), 7.59 (ddd, J
= 8.5, 7.5, 2.0 Hz, 1 H), 7.80 (dd, J = 8.0, 1.5 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 51.9 (t), 55.8 (q), 55.9 (q), 107.0 (s), 111.4 (d),
111.9 (d), 113.7 (s), 120.8 (d), 121.3 (d), 123.0 (s), 123.6 (s), 128.8
(s), 129.1 (s), 129.9 (d), 130.8 (d), 132.8 (d), 136.2 (d), 157.9 (s),
160.2 (s), 185.1 (s), 192.8 (s), 193.0 (s); exact mass (electrospray) m/
z calcd for C22H1679Br35Cl2NNaO5 (M + Na)+ 545.9481, found
545.9479.
1
yellow oil: FTIR (CDCl3, cast) 3246, 1646, 1600 cm−1; H NMR
(CDCl3, 500 MHz) δ 3.79 (s, 3 H), 3.86 (s, 3 H), 6.87 (d, J = 8.5 Hz,
1 H), 6.93 (td, J = 7.5, 1.0 Hz, 1 H), 7.05 (dd, J = 8.5, 1.0 Hz, 1 H),
7.17−7.23 (m, 2 H), 7.37−7.48 (m, 3 H), 7.57 (br, 1 H), 7.75 (dd, J =
8.0, 2.0 Hz, 1 H), 8.38 (d, J = 5.0 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 55.9 (q), 57.0 (q), 105.4 (s), 111.3 (d), 112.4 (d), 114.1 (s),
120.5 (d), 121.7 (s), 122.6 (d), 123.0 (d), 126.8 (s), 127.88 (s),
127.89 (s), 130.5 (d), 130.7 (d), 130.8 (s), 133.0 (d), 133.3 (d), 133.7
(s), 142.2 (d), 146.7 (s), 147.0 (s), 155.0 (s), 158.1 (s), 183.3 (s);
exact mass (electrospray) m/z calcd for C24H1779Br35Cl2N2NaO4 (M +
Na)+ 568.9641, found 568.9637.
Methyl 5-cyano-1-(2-oxo-2-phenylethyl)-1H-pyrrole-2-car-
boxylate (5.2). NaH (60% w/w in mineral oil, 102 mg, 2.55
mmol) was added to a stirred and cooled (0 °C) solution of 4 (318
mg, 2.12 mmol) in DMF (21 mL). Stirring at 0 °C was continued for
30 min, and bromoacetophenone (5.1) (548 mg, 2.75 mmol) was
added in one portion. The cold bath was left in place, but not
recharged, and stirring was continued for 3.5 h, during which time the
reaction mixture reached room temperature. The mixture was diluted
with saturated aqueous NH4Cl, and extracted with EtOAc. The
combined organic extracts were washed with brine, dried (MgSO4),
and evaporated. Flash chromatography of the residue over silica gel (3
× 20 cm), using 1:9 EtOAc−hexane to 1:3 EtOAc−hexane, gave 5.2
(477 mg, 84%) as a white solid: mp 110−115 °C; FTIR (CDCl3, cast)
3138, 2226, 1709 cm−1; 1H NMR (CDCl3, 500 MHz) δ 3.78 (s, 3 H),
5.95 (s, 2 H), 6.87 (d, J = 4.0 Hz, 1 H), 7.02 (d, J = 4.0 Hz, 1 H),
7.52−7.55 (m, 2 H), 7.64−7.67 (m, 1 H), 8.00−8.02 (m, 2 H); 13C
NMR (CDCl3, 125 MHz) δ 51.9 (q), 53.7 (t), 111.3 (s), 112.3 (s),
117.3 (d), 118.7 (d), 127.0 (s), 128.1 (d), 129.0 (d), 134.2 (d), 134.3
(s), 160.5 (s), 191.4 (s); exact mass (electrospray) m/z calcd for
C15H12N2NaO3 (M + Na)+ 291.0740, found 291.0741.
(2Z)-3-{3-Bromo-4,5-dichloro-2-[(2-methoxyphenyl)-
carbonyl]-1H-pyrrol-1-yl}-1-(2-methoxyphenyl)-2-(prop-2-en-
1-yloxy)prop-2-en-1-one (4.1). The method for 8c was followed,
using NaH (60% w/w in oil, 11.8 mg, 0.295 mmol), 3.5 (107 mg,
0.204 mmol) in DMF (4 mL) and allyl bromide (0.025 mL, 0.29
mmol) was added. In this case, the cold bath was removed, and stirring
was continued overnight. The reaction mixture was quenched with
saturated aqueous NH4Cl extracted with Et2O. Flash chromatography
of the crude product over silica gel (1.4 × 20 cm), using 3:50 to 1:10
EtOAc−hexanes, gave 4.1 (90.1 mg, 78%) as a light yellow oil: FTIR
1
(CDCl3, cast) 3078, 1670, 1640, 1599 cm−1; H NMR (CDCl3, 500
MHz) δ 3.75 (s, 3 H), 3.82 (s, 3 H), 4.43 (ddd, J = 6.0, 1.1.5, 1.5 Hz, 2
H), 5.11−5.15 (m, 2 H), 5.79 (ddt, J = 17.5, 10.0, 6.0 Hz, 1 H), 6.77
(s, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 6.95 (d, J = 8.5 Hz, 1 H), 7.01 (td, J
= 7.5, 1.0 Hz, 2 H), 7.38 (dd, J = 7.5, 1.5 Hz, 1 H), 7.44−7.49 (m, 3
H); 13C NMR (CDCl3, 125 MHz) δ 55.6 (q), 55.8 (q), 72.0 (t), 105.9
(s), 111.3 (d), 111.4 (d), 114.1 (s), 118.4 (t), 120.1 (d), 120.4 (d),
120.8 (d), 122.0 (s), 127.2 (s), 128.1 (s), 129.8 (s), 130.20 (d), 130.25
(d), 130.3 (d), 133.0 (d), 133.1 (d), 151.0 (s), 158.02 (s), 158.03 (s),
183.3 (s), 191.2 (s); exact mass (electrospray) m/z calcd for
C25H2079Br35Cl2NNaO5 (M + Na)+ 585.9794, found 585.9791.
(
)-3-{3-Bromo-4,5-dichloro-2-[(2-methoxyphenyl)-
carbonyl]-1H-pyrrol-1-yl}-1-(2-methoxyphenyl)hex-5-ene-1,2-
dione (4.2). A solution of 4.1 (90.4 mg, 0.159 mmol) in PhMe (3
mL) was stirred and refluxed for 30 h, cooled to room temperature
and evaporated. Flash chromatography of the yellow residue over silica
gel (1.4 × 20 cm), using 3:50 to 1:10 EtOAc−hexanes, gave 4.2 (76.4
mg, 85%) as a light yellow oil: FTIR (CDCl3, cast) 1722, 1662, 1628,
1599 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.98 (br, 1 H), 3.17 (br, 1
H), 3.67 (s, 3 H), 3.73−3.86 (m, 4 H), 5.04−5.16 (m, 2 H), 5.75 (br,
1 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.94−7.00 (m, 2 H), 7.06 (t, J = 7.5
Hz, 1 H), 7.18 (br d, J = 6.3 Hz, 1 H), 7.42−7.46 (m, 1 H), 7.53−7.57
(m, 1 H), 7.96 (br, 1 H); 13C NMR (CDCl3, 125 MHz) we were
unable to obtain a satisfactory spectrum as several expected signals
were not observed; exact mass (electrospray) m/z calcd for
C25H2079Br35Cl2NNaO5 (M + Na)+ 585.9794, found 585.9783.
( )-Methyl 5-cyano-1-(1-oxo-1-phenylpent-4-en-2-yl)-1H-
pyrrole-2-carboxylate (5.4) and Methyl 5-cyano-1-[(Z)-2-
phenyl-2-(prop-2-en-1-yloxy)ethenyl]-1H-pyrrole-2-carboxy-
late (5.3). A solution of 5.2 (155 mg, 0.578 mmol) in DMF (4 mL)
was added to a stirred and cooled (0 °C) mixture of NaH (60% w/w
in mineral oil, 23.3 mg, 0.582 mmol) and DMF (1 mL). Stirring at 0
°C was continued for 30 min and allyl bromide (0.05 mL, 0.6 mmol)
in DMF (1 mL) was added over 10 min. The cold bath was left in
place, but not recharged, and stirring was continued for 7 h, during
which time the reaction mixture reached room temperature. The
mixture was diluted with saturated aqueous NH4Cl and extracted with
EtOAc. The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (1 × 20 cm), using 1:20 EtOAc−hexane to 1:5 EtOAc−
hexane, gave 5.3 (21.6 mg, 12%) and 5.4 (42.7 mg, 24%) as colorless
oils. The starting ketone 5.2 (49.4 mg) was recovered.
(
)-3-{3-Bromo-4,5-dichloro-2-[(2-methoxyphenyl)-
carbonyl]-1H-pyrrol-1-yl}-5-(2-methoxyphenyl)-4,5-dioxopen-
tanal (4.3). NMO (41.2 mg, 0.352 mmol) and OsO4 (0.1 M in PhMe,
0.1 mL, 0.01 mmol) were added successively to a stirred solution of
4.2 (53.6 mg, 0.095 mmol) in a mixture of THF (1 mL) and water (1
mL) (protected from light). After 2 h, the reaction mixture was diluted
with EtOAc, washed with water, dried (MgSO4) and evaporated to
give a yellow residue. A solution of Pb(OAc)4 (54.8 mg, 0.124 mmol)
in CH2Cl2 (0.5 mL) was added to a stirred solution of the yellow
1
Compound 5.4: FTIR (CDCl3, cast) 2225, 1715 cm−1; H NMR
(CDCl3, 500 MHz) δ 3.02−3.16 (m, 2 H), 3.86 (s, 3 H), 5.01 (ddd, J
= 10.0, 2.0, 1.0 Hz, 1 H), 5.06 (ddd, J = 17.0, 3.0, 2.0 Hz, 1 H), 5.66−
5.72 (m, 1 H), 6.79 (d, J = 4.5 Hz, 1 H), 6.93 (d, J = 4.5 Hz, 1 H), 7.12
(br, 1 H), 7.41−7.45 (m, 2 H), 7.54 (tt, J = 7.5, 1.5 Hz, 1 H), 7.83 (d, J
L
dx.doi.org/10.1021/jo401892t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
= 7.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 35.9 (t), 52.1 (q),
62.8 (d), 110.5 (s), 113.2 (s), 117.8 (d), 119.4 (t), 120.2 (d), 126.2
(s), 128.3 (d), 128.8 (d), 132.1 (d), 133.3 (d), 135.3 (s), 161.0 (s),
194.9 (s); exact mass (electrospray) m/z calcd for C18H17N2O3 (M +
H)+ 309.1234, found 309.1234.
(electrospray) m/z calcd for C19H19NNaO5 (M + Na)+ 364.1155,
found 364.1155.
1
Compound 6.3: FTIR (CDCl3, cast) 1725, 1703 cm−1; H NMR
(CDCl3, 500 MHz) δ 2.70−2.80 (m, 1 H), 3.37−3.40 (m, 1 H), 3.82
(s, 6 H), 4.84−4.88 (m, 2 H), 5.59−5.69 (m, 1 H), 6.89 (s, 2 H), 7.20
(dd, J = 10.0, 4.5 Hz, 1 H), 7.23−7.28 (m, 2 H), 7.37 (tt, J = 7.5, 1.5
Hz, 1 H), 7.53−7.56 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 36.2
(t), 51.8 (q), 63.3 (d), 117.7 (d), 118.1 (t), 127.5 (s), 127.6 (d), 128.0
(d), 131.6 (d), 133.7 (d), 137.4 (s), 161.4 (s), 197.0 (s); exact mass
(electrospray) m/z calcd for C19H19NNaO5 (M + Na)+ 364.1155,
found 364.1154.
2,5-Dimethyl ( )-1-(1-oxo-1-phenylpent-4-en-2-yl)-1H-pyr-
role-2,5-dicarboxylate (6.3). A solution of a mixture of 6.3 and
6.2 (179 mg, 0.525 mmol) in PhMe (6 mL) was refluxed for 13 h,
cooled to room temperature and evaporated to give 6.3 as a thick,
colorless oil (178 mg, 99%), which was used directly in the next step.
Compound 6.3 had same spectral data as above.
2,5-Dimethyl ( )-1-(1,4-dioxo-1-phenylbutan-2-yl)-1H-pyr-
role-2,5-dicarboxylate (6.4) and 2,5-Dimethyl 1-(1-benzyl-2-
phenyl-1H-pyrrol-3-yl)-1H-pyrrole-2,5-dicarboxylate (6.5).
With the exception that THF was used instead of CH2Cl2, the
method for 4b was followed, using 6.3 (75.6 mg, 0.221 mmol), Sudan
Red 7B (ca. 0.1 mg) in THF (5 mL) and Me2S (0.03 mL, 0.4 mmol).
During the reduction the cold bath was left in place, but not recharged,
and stirring was continued for 3 h, during which time the reaction
mixture reached 0 °C. Iodine (5.6 mg, 0.022 mmol) and BnNH2 (0.03
mL, 0.3 mmol) were added. The cold bath was left in place but not
recharged, and stirring was continued for 4 h. The mixture was diluted
with aqueous NaHSO3 (10% w/v) and extracted with EtOAc. The
combined organic extracts were washed with brine, dried (MgSO4)
and evaporated at <12 °C (cold water bath with some ice). The
residue was dissolved in MeOH (2 mL) and cooled in an ice bath.
NaBH4 (4.2 mg, 0.11 mmol) was added, and the cold bath was left in
place, but not recharged, and stirring was continued for 2.5 h. The
mixture was diluted with saturated aqueous NH4Cl and extracted with
EtOAc. The combined organic extracts were washed with brine, dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (1 × 15 cm), using 1:5 EtOAc−hexane, gave 6.5 (37.4 mg,
41% over four steps) as a colorless oil. Compound 6.5: FTIR (CDCl3,
cast) 1737, 1718 cm−1; 1H NMR (CDCl3, 500 MHz) δ 3.71 (s, 6 H),
5.07 (s, 2 H), 6.28 (d, J = 3.5 Hz, 1 H), 6.75 (d, J = 3.5 Hz, 1 H), 6.85
(s, 2 H), 7.03−7.08 (m, 4 H), 7.14−7.17 (m, 3 H), 7.22−7.25 (m, 1
H), 7.30−7.33 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 50.9 (q),
51.3 (t), 107.8 (d), 116.4 (d), 119.9 (d), 120.8 (s), 126.2 (d), 127.2
(d), 127.6 (d), 128.1 (d), 128.6 (d), 129.6 (d), 130.2 (s), 130.3 (s),
138.7 (s), 160.2 (s); exact mass (electrospray) m/z calcd for
C25H22N2NaO4 (M + Na)+ 437.1472, found 437.1469.
1
Compound 5.3: FTIR (CDCl3, cast) 3135, 2229, 1722 cm−1; H
NMR (CDCl3, 500 MHz) δ 3.85 (s, 3 H), 4.16 (ddd, J = 6.0, 1.5, 1.5
Hz, 2 H), 5.07−5.13 (m, 2 H), 5.71 (ddt, J = 17.5, 10.5, 5.5 Hz, 1 H),
6.61 (s, 1 H), 6.84 (d, J = 4.5 Hz, 1 H), 6.96 (d, J = 4.5 Hz, 1 H),
7.42−7.43 (m, 3 H), 7.58−7.60 (m, 2 H); 13C NMR (CDCl3, 125
MHz) δ 51.8 (q), 71.0 (t), 108.1 (d), 111.7 (s), 112.8 (s), 116.6 (d),
117.7 (t), 118.7 (d), 127.4 (s), 127.7 (d), 128.6 (d), 129.8 (d), 132.7
(s), 132.8 (d), 155.0 (s), 160.0 (s); exact mass (electrospray) m/z
calcd for C18H17N2O3 (M + H)+ 309.1234, found 309.1234.
( )-Methyl 5-cyano-1-(1-oxo-1-phenylpent-4-en-2-yl)-1H-
pyrrole-2-carboxylate (5.4). A solution of 5.3 and 5.4 (45.9 mg,
0.149 mmol) in PhMe (1.5 mL) was refluxed for 18 h, cooled and
evaporated to afford 5.4 (45.7 mg, ca. 99%) as a thick, light yellow oil.
Methyl ( )-5-cyano-1-(1,4-dioxo-1-phenylbutan-2-yl)-1H-
pyrrole-2-carboxylate (5.5) and Methyl 5-cyano-1-(2-phenyl-
1H-pyrrol-3-yl)-1H-pyrrole-2-carboxylate (5.6). The method for
4b was followed, using 5.4 (45.7 mg, 0.147 mmol), Sudan Red 7B (ca.
0.5 mg) in CH2Cl2 (5 mL), Me2S (0.03 mL, 0.4 mmol) and a
reduction period of 8 h. The mixture was evaporated directly at ca. 10
°C to give 5.5 as a thick, yellow oil, which was used immediately, as
follows.
The method for 3f was followed, using NH4OAc (110 mg, 1.43
mmol), the above crude keto aldehyde 5.5 in AcOH (3 mL) and a
reaction time of 3.5 h. Flash chromatography of the crude product
over silica gel (1 × 20 cm), using 1:4 EtOAc−hexane, gave 5.6 (30.6
mg, 71% over three steps) as a white solid: mp 152−156 °C; FTIR
1
(CDCl3, cast) 3369, 3138, 2230, 1716 cm−1; H NMR (CDCl3, 500
MHz) δ 3.70 (s, 3 H), 6.31 (apparent t, J = 3.0 Hz, 1 H), 6.79
(apparent t, J = 3.0 Hz, 1 H), 6.85 (d, J = 4.5 Hz, 1 H), 6.92 (dt, J =
6.5, 1.5 Hz, 2 H), 7.02 (d, J = 4.0 Hz, 1 H), 7.17−7.24 (m, 3 H), 8.62
(br, 1 H); 13C NMR (CDCl3, 125 MHz) δ 51.8 (q), 109.1 (d), 112.4
(s), 112.7 (s), 117.3 (d), 117.4 (d), 118.0 (s), 118.9 (d), 125.1 (d),
127.2 (d), 127.5 (s), 128.3 (s), 129.0 (d), 130.3 (s), 159.4 (s); exact
mass (electrospray) m/z calcd for C17H13N3NaO2 (M + Na)+
314.0900, found 314.0898.
2,5-Dimethyl 1-(2-oxo-2-phenylethyl)-1H-pyrrole-2,5-dicar-
boxylate (6.1). The method for 5.2 was followed, using NaH (60%
w/w in mineral oil, 80.0 mg, 2.00 mmol), 3 (332 mg, 1.82 mmol) in
DMF (19 mL), bromoacetophenone (5.1) (435 mg, 2.18 mmol) and a
reaction time of 6 h. Flash chromatography of the crude product over
silica gel (2 × 15 cm), using 1:9 EtOAc−hexane, gave 6.1 (493 mg,
90%) as a white solid: mp 116−121 °C; FTIR (CDCl3, cast) 1723,
Compound 6.4: FTIR (CDCl3, cast) 1723 cm−1; 1H NMR (CDCl3,
500 MHz) δ 2.98 (ddd, J = 17.5, 6.0, 1.0 Hz, 1 H); 3.87 (br, 6 H), 3.94
(ddd, J = 17.5, 6.0, 1.0 Hz, 1 H), 6.92 (s, 2 H), 7.27−7.31 (m, 2 H),
7.39−7.44 (m, 2 H), 7.50−7.52 (m, 2 H), 9.89 (t, J = 1.0 Hz, 1 H);
13C NMR (CDCl3, 125 MHz) δ 46.2 (t), 52.0 (q), 59.0 (d), 118.0 (d),
127.5 (d), 127.6 (s), 128.2 (d), 132.1 (d), 136.2 (s), 195.8 (s), 198.4
(d); exact mass (electrospray) m/z calcd for C18H17NNaO6 (M +
Na)+ 366.0948, found 366.0944.
1
1705 cm−1; H NMR (CDCl3, 500 MHz) δ 3.78 (s, 6 H), 6.49 (s, 2
H), 7.01 (s, 2 H), 7.49−7.53 (m, 2 H), 7.61 (tt, J = 7.5, 1.5 Hz, 1 H),
8.02−8.04 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 51.6 (q), 53.1
(t), 116.8 (d), 127.6 (s), 128.0 (d), 128.8 (d), 133.6 (d), 135.0 (s),
161.4 (s), 193.5 (s); exact mass (electrospray) m/z calcd for
C16H16NO5 (M + H)+ 302.1023, found 302.1023.
2,5-Dimethyl ( )-1-(1-oxo-1-phenylpent-4-en-2-yl)-1H-pyr-
role-2,5-dicarboxylate (6.3) and 2,5-Dimethyl 1-[(Z)-2-phenyl-
2-(prop-2-en-1-yloxy)ethenyl]-1H-pyrrole-2,5-dicarboxylate
(6.2). The method for 5.3 was followed, using 6.1 (320 mg, 1.06
mmol) in DMF (11 mL), NaH (60% w/w in mineral oil, 42.5 mg, 1.06
mmol) and DMF (5 mL), allyl bromide (0.09 mL, 1 mmol) in DMF
(10 mL), an addition period of 20 min, and an overnight reaction time.
Flash chromatography of the crude product over silica gel (2 × 20
cm), using 1:25 EtOAc−hexane, gave 6.3 (140 mg, 39%) and 6.2 (138
mg, 38%) as colorless oils. Compound 6.3 contained an impurity.
ASSOCIATED CONTENT
■
S
* Supporting Information
ORTEP diagram of 3f. Copies of NMR spectra and, for
compounds 3c and 3f, X-ray data. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
Compound 6.2: FTIR (CDCl3, cast) 1734, 1711 cm−1; H NMR
AUTHOR INFORMATION
■
(CDCl3, 500 MHz) δ 3.83 (s, 6 H), 3.94 (ddd, J = 6.0, 1.5, 1.5 Hz, 2
H), 4.99 (ddd, J = 8.0, 3.0, 1.5 Hz, 1 H), 5.02 (apparent t, J = 1.5 Hz, 1
H), 5.53−5.61 (m, 1 H), 6.92 (s, 1 H), 6.94 (s, 2 H), 7.37−7.42 (m, 3
H), 7.59−7.61 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 51.6 (q),
70.9 (t), 110.8 (d), 116.3 (d), 117.3 (t), 127.1 (d), 128.6 (d), 128.9
(s), 129.1 (d), 133.2 (d), 133.8 (s), 151.9 (s), 160.8 (s); exact mass
Corresponding Author
*E-mail: derrick.clive@ualberta.ca.
Notes
The authors declare no competing financial interest.
M
dx.doi.org/10.1021/jo401892t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(21) Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45, 1301−
1305.
(22) (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada for financial support, Dr. M. J. Ferguson and
Dr. R. McDonald for the X-ray measurements, and S.
Fernandopulle for assistance.
Org. Chem. 1981, 46, 3936−3938. (b) Krohn, K.; Frese, P.; Florke, U.
̈
Chem.Eur. J. 2000, 6, 3887−3896.
(23) Leading reference to 3-hydroxypyridines: Yoshida, K.; Kawagoe,
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11246.
DEDICATION
■
Dedicated with respect and admiration to Professor Victor
Snieckus.
(25) For the closest analogy we could find (by a search of the Reaxys
database) of an example of simultaneous O- and C-alkylation in the
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(26) A byproduct of the allylation appeared to be (1H NMR) the
result of double allylation α to the ketone carbonyl.
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N
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