Further studies on the application of vinylogous amides and β-halovinylaldehydes to the regiospecific synthesis of unsymmetrical, polyfunctionalized 2,3,4- and 1,2,3,4- substituted pyrroles

Article abstract of DOI:10.1016/j.tet.2018.04.017

Highly functionalized pyrroles with appropriate regiochemical functionality represent an important class of marine natural products and potential drug candidates. We describe herein a detailed study of the reaction of α-aminoacid esters with vinylogous amides and also β-halovinylaldehydes for the regiospecific synthesis of 2,3,4-trisubstituted and 1,2,3,4-tetrasubstituted pyrroles. Since the vinylogous amides and β-halovinylaldehydes are readily available precursors, rapid access to a wide variety of unsymmetrically substituted pyrroles is accomplished via this methodology.

Full text of DOI:10.1016/j.tet.2018.04.017

Accepted Manuscript
Further studies on the application of vinylogous amides and β-halovinylaldehydes to
the regiospecific synthesis of unsymmetrical, polyfunctionalized 2,3,4- and 1,2,3,4-
substituted pyrroles
John T. Gupton, Alex Shimozono, Evan Crawford, Joe Ortolani, Evan Clark, Matt
Mahoney, Campbell Heese, Jeffrey Noble, Carlos Perez Mandry, Rene Kanters,
Raymond N. Dominey, Emma W. Goldman, James A. Sikorski, Daniel C. Fisher
PII:
S0040-4020(18)30396-X
10.1016/j.tet.2018.04.017
TET 29432
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 February 2018
Revised Date: 4 April 2018
Accepted Date: 5 April 2018
Please cite this article as: Gupton JT, Shimozono A, Crawford E, Ortolani J, Clark E, Mahoney M, Heese
C, Noble J, Mandry CP, Kanters R, Dominey RN, Goldman EW, Sikorski JA, Fisher DC, Further studies
on the application of vinylogous amides and β-halovinylaldehydes to the regiospecific synthesis of
unsymmetrical, polyfunctionalized 2,3,4- and 1,2,3,4- substituted pyrroles, Tetrahedron (2018), doi:
10.1016/j.tet.2018.04.017.
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ACCEPTED MANUSCRIPT
Further studies on the application of vinylogous amides and β-halovinylaldehydes to
the regiospecific synthesis of unsymmetrical, polyfunctionalized 2,3,4- and 1,2,3,4-
substituted pyrroles
John T. Guptona*, Alex Shimozonoa, Evan Crawforda, Joe Ortolania, Evan Clarka, Matt Mahoneya,
Campbell Heesea, Jeffrey Noblea, Carlos Perez Mandrya, Rene Kantersa, Raymond N. Domineya,
Emma W. Goldmana, James A. Sikorskib and Daniel C. Fisherc.
aDepartment of Chemistry, University of Richmond, Richmond, VA 23173, USA
bChemistry and Drug Discovery, Chesterfield, MO 63005, USA
cSt. Christopher’s School, Richmond, VA 23173, USA
Abstract- Highly functionalized pyrroles with appropriate regiochemical functionality represent
an important class of marine natural products and potential drug candidates. We describe herein
a detailed study of the reaction of α-aminoacid esters with vinylogous amides and also β-
halovinylaldehydes for the regiospecific synthesis of 2,3,4-trisubstituted and 1,2,3,4-
tetrasubstituted pyrroles. Since the vinylogous amides and β-halovinylaldehydes are readily
available precursors, rapid access to a wide variety of unsymmetrically substituted pyrroles is
accomplished via this methodology.
1. Introduction
HO
OH
MeO
HO
MeO
MeO
HO
H
N
H
N
OH
O
N
O
O
Cl
Cl
MeO2C
CO2Me
N
N
H
O
OH
3, Lukianol A
1, Lynamicin D
2, Lamellarin D
Figure 1. Pyrrole Containing Natural Products
Our previous studies have established that vinamidinium salts1 and related compounds are
useful building blocks for the construction of five and six membered heterocyclic compounds
and in particular highly functionalized, unsymmetrical pyrroles. The presence of the pyrrole
core in a large number of natural (Fig. 1) and synthetic products has attracted the attention of
many others and as a result, various synthetic approaches are currently available2. The attention
given to such pyrrole containing natural products arises from their very important biological
properties3. Such properties include potent anti-proliferative activity of lamellarin D4 (2, Fig. 1)
and lukianol A5 (3, Fig. 1) on various cancer cell lines including those, which exhibit multidrug-
resistance. Lynamicin D6 (1, Fig. 1) and related compounds have demonstrated good antibiotic
activity against Staphylococcus aureus ATCC 43300-MRSA and Haemophilus influenzae
ATCC 49247. Consequently, short and efficient methods for the regiocontrolled synthesis of
symmetrical and unsymmetrical, polyfunctionalized pyrroles are of some importance.
Keywords: Vinylogous Amide; β-Halovinylaldehyde; Pyrrole; Marine Natural Products.
*Corresponding author. Tel +1 804 287-6498: fax: +1 804 287-1897; e-mail:
jgupton@richmond.edu.
1

ACCEPTED MANUSCRIPT
The ideal method for synthesizing polyfunctionalized pyrroles should allow for a high yielding,
regiospecific preparation from readily available starting materials in as few synthetic steps as
possible. In 1999 we reported7 a short and efficient synthesis of the Furstner pyrrole
intermediate, which had been converted to the marine natural product Lukianol A (3, Fig. 1).
The key pyrrole core for this intermediate was prepared by the condensation reaction of a single
vinylogous amide or it’s corresponding β-halovinylaldehyde with several glycine derivatives.
These early results suggested that both vinylogous amides and β-halovinylaldehydes could meet
the general requirements of ideal building blocks for the high yielding, regiospecific preparation
of appropriately functionalized pyrroles. We now report a thorough investigation of vinylogous
amides and β-halovinylaldehydes as efficient precursors for unsymmetrical 1,2,3,4-
tetrasubstituted and 2,3,4-trisubstituted pyrroles.
2. Results and Discussions
Since a significant number of the important bioactive pyrroles3 contain aryl groups at the C-3
and C-4 positions of the pyrrole, we decided to define optimum conditions for the construction
of a variety of aryl benzyl ketones as starting materials for our work. Although many Friedel-
Craft acylation conditions8 are available, we liked the idea of using one equivalent of triflic
anhydride, (Scheme 1 and Table 1) to mediate9 such reactions due to high yields, and very clean
and mild reaction conditions. These reactions were typically run overnight at room temperature,
required minimum work up and the crude products were exceptionally pure and could be used in
subsequent steps without further purification.
O
O
F3C S O S CF3
O
O
O
O
6
Ar1
Ar2-H
5
Ar1
+
Ar2
OH
DCM, rt
7
4
Scheme 1. Triflic Anhydride Mediated Acylation with Aryl Acetic Acids
Table 1. Preparation of Aryl Benzyl Ketones
Compound Ar1
Number
Ar2
% Yield
7a
7b
7c
7d
7e
7f
7g
7h
7i
4-MePh
2,4-(MeO)2Ph
2,3,4-(MeO)3Ph 71
94
4-MePh
4-MePh
Ph
4-BrPh
4-MePh
4-ClPh
3,4-(MeO)2Ph
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
89
98
81
98
90
71
79
2,3,4-(MeO)3Ph 4-MeOPh
3,4-(MeO)2Ph 4-MeOPh
The preparation of vinylogous amides from active methylene compounds is well known10 and
with a variety of benzyl ketones in hand we employed N,N-dimethylformamide dimethyl acetal
in refluxing DMF for this transformation. Nearly all reactions proceeded in high yield with little
or no purification of the crude products required after concentration of the reaction mixtures.
2

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The only exception was in the case of compound 8d (Table 2) in which case the product yield
was lower and this could be due to steric issues.
O
O
DMF Acetal
DMF, Heat
Ar
R
Ar
R
Me2N
H
7
8
Scheme 2. Preparation of Vinylogous Amides from Benzyl Ketones
Table 2. Preparation of Vinylogous Amides
Compound Ar
Number
R
% Yield
8a
8b
8c
8d
8e
8f
8g
8h
8i
4-MeOPh
Me
4-MeOPh
4-MeOPh
99
99
96
4-MeOPh
4-MePh
4-MePh
4-MePh
4-MePh
4-BrPh
4-ClPh
Ph
2,3,4-(MeO)3Ph 54
3,4-(MeO)2Ph
2,4-(MeO)2Ph
4-MeOPh
4-MeOPh
4-MeOPh
91
95
91
99
85
83
85
8j
8k
2,3,4-(MeO)3Ph 4-MeOPh
3,4-(MeO)2Ph 4-MeOPh
In our previous studies of pyrrole forming reactions1 with glycine derivatives and vinamidinium
salts, we proposed that the amino acid ester undergoes an amine exchange reaction with one of
the amine groups at the vinamidinium salt terminus followed by base-mediated cyclization.
Consequently we decided to see if we could accomplish the same exchange process with a
vinylogous amide and N-methyl glycine ethyl ester and actually isolate and characterize the
suggested intermediate (Scheme 3 and Table 3). A number of examples were evaluated and they
gave good yields by refluxing the reactants in ethanol. Because N-methyl glycine was purchased
and used as the hydrochloride salt, we employed trifluoroacetic acid as an additive for the N-
benzyl glycine exchange process, since it was purchased as the free base. The presence of one
equivalent of acid clearly facilitated the exchange reaction. In addition NOESY NMR analysis
of one of the reaction products (10a) indicated that when R1 was an aryl group the E
configuration of the amine exchanged product was obtained as shown in Scheme 3.
O
O
Ar1
R1
Ar1
Ethanol
R1
R2NHCH2CO2Et
9
R2
+
N
H
Me2N
H
Additive and Heat
8
CO2Et
10
Scheme 3. The Amine Exchange Reaction
3

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Table. 3 Amine Exchange Reaction of Vinylogous Amides with Glycine Derivatives
Compound Ar1
Number
R1
R2 Additive % Yield
10a
10b
10c
10d
10e
10f
10g
4-MePh
4-MePh
4-MeOPh 4-MeOPh
4-MeOPh Me
4-MePh
4-MePh
4-MeOPh 4-MeOPh
4-MeOPh
3,4-(MeO)2Ph
Me None
Me None
Me None
Me None
64
54
100
89
93
2,3,4-(MeO)3Ph Me None
4-MeOPh
Bn CF3CO2H 75
Bn CF3CO2H 84
Our previous cyclization studies with vinamidinium salts and glycine derivatives employed base
mediated conditions1 for pyrrole formation. We therefore selected sodium hydride in THF at
room temperature for our intitial cyclization studies with the amino acid ester exchanged
vinylogous amide (10d) and the results are depicted in Scheme 4.
MeO
MeO
O
MeO
Me
O
Me
NaH, THF
rt, O.N.
Me
Me
N
H
H
H
+
CO2Et
N
O
Me
CO2Et
10d
11
33%
12a
66%
Scheme 4. Base Mediated Pyrrole Formation from Sarcosine Exchanged Vinylogous
Amide
We were pleased to obtain a 66% yield of the desired pyrrole (12a) based on 1H NMR analysis
of the crude product and comparison with an authentic sample11.The product regiochemistry
was established by NOESY NMR analysis of 12a11 (Table 4). Given the E stereochemistry of
the starting material (10d) it was clear that isomerization about the double bond occurred prior
to the cyclization step. We were also able to determine that the side product (11) formed in the
reaction (in 33% yield) was a ketoaldehyde (11), which we assumed was formed by hydrolysis
of the sarcosine exchanged vinylogous amide (10d). Since water was generated in the
cyclization step, this presented an obvious problem. To further verify our assumptions the
sarcosine exchanged vinylogous amide (10d) was treated with aqueous sodium hydroxide in
THF at room temperature overnight in which case the keto aldehyde (11) was produced in 95%
1
yield (Scheme 5) and was identical by H NMR to the material obtained in the base mediated
cyclization (Scheme 4) to form the pyrrole (12a).Although the keto aldehyde (11) could in
principle react with sarcosine to regenerate the exchanged vinylogous amide (10d) and then
cyclize, the basic reaction conditions should cause deprotonation of the keto aldehyde (11) and
4

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make it unavailable for such a process. It should be noted that an attempt was made to remove
water during the dehydration step by running the cyclization reaction (as described in Scheme 4)
in toluene with azeotropic removal of water. Interestingly, these conditions did not result in a
meaningful improvement in the yield of the desired pyrrole versus the reaction in THF at room
temperature.
MeO
O
MeO
O
Me
Me
NaOH, H2O/THF
rt, O.N.
Me
N
H
H
H
O
CO2Et
10d
11, 95% Yield
Scheme 5. Hydrolysis of Sarcosine Exchanged Vinylogous Amide
Because of the issues associated with the base mediated cyclization conditions we turned our
attention to an acid mediated process as described in Scheme 6 and Table 4.
O
Ar1
R2
Ar
R1
R1
HOAc
N
H
CO2Et
N
R2
Reflux
CO2Et
10
12
Scheme 6. Acid Mediated Formation of 1,2,3,4-Tetrasubstituted Pyrroles from Sarcosine
Exchanged Vinylogous Amides
Table 4. Acid Mediated Formation of 1,2,3,4-Tetrasubstituted Pyrroles
Compound Ar
Number
R1
R2 % Yield
12a
12b
12c
12d
12e
12f
4-MeOPh Me
4-MeOPh 4-MeOPh
Me 94
Me 95
Me 81
4-MePh
4-MePh
4-MeOPh
3,4-(MeO)2Ph Me 88
4-MeOPh 4-MeOPh
4-MePh 4-MeOPh
Bn 80
Bn 88
For the six examples studied (Scheme 6, Table 4), refluxing the respective vinylogous amide
(10) in glacial acetic acid gave relatively clean pyrrole (12a-12f) with little if any keto aldehyde
(11) formed from the hydrolytic side reaction. Any hydrolysis, which may have occurred, would
still allow for the reaction of the N-substituted glycine with the keto aldehyde (11) thereby
reproducing the exchanged vinylogous amide (10) and subsequently forming the pyrrole (12) in
an irreversible cyclization step. Therefore, no discernible yield loss of pyrrole would be
expected given the deprotonation of the keto aldehyde (11) in an acidic environment would not
5

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be possible. Upon reaction of the keto aldehyde (11) with N-methyl glycine ethyl ester
hydrochloride in refluxing acetic acid (Scheme 7) a 55% yield of the respective pyrrole (12a)
was obtained after normal reaction work up thereby verifying its (11) viability as a pyrrole
precursor.
Scheme 7. Acetic Acid Mediated Cyclization of Ketoaldehyde (11) to Pyrrole (12a).
Given the success of the acid-mediated reaction conditions, we decided to evaluate a one pot
reaction where the N-substituted glycine derivative (9) would undergo exchange with the
vinylogous amide (8) in situ followed by cyclization to the respective pyrrole (12) in refluxing
glacial acetic acid (Scheme 8). A total of 13 examples were evaluated (Table 5) and very
respectable yields of 1,2,3,4-tetrasubstituted pyrrole (12a-12m) products were obtained in all
cases.
O
Ar
R1
HOAc
Ar
R1
R2NHCH2CO2Et
9
+
Reflux
CO2Et
N
R2
Me2N
H
8
12
Scheme 8. Acetic Acid Mediated One Pot Cyclization of Vinylogous Amides to 1,2,3,4-
Tetrasubstituted Pyrroles
Table 5. One Pot Cyclization of Vinylogous Amides to 1,2,3,4-Tetrasubstituted Pyrroles
Compound Ar
Number
R1
R2 % Yield
12a
12b
12c
12d
12g
12h
12i
12j
12k
12l
4-MeOPh
Me
4-MeOPh
4-MeOPh
Me 81
Me 73
Me 86
4-MeOPh
4-MePh
4-MePh
Ph
4-BrPh
4-ClPh
3,4-(MeO)2Ph
2,3,4-(MeO)3Ph 4-MeOPh
4-MeOPh
4-MePh
4-MeOPh
4-MePh
3,4-(MeO)2Ph Me 87
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
Me 72
Me 87
Me 87
Me 91
Me 91
Bn 61
Me
12m
12e
12f
3,4-(MeO)2Ph Bn 60
4-MeOPh
4-MeOPh
Bn 58
Bn 67
6

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It is proposed that the above cyclization occurs after isomerization of the E-vinylogous
exchanged amides (10) to the Z isomers. This isomerization would be followed by enolization
of the ester group and then an acid mediated intramolecular condensation with subsequent
dehydration should yield the desired tetrasubstituted pyrroles (12).
It is important to note that a significant number of bioactive3, pyrrole natural products and their
synthetic counterparts require the nitrogen of the pyrrole to be unsubstituted. Attempts to use
glycine ester hydrochloride in place of N-substituted glycines under the previously described
conditions showed no indication of pyrrole formation. We have previously had success7 in
converting vinylogous amides (8) to β-halovinylaldehydes12 (13) in high yield and we
anticipated that such substances would offer an alternative three-carbon building block for
successful condensation with glycine ester hydrochloride. After preparation of a model β-
halovinylaldehyde (13c) as a mixture of E (13c-1) and Z (13c-2) isomers, the isomeric products
were separated chromatographically and individually characterized along with NOESY NMR
analysis. The isomers (13c-1 and 13c-2) were then separately reacted with glycine ester
hydrochloride in refluxing DMF (Scheme 9) whereby the desired N-unsubstituted pyrrole (12c,
Table 6) was produced in both reactions in generally good yields (83% for the E isomer and
68% for the Z isomer).
Scheme 9. Formation of N-H-2,3,4-Trisubstituted Pyrrole (12c) from Individual β-
Chlorovinyl Aldehyde Isomers (13c-1 and 13c-2)
Since both individual isomers were converted to the respective pyrrole (Scheme 9), a variety of
chlorovinyl aldehydes (13) were prepared and the crude isomeric products were subjected to
reaction with glycine ethyl ester in refluxing DMF. The respective unsymmetrical 2,3,4-
trisubstituted pyrroles (12n-12t) were subsequently obtained in generally good yields (Table 6).
7

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Interestingly, similar reactions with either N-methylglycine ethyl ester or N-benzylglycine ethyl
ester also produced pyrroles (12b,12c,12d,12g,12h,12f and12m) in good yield as well and the
pyrrole products were identical to those prepared by the previously described vinylogous
amide/acetic acid route (Scheme 8, Table 5). It is also worth noting that no added acid or base
was required to initiate the amine exchange or the cyclization processes in refluxing DMF. It is
assumed that trace amounts of acid from the salts of the amino acid esters or from elimination of
HCl during the elimination step could facilitate the observed process. It is also assumed that the
amine group of the amino acid ester would react preferentially with the aldehyde group and not
the chlorovinyl group for steric reasons.
Ar
R1
R2NHCH2CO2Et
9
O
Cl
H
1. POCl3 in
DCM at rt
Ar
R1
Ar
R1
CO2Et
N
R2
2.Aq. NaHCO3
workup
Me2N
H
DMF and Heat
O
8
13
12
Scheme 10. Formation of Unsymmetrical 2,3,4-Trisubstitutedpyrroles and Unsymmetrical
1,2,3,4-Tetrasubstitutedpyrroles via β-Chlorovinyl Aldehydes
Table 6. Unsymmetrical 2,3,4-Trisubstitutedpyrroles and Unsymmetrical 1,2,3,4-
Tetrasubstitutedpyrroles via β-Chlorovinyl Aldehydes
Compound Ar
Number
R1
R2 % Yield
12n
12o
12p
12q
12r
4-MeOPh
4-MeOPh
3,4-(MeO)2Ph H
4-MeOPh
Me
4-MeOPh
4-MeOPh
H
84
59
85
45
86
85
66
4-MePh
4-MePh
4-MeOPh
Ph
4-BrPh
3,4-(MeO)2Ph 4-MeOPh
H
H
H
H
H
12s
12t
12b
12c
12g
12h
12d
12m
12f
4-MeOPh
4-MePh
Ph
4-BrPh
4-MePh
4-MeOPh
4-MePh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
3,4-(MeO)2Ph Me 81
3,4-(MeO)2Ph Bn 60
Me 80
Me 82
Me 67
Me 73
4-MeOPh
Bn 69
3.Conclusions
In summary we have described a two-step process for regiospecifically preparing unsymmetrical
1,2,3,4-tetrasubstituted pyrroles (12) in good yield from benzyl ketones via acetic acid mediated
condensation of the corresponding vinylogous amides (8) with N-substituted glycine derivatives (9).
Additionally, a step wise process involving the reaction of the vinylogous amide exchanged
materials (10) with refluxing acetic acid was found to produce the respective pyrroles thereby
helping to clarify the nature of the one pot, pyrrole forming reaction. Since N-unsubstituted pyrroles
could not be made by the acetic acid mediated route, the vinylogous amides (8) were converted to
an isomeric mix of β-halovinylaldehydes (13) via reaction with phosphorous oxychloride.
Subsequent reaction of the crude isomeric β-halovinylaldehydes (13) with both N-unsubstituted and
N-substituted glycines in refluxing DMF produced unsymmetrical 2,3,4-trisubstituted pyrroles (12)
8

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and unsymmetrical 1,2,3,4-tetrasubstituted pyrroles (12), repectively in good yield. The isolation,
characterization and individual conversion of E and Z chloroenals to a 2,3,4-trisubstituted pyrrole
(12c) establishes viability of both isomers to be successfully converted to the desired product. In an
overall sense a very compact sequence of reactions was shown to regiospecifically produce
functionalized, unsymmetrical, polysubstututed pyrroles thereby making it possible for rapid
generation of various libraries of compounds bearing the pyrrole scaffold.
4. Experimental
4.1 General
All chemicals were used as received from the manufacturer (Aldrich Chemicals and Fisher
Scientific). All solvents were dried over 4 angstrom molecular sieves prior to their use. NMR
spectra were obtained on either a Bruker 300 MHz spectrometer, or a Bruker 500 MHz
spectrometer in either CDCl3, d6-DMSO or d6-acetone solutions. IR spectra were recorded on a
Nicolet Avatar 320 FT-IR spectrometer with an HATR attachment. High resolution mass spectra
were obtained on a Shimadzu IT-TOF mass spectrometer at the University of Richmond. Low
resolution GC-MS spectra were obtained on a Shimadzu QP 5050 instrument. Melting points and
boiling points are uncorrected. Chromatographic purifications were carried out on a Biotage SP-1
instrument or a Biotage Isolera instrument (both equipped with a silica cartridge). Gradient elution
with ethyl acetate/hexane was accomplished in both instances. The reaction products were normally
eluted within the range of 4-8 column volumes of eluant with a gradient mixture of 60-80% ethyl
acetate in hexane. TLC analyses were conducted on silica plates with hexane/ethyl acetate as the
13
eluant. All purified reaction products gave TLC results, flash chromatograms, and
spectra consistent with a sample purity of >95%.
C NMR
4.1.1 1-(2,4-Dimethoxyphenyl)-2-p-tolylethanone (7a). Into a 100 mL round bottom flask
equipped with magnetic stirring was placed 4-tolylacetic acid (0.524 g, 3.61 mmol) along with 15
mL of dry dichloromethane (DCM). To this mixture with ice bath cooling was added 1,3-
dimethoxybenzene (0.542 g, 3.61 mmol) and 4.33 mL (4.33 mmol) of a 1.00 M solution of triflic
anhydride in anhydrous DCM. The resulting mixture was stirred overnight, diluted with 20 mL of
saturated aqueous bicarbonate and extracted with DCM (3 x 20 mL). The DCM solution was dried
over anhydrous sodium sulfate, filtered through a fritted glass funnel and the filtrate was then
passed through a short plug of silica gel and the plug was then washed with 50 mL of ethyl acetate.
The combined filtrates were concentrated in vacuo to yield a dark grey solid (0.918 g, 94% yield),
1
which exhibited the following physical properties: mp 63-65 °C; H NMR (500 MHz, CDCl3) δ
7.81 (d, J = 8.7 Hz, 1H), 7.12 (broad s, 4H), 6.53 (dd, J = 8.7 Hz, J = 2.3 Hz, 1H), 6.47 (d, J = 2.3
13
Hz, 1H), 4.25 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H) and 2.33 (s, 3H); C NMR (75 MHz, CDCl3) δ
198.0, 164.5, 160.6, 135.9, 133.1, 132.6, 129.5, 129.0, 121.0, 105.2, 98.4, 55.5, 55.4, 49.5 and 21.0;
IR (neat) 1665 cm-1; HRMS (ES, M+Na) m/z calcd for C17H18O3Na 293.1148, found 293.1158.
4.1.2 2-p-Tolyl-1-(2,3,4-trimethoxyphenyl)ethanone (7b). This material was prepared in a
manner identical to the previous example (7a) with the exception that 1,2,3-trimethoxybenzene was
used as the aromatic hydrocarbon component instead of 1,3-dimethoxybenzene in which case a dark
oil (0.379 g, 71% yield) was obtained. This material exhibited the following physical properties: bp
146-147 °C at 0.54 torr; 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J = 9.0 Hz, 1H), 7.12 (broad s, 4H),
6.70 (d, J = 9.0 Hz, 1H), 4.25 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H) and 2.33 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 196.6, 157.3, 153.8, 142.1, 136.1, 132.1, 129.5, 129.1, 126.0, 125.8,
107.2, 61.6, 60.9, 56.1, 48.9 and 21.1; IR (neat) 1680 cm-1; HRMS (ES, M+Na) m/z calcd for
C18H20O4Na 323.1254, found 323.1236.
9

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4.1.3 1-(3,4-Dimethoxyphenyl)-2-p-tolylethanone (7c). This material was prepared in a manner
identical to the previous example (7a) with the exception that 1,2-dimethoxybenzene was used as
the aromatic hydrocarbon component instead of 1,3-dimethoxybenzene in which case a dark oil
1
(89% yield) was obtained, which exhibited a H NMR spectrum identical to the reported values13.
1H NMR (300 MHz, CDCl3) δ 7.68 (dd, J = 8.3 Hz, J = 2.0 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.18
(d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.3 Hz, 1H), 4.22 (s, 2H), 3.95 (s, 3H),
3.93 (s, 3H) and 2.34 (s, 3H).
4.1.4 1-(4-Methoxyphenyl)-2-phenylethanone (7d). This material was prepared in a manner
identical to the previous example (7a) with the exception that methoxybenzene was used as the
aromatic hydrocarbon component and phenyl acetic acid was used as the acyl component. A solid
1
(98% yield) was obtained, which exhibited a H NMR spectrum identical to the reported values14.
1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 10.0 Hz, 2H), 7.31 (m, 5H), 6.95 (d, J = 10.0 Hz, 2H),
4.26 (s, 2H) and 3.88 (s, 3H).
4.1.5 2-(4-Bromophenyl)-1-(4-methoxyphenyl)ethanone (7e). This material was prepared in a
manner identical to the previous example (7a) with the exception that 4-bromophenyl acetic acid
1
was used as the acyl component. A solid (81% yield) was obtained, which exhibited a H NMR
spectrum identical to the reported values14. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 8.9 Hz, 2H),
7.46 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 4.20 (s, 2H) and 3.89
(s, 3H).
4.1.6 1-(4-Methoxyphenyl)-2-p-tolylethanone (7f). This material was prepared in a manner
identical to the previous example (7a) with the exception that 4-tolyl acetic acid was used as the
1
acyl component. A solid (98% yield) was obtained, which exhibited a H NMR spectrum identical
1
to the reported values14. H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.1
Hz, 2H), 7,14 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 4.21 (s, 2H), 3.88 (s, 3H) and 2.34 (s,
3H).
4.1.7 2-(4-Chlorophenyl)-1-(4-methoxyphenyl)ethanone (7g). This material was prepared in a
manner identical to the previous example (7a) with the exception that 4-chlorophenyl acetic acid
1
was used as the acyl component. A solid (90% yield) was obtained, which exhibited a H NMR
spectrum identical to the reported values15. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 8.9 Hz, 2H),
7.31 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 4.22 (s, 2H) and 3.89 (s,
3H).
4.1.8 1-(4-Methoxyphenyl)-2-(2,3,4-trimethoxyphenyl)ethanone (7h). This material was
prepared in a manner identical to the previous example (7a) with the exception that 2,3,4-
trimethoxyphenyl acetic acid was used as the acyl component. A solid (71% yield) was obtained
after flash purification on A Biotage Isolera instrument with a silica column. This material exhibited
the following physical properties: mp 55-56 °C; 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 9.0 Hz,
2H), 6.96 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H),4.20 (s, 2H), 3.89
(s, 6H), 3.87 (s, 3H) and 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 196.6, 163.4, 152.9, 151.7,
142.3, 130.7, 129.9, 124.9, 121.6, 113.7, 107.4, 60.8, 60.7, 56.0, 55.4, and 39.2; IR (neat) 1680 cm-
1; HRMS (ES, M+Na) m/z calcd for C18H20O5Na 339.1203 found 339.1200.
4.1.9 2-(3,4-Dimethoxphenyl)-1-(4-methoxyphenyl)ethanone (7i). This material was prepared in
a manner identical to the previous example (7a) with the exception that 3,4-dimethoxyphenyl acetic
1
acid was used as the acyl component. A dark oil (79% yield) was obtained, which exhibited a H
1
NMR spectrum identical to the reported values16. H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 8.8
10

ACCEPTED MANUSCRIPT
Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.85-6.80 (m, 3H), 4.19 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H) and
3.87 (s, 3H).
4.1.10 4-Dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one (8a). Into a 20 mL microwave vial
equipped with a magnetic stir bar and crimping cap was added 4-methoxyphenylacetone (0.545 g,
3.32 mmol), N,N-dimethylformamide dimethyl acetal (3.18 g, 26.6 mmol), and dimethylformamide
(5 mL). The reaction mixture was heated in a microwave reactor for 2 hours at 100 °C. The solvent
was removed in vacuo, the crude mixture was diluted with water (30 mL), and the aqueous solution
was extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with
aqueous lithium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo
to yield an orange solid (0.721 g, 99% yield), which exhibited the following properties: mp 51-53
°C; 1H NMR (CDCl3; 500 MHz) δ 7.60 (s, 1H), 7.11 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H),
3.85 (s, 3H), 2.72 (s, 6H), 1.95 (s, 3H); 13C NMR (CDCl3; 75 MHz) δ 27.41, 42.91, 55.11, 110.51,
113.27, 130.27, 133.03, 149.03, 158.36, and 196.77; IR (neat) 1647 cm-1; HRMS (ES, M+H) m/z
calcd for C13H17NO2 220.1332 found 220.1300.
4.1.11 4-Dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one (8a). Into a 200 mL round bottom
flask equipped with a magnetic stir bar and reflux condenser was added 4-methoxyphenylacetone
(3.10 g, 18.9 mmol), N,N-dimethylformamide dimethyl acetal (13.56 g, 113 mmol), and dimethyl-
formamide (15 mL). The reaction mixture was heated to reflux for 6 hours, cooled to room
temperature, and the solvent was removed in vacuo. The reaction mixture was diluted with water
(30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed
with aqueous lithium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated in
1
vacuo to yield a substance (3.78 g, 91% yield), which was identical by H NMR to 4-
dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one (8a) prepared via microwave irradiation.
4.1.12 3-Dimethylamino-1,2-bis-(4-methoxyphenyl)-propenone (8b). This material was prepared
in a manner identical to the previous reflux example (8a) with the exception that desoxyanisoin
was used as the ketone in which case a yellow solid was obtained (2.39 g, 99% yield), which was
identical by 1H NMR analysis to a previously prepared sample7.
4.1.13 3-Dimethylamino-1-(4-methoxyphenyl)-2-p-tolyl-propenone (8c). This material was
prepared in a manner identical to the previous reflux example (8a) with the exception that 1-(4-
methoxyphenyl)-2-p-tolyl-ethanone was used as the ketone in which case an orange solid (1.31 g,
96 % yield) was obtained. An analytical sample was prepared via a Biotage Isolera flash
1
chromatography system, which displayed the following properties: mp 60-62°C; H NMR (300
MHz, CDCl3) δ 7.43 (d, J = 8.8 Hz, 2H), 7.34 (s, 1H), 7.08-6.97 (m, 4H), 6.75 (d, J = 8.8 Hz, 2H),
3.77 (s, 3H), 2.71 (s, 6H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 193.89, 160.61, 153.06,
135.62, 134.64, 134.27, 131.87, 130.93, 128.36, 112.77, 111.73, 55.19, 43.42, 21.18; IR (neat) 1629
cm-1 HRMS (ES, M+H) m/z calcd for C19H21NO2 296.1645 found 296.1640.
4.1.14 3-Dimethylamino-2-p-tolyl-1-(2,3,4-trimethoxyphenyl)-propenone (8d). This material
was prepared in a manner identical to the previous reflux example (8a) with the exception that 2-p-
tolyl-1-(2,3,4-trimethoxyphenyl)ethanone was used as the ketone. The crude material was dissolved
in a minimal amount of ethyl acetate and filtered through a short plug of silica with a 3:2 mixture of
hexane/ethyl acetate (100 mL) followed by ethyl acetate (75 mL) and acetonitrile (25 mL). The
solvent from the second fraction was removed in vacuo to yield an orange solid (0.614g, 54 %
yield). An analytical sample was prepared via a Biotage Isolera flash chromatography system
which displayed the following properties: mp 62-64°C; 1H NMR (300 MHz, CDCl3) δ 7.16 (s, 1H),
7.10 (broad s, 4H), 6.94 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.86
11

ACCEPTED MANUSCRIPT
(s, 3H), 2.70 (s, 6H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 193.02, 154.14, 153.74, 150.79,
141.82, 135.70, 133.48, 131.81, 129.82, 128.19, 123.37, 113.32, 106.95, 61.76, 60.84, 55.98, 43.32,
21.14; IR (neat) 1636; HRMS (ES, M+H) m/z calcd for C21H25NO4 356.1856 found 356.1850.
4.1.15 1-(3,4-Dimethoxyphenyl)-3-dimethylamino-2-p-tolylpropenone (8e). this material was
prepared in a manner identical to the previous reflux example (8a) with the exception that 1-(3,4-
dimethoxyphenyl)-2-p-tolyl-ethanone was used as the ketone in which case an orange solid (1.12 g,
91 % yield) was obtained. An analytical sample was prepared via a Biotage Isolera flash
1
chromatography system, which displayed the following properties: mp 128-129 °C; H NMR (300
MHz, CDCl3) δ 7.45 (s, 1H), 7.12 (dd, J = 8.3 Hz, J = 2.0 Hz, 1H), 7.05 (broad s, 4H), 6.98 (d, J =
2.0 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 3.87 (s, 3H), 3.72 (s, 3H), 2.77 (s, 6H), 2.33 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 193.41, 152.82, 150.15, 147.81, 135.67, 134.90, 134.18, 131.92, 128.40,
122.73, 112.70, 111.42, 109.72, 55.80, 55.65, 43.49, 21.13; IR (neat) 1622; HRMS (ES, M+H) m/z
calcd for C20H23NO3 326.1751 found 326.1765.
4.1.16 1-(2.4-Dimethoxyphenyl)-3-dimethylamino-2-p-tolyl-propenone (8f). This material was
prepared in a manner identical to the previous reflux example (8a) with the exception that 1-(2,4-
dimethoxyphenyl)-2-p-tolyl-ethanone was used as the ketone in which case an orange solid (1.29 g,
95 % yield) was obtained. An analytical sample was prepared via a Biotage Isolera flash
1
chromatography system, which displayed the following spectral properties: 134-135°C; H NMR
(300 MHz, CDCl3) δ 7.23 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.05-6.95 (m, 4H), 6.38 (dd, J = 8.2 Hz,
J = 2.3 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 2.64 (s, 6H), 2.26 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 193.64, 160.94, 157.47, 153.09, 135.40, 133.88, 131.91, 129.78, 127.91,
125.19, 113.31, 104.15, 98.60, 55.57, 55.29, 43.34, 21.16; IR (neat) 1622 cm-1; HRMS (ES, M+H)
m/z calcd for C20H23NO3 326.1751 found 326.1695.
4.1.17 2-(4-Bromophenyl)-3-dimethylamino-1-(4-methoxyphenyl)-propenone (8g). This
material was prepared in a manner identical to the previous reflux example (8a) with the exception
that 2-(4-bromophenyl)-1-(4-methoxyphenyl)-ethanone was used as the ketone in which case an
orange solid (1.29 g, 95 % yield) was obtained. An analytical sample was prepared via a Biotage
1
Isolera flash chromatography system, which displayed the following properties: 103-104°C; H
NMR (300 MHz, CDCl3) δ 7.41 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 7.01 (d,
J = 8.4 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 3.77 (s, 3H), 2.70 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
193.58, 160.81, 153.61, 136.82, 133.86, 133.61, 130.86, 130.68, 120.04, 112.97, 110.52, 55.25,
43.65; IR (neat) 1629 cm-1; HRMS (ES, M+H) m/z calcd for C18H18NO2Br 360.0594 found
360.0600.
4.1.18 2-(4-Chlorophenyl)-3-dimethylamino-1-(4-methoxyphenyl)-propenone (8h). This
material was prepared in a manner identical to the previous reflux example (8a) with the exception
that 2-(4-chlorophenyl)-1-(4-methoxyphenyl)-ethanone was used as the ketone in which case a
yellow solid (1.20 g, 99 % yield) was obtained. An analytical sample was prepared via a Biotage
Isolera flash chromatography system, which displayed the following properties: mp 113-116°C; 1H
NMR (300 MHz, Acetone-d6) δ 7.44 (d, J = 8.8 Hz, 2H), 7.33-7.26 (m, 3H), 7.17 (d, J = 8.5 Hz,
2H), 6.87 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.77 (s, 6H); 13C NMR (75 MHz, Acetone-d6 ) δ 192.23,
160.83, 153.30, 137.29, 134.44, 133.64, 131.02, 130.63, 127.22, 112.83, 110.01, 54.74, 42.87; IR
(neat) 1629; HRMS (ES, M+H) m/z calcd for C18H18NO2Cl 316.1099 found 316.1099.
4.1.19 3-Dimethylamino-1-(4-methoxyphenyl)-2-phenylpropenone (8i). This material was
prepared in a manner identical to the previous reflux example (8a) with the exception that 1-(4-
methoxyphenyl)-2-phenylethanone was used as the ketone in which case an 85 % yield of a
12

ACCEPTED MANUSCRIPT
1
semisolid was obtained, which displayed an identical H NMR spectrum to the reported values15
;1H NMR (300 MHz, CDCl3) δ 7.44 (d, J = 8.9 Hz, 2H), 7.41 (s, 1H), 7.31 – 7.13 (m, 5H), 6.77 (d,
J = 8.9 Hz, 2H), 3.80 (s, 3H), 2.75 (s, 6H).
4.1.20 3-Dimethylamino-1-(4-methoxyphenyl)-2-(2,3,4-trimethoxyphenyl)-propenone (8j). This
material was prepared in a manner identical to the previous reflux example (8a) with the exception
that 1-(4-methoxyphenyl)-2-(2,3,4-trimethoxyphenyl)-ethanone was used as the ketone in which
case an orange solid (2.29 g, 83 % yield) was obtained. An analytical sample was prepared via a
Biotage Isolera flash chromatography system, which displayed the following properties: mp 85-86
°C; 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.7 Hz, 2H), 7.31 (s, 1H), 6.87-6.78 (m, 3H), 6.64 (d,
J = 8.7 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.76 (s, 3H), 2.75 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 194.17, 160.67, 153.78, 152.80, 152.37, 142.15, 134.50, 130.65, 127.69, 124.27,
112.87, 107.33, 106.77, 60.73, 60.37, 55.93, 55.25, 42.78; IR (neat) 1630; HRMS (ES, M+H) m/z
calcd for C21H25NO5 372.1805 found 372.1824.
4.1.21 3-Dimethylamino-2-(3,4-dimethoxyphenyl)-1-(4-methoxyphenyl)propenone (8k). This
material was prepared in a manner identical to the previous reflux example (8a) with the exception
that 2-(3,4-dimethoxyphenyl)-1-(4-methoxyphenyl)-ethanone was used as the ketone in which case
an orange solid (1.06 g, 85 % yield) was obtained. An analytical sample was prepared via a Biotage
Isolera flash chromatography system, which displayed the following properties: mp 68-70 °C; 1H
NMR (500 MHz, CDCl3) δ 7.46 (d, J = 8.7 Hz, 2H), 7.37 (s, 1H), 6.82 – 6.77 (m, 3H), 6.72 (dd, J =
8.1, 1.9 Hz, 1H), 6.69 (d, J = 1.9 Hz, 1H), 3.89 (s, 4H), 3.82 (s, 4H), 3.81 (s, 4H), 2.77 (s, 7H).; 13C
NMR (75 MHz, CDCl3) δ 193.95, 160.64, 152.99, 148.18, 147.54, 134.20, 130.86, 130.27, 124.44,
115.50, 112.81, 111.56, 110.53, 55.85, 55.79, 55.21, 43.35.; IR (neat) 1628; HRMS (ES, M+H) m/z
calcd for C20H23NO4 342.1700 found 342.1716.
4.1.22 {[2-(4-Methoxyphenyl)-3-oxo-but-1-enyl]methylamino}acetic acid ethyl ester (10d). Into
a 100 mL round bottom flask equipped with a magnetic stir bar and a reflux condenser was added 4-
dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one (2.86 g, 13.0 mmol), sarcosine ethyl ester
hydrochloride (5.01 g, 32.6 mmol) and ethanol (30 mL). The reaction mixture was heated at reflux
for 4 hours. The solvent was removed in vacuo, the crude reaction mixture was diluted with water
(50 mL), and the aqueous solution was extracted with ethyl acetate (3 x 20 mL). The combined
organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and
concentrated in vacuo to yield a dark orange oil (3.44 g, 91%), which exhibited the following
properties: bp 104-105 °C at 0.45 torr; 1H NMR (CDCl3, 300 MHz) δ 7.52 (s, 1H), 7.11 (d, J = 8.6
Hz, 2H) 6.87 (d, J=8.6 Hz, 2H), 4.13 (q, 7.1 Hz, 2H), 3.83 (s, 3H), 3.69 (s, 2H), 2.78 (s, 3H), 1.95
(s, 3H), 1.25 (t, J= 7.1 Hz, 3H); 13C NMR (CDCl3; 75 MHz) δ 13.94, 27.35, 42.56, 55.05, 55.50,
61.08, 112.02, 113.42, 129.29, 132.76, 148.47, 158.56, 168.61, and 197.28; IR (neat) 1742 and
1658 cm-1; HRMS (ES, M+H) m/z calcd for C16H21NO4 292.1543 found 292.1513.
4.1.23 {[2-(4-Methoxyphenyl)-3-oxo-but-1-enyl]methylamino}acetic acid ethyl ester via
microwave heating (10d). Into a 20 mL microwave vial equipped with a magnetic stir bar and a
crimping cap was added 4-dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one (0.652 g, 2.97
mmol), sarcosine ethyl ester hydrochloride (1.14 g, 7.42 mmol), and ethanol (10 mL). The reaction
mixture was heated in a microwave reactor for 2 hours at 100 °C. The solvent was removed in
vacuo, the crude mixture was diluted with water (30 mL) and the aqueous solution was extracted
with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (20 mL),
dried over anhydrous sodium sulfate, and concentrated in vacuo to yield a dark orange oil (0.774 g,
89 % yield), which was identical by 1H NMR (CDCl3, 300 MHz) 7.52 (s, 1H), 7.11 (d, J=8.6 Hz,
2H) 6.87 (d, J=8.6 Hz, 2H), 4.13 (q, 7.1 Hz, 2H), 3.83 (s, 3H), 3.69 (s, 2H), 2.78 (s, 3H), 1.95 (s,
13

ACCEPTED MANUSCRIPT
3H), 1.25 (t, J= 7.1 Hz, 3H)] to {[2-(4-methoxyphenyl)-3-oxo-but-1-enyl]-methylamino}acetic acid
ethyl ester prepared via normal heating.
4.1.24 {[3-(4-Methoxyphenyl)-3-oxo-2-p-tolylpropenyl]methylamino}acetic acid ethyl ester
(10a). This material was prepared in a manner identical to the reflux exchange example (10d) with
the exception that 3-dimethylamino-1-(4-methoxyphenyl)-2-p-tolylpropenone was used as the
vinylogous amide in which case the crude product was passed through a short plug of silica using
100 mL of a 30:70 ethyl acetate:hexane mix followed by two 100 mL portions of ethyl acetate. The
second 100 mL fraction was concentrated in vacuo yield to yield an orange oil (1.00 g, 64% yield).
An analytical sample was prepared on a Biotage Isolera flash chromatography system to yield a
1
yellow oil, which displayed the following properties: bp 160-161°C @ 0.285 torr; H NMR (300
MHz, CDCl3) δ 7.49 (d, J = 8.8 Hz, 2H), 7.23 (s, 1H), 7.07 (s, 4H), 6.78 (d, J = 8.8 Hz, 2H), 4.14
(q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.70 (s, 2H), 2.74 (s, 3H), 2.32 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).;
13C NMR (75 MHz, CDCl3) δ 194.47, 168.80, 160.91, 152.44, 136.06, 133.84, 133.81, 131.58,
131.07, 128.57, 113.59, 112.87, 61.26, 56.38, 55.22, 42.77, 21.20, 14.09; IR (neat) 1737 and 1586
cm-1; HRMS (ES, M+H) m/z calcd for C22H25NO4 368.1858 found 368.1856.
4.1.25 {[3-(3,4-Dimethoxyphenyl)-3-oxo-2-p-tolylpropenyl]methylamino}acetic acid ethyl ester
(10b). This material was prepared in a manner identical to the previous reflux example (10d) with
the exception that 1-(3,4-dimethoxyphenyl)-3-dimethylamino-2-p-tolylpropenone was used as the
vinylogous amide in which case the crude product was purified using a Biotage Isolera flash
chromatography system to yield a yellow solid (0.509 g, 54% yield), which displayed the following
properties: mp 87-88 °C; 1H NMR (500 MHz, CDCl3 ) δ 7.33 (s, 1H), 7.17 (dd, J = 8.3 Hz , J = 2.0
Hz, 1H), 7.09 (s, 4H), 7.05 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H),
13
3.89 (s, 3H), 3.77 (s, 3H), 3.75 (s, 2H), 2.78 (s, 3H), 2.34 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).; C
NMR (75 MHz, CDCl3) δ 194.06, 168.79, 152.34, 150.43, 147.92, 136.06, 134.05, 133.76, 131.59,
128.57, 122.82, 113.27, 112.61, 109.75, 61.26, 55.80, 55.67, 42.72, 21.15, 14.07.; IR (neat) 1740
and 1556 cm-1; HRMS (ES, M+H) m/z calcd for C23H27NO5 398.1962 found 398.1961.
4.1.26 {[2,3-Bis(4-methoxyphenyl)-3-oxopropenyl]methylamino}acetic acid ethyl ester (10c).
This material was prepared in a manner identical to the previous reflux example (10d) with the
exception that 3-dimethylamino-1,2-bis(4-methoxyphenyl)propenone was used as the vinylogous
amide in which case a dark orange solid (1.46 g, 99% yield) was obtained. An analytical sample
was prepared via a Biotage Isolera flash chromatography system yielding a yellow solid, which
displayed the following properties: mp 98-99 °C; 1H NMR (300 MHz, CDCl3 ) δ 7.45 (d, J = 8.6
Hz, 2H), 7.19 (s, 1H), 7.07 (d, J = 8.6 Hz, 2H), 6.74-6.79 (m, 4H), 4.10 (q, J = 7.1Hz, 2H), 3.74 (s,
6H), 3.68 (s, 2H), 2.70 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.53,
168.82, 160.90, 158.30, 152.60, 133.81, 132.72, 131.01, 129.05, 113.33, 113.16, 112.89, 61.24,
56.33, 55.20, 55.11, 42.67, 14.07; IR (neat) 1746 and 1625 cm-1 ; HRMS (ES, M+H) m/z calcd for
C22H25NO5 384.1805 found 384.1832.
4.1.27 {Methyl-[3-oxo-2-p-tolyl-3-(2,3,4-trimethoxyphenyl)propenyl]amino}acetic acid ethyl
ester (10e). This material was prepared in a manner identical to the previous reflux example (10d)
with the exception that 3-dimethylamino-2-p-tolyl-1-(2,3,4-trimethoxyphenyl)propenone was used
as the vinylogous amide in which case a dark orange solid (1.41g, 93%) was obtained. An
analytical sample was prepared via a Biotage Isolera flash chromatography system, which exhibited
the following properties: 54-56 °C; 1H NMR (500 MHz, CDCl3) δ 7.11 (broad s, 4H), 6.96 (d, J =
8.6 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.87 (s,
3H), 3.66 (s, 2H), 2.77 (s, 3H), 2.34 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).; 13C NMR (75 MHz, CDCl3) δ
193.78, 168.55, 154.01, 153.42, 151.01, 141.89, 136.25, 132.78, 131.59, 129.41, 128.51, 123.57,
14

ACCEPTED MANUSCRIPT
115.11, 106.90, 61.87, 61.25, 60.93, 56.04, 21.21, 14.04.; IR (neat) 1742 and 1578 cm-1; HRMS
(ES, M+H) m/z calcd for C24H29NO6 428.2068 found 428.2110.
4.1.28 Benzyl-[3-(4-methoxyphenyl)-3-oxo-2-p-tolyl-propenyl]amino}acetic acid ethyl ester
(10f). Into a 100 ml round bottom flask equipped with a reflux condenser and a stir bar was added
(3-dimethylamino-1-(4-methoxyphenyl)-2-p-tolylpropenone (0.755 g, 2.56 mmol), N-benzyl
glycine ethyl ester (.985 g, 5.12 mmol), ethanol (20 ml), and trifluoroacetic acid (0.329 ml, 5.12
mmol). The reaction mixture was heated to reflux overnight, cooled to room temperature, and the
solvent was removed in vacuo to yield a crude yellow oil. Purification on a Biotage Isolera
automated flash chromatography system (hexane/ethyl acetate gradient) produced a yellow solid
1
(0.820 g, 72% yield), which displayed the following properties: 92-93 °C; H NMR (300 MHz,
CDCl3) δ 7.52 (d, J = 8.7 Hz, 2H), 7.44 (s, 1H), 7.40-7.30 (m, 3H), 7.19 (dd, J = 7.7, 1.8 Hz, 2H),
7.09 (s, 4H), 6.81 (d, J = 8.8 Hz, 2H), 4.31 (s, 2H), 4.08 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.58 (s,
2H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.74, 168.75, 160.98, 152.27, 136.34,
135.94, 133.77, 133.67, 131.41, 131.04, 128.91, 128.84, 128.07, 127.98, 113.92, 113.03, 112.96,
61.13, 59.63, 55.24, 51.39, 21.23, 14.02.; IR (neat) 1737 and 1586 cm-1; HRMS (ES, M+H) m/z
calcd for C28H29NO4 444.2169 found 444.2136.
4.1.29 {Benzyl-[2,3-bis(4-methoxyphenyl)-3-oxo-propenyl]amino}acetic acid ethyl ester (10g).
This material was prepared in a manner identical to the previous example (10f) with the exception
that 3-dimethylamino-1,2-bis-(4-methoxyphenyl)-propenone was used as the vinylogous amide in
which case a yellow solid (0.637 g, 84% yield) was obtained, which displayed the following
1
properties: 89-91 °C; H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 9.0 Hz, 2H), 7.44 (s, 1H), 7.40-
7.29 (m, 3H), 7.17 (d, J = 9.0, 2H), 7.12 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 6.79 (d, J =
9.0 Hz, 2H), 4.31 (s, 2H), 4.08 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.61 (s, 2H), 1.21 (t, J
= 7.2 Hz, 3H).; 13C NMR (75 MHz, CDCl3) δ 194.85, 168.78, 160.99, 158.52, 152.36, 135.96,
133.77, 132.60, 131.04, 128.85, 128.83, 128.08, 127.97, 113.62, 113.57, 112.98, 61.16, 59.52,
55.24, 55.14, 51.45, 14.02. IR (neat) 1749 and 1586 cm-1. HRMS (ES, M+H) calcd for C28H29NO5
460.2118 found 460.2128.
4.1.30. 4-(4-Methoxyphenyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (12a) and
2-(4-methoxyphenyl)-3-oxo-butyraldehyde (11) under base mediated conditions. Into a 100 mL
three neck round bottom flask equipped with a magnetic stir bar and reflux condenser under an inert
atmosphere was placed dry THF (30 mL) sodium hydride (0.137 g, 3.40 mmol) and {[2-(4-
methoxyphenyl)-3-oxo-but-1-enyl]methylamino}acetic acid ethyl ester (0.500 g, 1.72 mmol). The
reaction mixture was stirred at room temperature overnight, brought to neutral pH with acetic acid
and diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (3 x 20 mL)
and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium
sulfate, and concentrated in vacuo to yield a dark oil, which by 1H NMR analysis was suggestive of
a 60:40 mixture of 4-(4-methoxyphenyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester7 and
2-(4-methoxyphenyl)-3-oxo-butyraldehyde (11)17.
4.1.31. 2-(4-Methoxyphenyl)-3-oxobutyraldehyde (11). Into a 100 mL round bottom flask
equipped with a magnetic stir bar and a rubber septum was placed {[2-(4-methoxyphenyl)-3-oxo-
but-1-enyl]-methylamino}-acetic acid ethyl ester (1.41 g, 4.85 mmol), 25 % by weight aqueous
sodium hydroxide (2 mL), THF (15 mL) and water (15 mL). The reaction mixture was stirred
overnight at room temperature, brought to neutral pH with acetic acid, and diluted with water (50
mL). This mixture was then extracted with ethyl acetate (3 x 20 mL) and the combined organic
phases were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated in
vacuo to yield a dark oil (0.886 g, 95 %). An analytical sample was prepared via a Biotage Isolera
15

ACCEPTED MANUSCRIPT
1
flash chromatography system and it displayed the following properties: mp. 43-45 °C; H NMR
(300 MHz, CDCl3 ) δ 15.33 (d, J = 6.5 Hz, 1H), 8.20 (d, J = 6.5 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H),
13
6.94 (d, J = 8.7 Hz, 2H), 3.85 (s, 3H), 2.09 (s, 3H); C NMR (75 MHz, CDCl3) δ 193.40, 178.98,
159.05, 131.33, 127.37, 116.94, 114.08, 55.28, 24.68; IR (neat) 2559 cm-1, 1645 cm-1; HRMS (ES,
M+H) m/z calcd for C11H12O3 193.0859 found 193.0841.
4.1.32. 4-(4-Methoxyphenyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (12a) in a
stepwise reaction. Into a 100 mL round bottom flask equipped with a magnetic stir bar and a reflux
condenser was placed {[2-(4-methoxyphenyl)-3-oxo-but-1-enyl]methylamino}acetic acid ethyl
ester (0.500 g, 2.28 mmol) and glacial acetic acid (15 mL). The reaction mixture was heated at
reflux overnight. The crude reaction mixture was diluted with ethyl acetate (35 mL), washed with
saturated aqueous sodium bicarbonate solution (3 x 20 mL) and brine (20 mL), and dried over
anhydrous sodium sulfate. The organic phases were combined and concentrated in vacuo to yield a
brown oil (0.440 g, 94% yield). From this material, an analytical sample was prepared via flash
chromatography on a Biotage Isolera system using a hexane/ethyl acetate gradient, which yielded a
yellow solid that displayed the following properties: mp 49-51°C; 1H NMR (300 MHz, Acetone-d6)
δ 7.27 (d, J = 8.8 Hz, 2H), 6.99-6.91 (m, 3H), 4.31 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 3.81 (s, 3H),
13
2.36 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H) ; C NMR (75 MHz, Acetone-d6) δ 161.58, 158.30, 129.49,
127.71, 126.98, 125.82, 124.30, 120.41, 113.77, 59.16, 54.62, 36.79, 13.93, 11.82; IR (neat) 1685
cm-1; HRMS (ES, M+H) m/z calcd for C16H 19NO3 274.1438 found 274.1412.
4.1.33. 3,4-Bis(4-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (12b) in a
stepwise reaction. This material was prepared in a manner identical to the previous example (12a)
with the exception that {[2,3-bis(4-methoxyphenyl)-3-oxo-propenyl]methylamino}acetic acid ethyl
ester was used as the exchanged vinylogous amide in which case a brown oil (0.451 g, 95%) was
obtained. An analytical sample was prepared via automated flash chromatography on a Biotage
Isolera system using a hexane/ethyl acetate gradient, which yielded a yellow solid that was identical
1
by H analysis to 3,4-bis-(4-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
previously prepared by our group.1
4.1.34. 3-(4-Methoxyphenyl)-1-methyl-4-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (12c)
in a stepwise reaction. This material was prepared in a manner identical to the previous example
(12a) with the exception that {[3-(4-methoxyphenyl-3-oxo-2-p-tolyl-propenyl]-methylamino}acetic
acid ethyl ester was used as the exchanged vinylogous amide and the crude reaction mixture was
filtered through a short plug of silica using a 1:1 solution of ethyl acetate:hexane (120 ml) in which
case a brown-orange solid (0.349 g, 81% yield) was obtained. An analytical sample was prepared
via automated flash chromatography to yield a yellow solid, which displayed the following
1
properties: mp 102-103 °C; H NMR (500 MHz, CDCl3) δ 7.14 (d, J = 8.7 Hz, 2H), 7.03-6.96 (m,
4H), 6.93 (s, 1H), 6.84 (d, J = 8.7 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.99 (s, 3H), 3.84 (s, 3H), 2.29
(s, 3H), 1.03 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.88, 158.34, 135.28, 131.74,
131.69, 130.66, 128.83, 128.34, 127.96, 126.68, 124.11, 120.70, 112.90, 59.60, 55.18, 37.53, 21.02,
13.84; IR (neat) 1686 cm-1; HRMS (ES, M+Na) m/z calcd for C22H23NO3 372.1570 found 372.1579.
4.1.35. 3-(3,4-Dimethoxyphenyl)-4-p-tolyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
(12d) in a stepwise reaction. This material was prepared in a manner identical to the previous
example (12a) with the exception that {[3-(3,4-dimethoxyphenyl-3-oxo-2-p-tolyl-propenyl]-
methylamino}acetic acid ethyl ester was used as the exchanged vinylogous amide in which case a
brown solid (0.378 g, 88%) was obtained. An analytical sample was prepared via flash
chromatography on a Biotage Isolera system using a hexane/ethyl acetate gradient, which yielded a
yellow solid that displayed the following properties: mp 114-117 °C; 1H NMR (300 MHz, CDCl3 )
16

ACCEPTED MANUSCRIPT
δ 6.98 (s, 4H), 6.90 (s, 1H), 6.83-6.73 (m, 3H), 4.10 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H),
13
3.74 (s, 3H), 2.27 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 161.79, 148.01,
147.79, 135.26, 131.65, 130.64, 128.81, 128.67, 127.91, 126.63, 124.09, 123.06, 120.67, 114.46,
110.49, 59.57, 55.78, 55.73, 37.43, 20.99, 13.94; IR (neat) 1687 cm-1; HRMS (ES, M+Na) m/z calcd
for C23H25NO4 402.1676 found 402.1693.
4.1.36. 1-Benzyl-3,4-bis-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (12e) in a
stepwise reaction. This material was prepared in a manner identical to the previous example (12a)
with the exception that {benzyl-[2,3-bis-(4-methoxyphenyl)-3-oxo-propenyl]amino}acetic acid
ethyl ester was used as the exchanged vinylogous amide in which case a light yellow solid was
obtained (0.367 g, 80% yield), which displayed the following properties: mp 128-129 °C; (500
MHz, CDCl3) δ 7.36 (t, J = 10.0 Hz, 2H), 7.31 (t, J =10.0 Hz, 1H), 7.25 (d, J = 10.0 Hz, 2H), 7.16
(d, J = 10.0 Hz, 2H), 7.02 (d, J = 10.0 Hz, 2H), 6.99 (s, 1H), 6.85 (d, J = 10.0 Hz, 2H), 6.74 (d, J =
10.0 Hz, 2H), 5.61 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 0.96 (t, J = 7.1 Hz,
3H).; 13C NMR (75 MHz, CDCl3) δ 161.70, 158.36, 157.88, 138.20, 131.80, 130.99, 129.18,
128.66, 128.30, 127.49, 127.13, 125.80, 124.37, 120.33, 113.60, 112.92, 59.67, 55.19, 55.15, 52.72,
13.73; IR (neet) 1689 cm-1; HRMS (ES, M+Na) m/z calcd for C28H27NO4 464.1832 found 464.1854.
4.1.37. 1-Benzyl-3-(4-methoxyphenyl)-4-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (12f)
in a stepwise reaction. This material was prepared in a manner identical to the previous procedure
(12a) with the exception that {benzyl-[3-(4-methoxyphenyl)-3-oxo-2-p-tolyl-propenyl]amino}acetic
acid ethyl ester was used as the exchanged vinylogous amide in which case an orange solid (0.598,
88% yield) was obtained. This material displayed the following properties: mp 89-91oC; 1H NMR
(300 MHz, CDCl3) δ 7.40 – 7.29 (m, 3H), 7.31(d, J = 10.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 7.01
(s, 1H), 6.99 (s, 4H), 6.84 (d, J = 9.0 Hz, 2H), 5.60 (s, 2H), 4.02 (d, J = 7.1 Hz, 2H), 3.83 (s, 3H),
2.28 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H).; 13C NMR (75 MHz, CDCl3) δ 161.70, 158.38, 138.17,
135.36, 131.77, 131.63, 131.11, 128.82, 128.66, 128.30, 127.97, 127.49, 127.13, 126.07, 124.64,
120.41, 112.91, 59.68, 55.19, 52.75, 21.03, 13.73; IR (neat) 1693 cm-1; HRMS (ES, M+Na) calcd
for C28H27NO3 448.1883 found 448.1848.
4.1.38 4-(4-Methoxyphenyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (12a) by a
one-pot reaction. Into a 100 mL round bottom flask equipped with a magnetic stir bar and a reflux
condenser was placed 4-dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one (0.500 g, 2.28 mmol),
sarcosine ethyl ester hydrochloride (0.876 g, 5.70 mmol), and glacial acetic acid (15 mL). The
reaction mixture was heated at reflux overnight and the crude reaction mixture was diluted with
ethyl acetate (35 mL), washed with saturated aqueous sodium bicarbonate (3 x 20 mL) and brine
(20 mL), and dried over anhydrous sodium sulfate. After filtration the organic phase was
concentrated in vacuo to yield a brown oil (0.507 g, 81%). An analytical sample was prepared via
flash chromatography on a Biotage Isolera system using a hexane/ethyl acetate gradient, which
yielded a yellow solid, which was identical by 1H NMR to 4-(4-methoxyphenyl)-1,3-dimethyl-1H-
pyrrole-2-carboxylic acid ethyl ester (12a) prepared via the stepwise route.
4.1.39 3,4-Bis-(4-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester by a one-
pot reaction (12b). This material was prepared in a manner identical to the previous example (12a)
with the exception that 3-dimethylamino-1,2-bis-(4-methoxyphenyl)propenone was used as the
vinylogous amide in which case automated flash chromatography yielded a yellow solid (0.426 g,
1
73 %), which was identical by H NMR to a sample of 3,4-bis-(4-methoxyphenyl)-1-methyl-1H-
pyrrole-2-carboxylic acid ethyl ester (12b) previously prepared by our group.1
17

ACCEPTED MANUSCRIPT
4.1.40 3-(4-Methoxyphenyl)-4-p-tolyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester by a
one-pot reaction (12c). This material was prepared in a manner identical to the previous example
(12a) with the exception that 3-dimethylamino-1-(4-methoxyphenyl)-2-p-tolyl-propenone was used
as the vinylogous amide in which case an orange solid (0.530 g, 86% yield) was obtained. An
analytical sample was prepared via automated flash chromatography to yield a yellow solid, which
was identical by 1H NMR to 3-(4-methoxyphenyl)-4-p-tolyl-1-methyl-1H-pyrrole-2-carboxylic acid
ethyl (12c) prepared via the stepwise route.
4.1.41 3-(3,4-Dimethoxyphenyl)-4-p-tolyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester
(12d) by a one-pot reaction. This material was prepared in a manner identical to the previous
example (12a) with the exception that 3-dimethylamino-1-(3,4-dimethoxyphenyl)-2-p-tolyl-
propenone was used as the vinylogous amide in which case a brown solid (0.464 g, 87% yield) was
obtained. An analytical sample was prepared via flash chromatography on a Biotage Isolera system
using a hexane/ethyl acetate gradient yielding a yellow solid, which was identical by 1H NMR to 3-
(3,4-dimethoxyphenyl)-4-p-tolyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (12d) prepared
via the stepwise route.
4.1.42 3-(4-Methoxyphenyl)-1-methyl-4-phenyl-1H-2-carboxylic acid ethyl ester in a one-pot
reaction (12g). This material was prepared in a manner identical to the previous example (12a)
with the exception that 3-dimethylamino-1-(4-methoxyphenyl)-2-phenyl-propenone (0.689 g, 2.45
mmol) was used as the vinylogous amide in which case an oily solid (0.591 g, 72%) was obtained.
An analytical sample was prepared via flash chromatography on a Biotage Isolera system using a
hexane/ethyl acetate gradient in which case a yellow solid was obtained and displayed the following
properties: : mp 85-87 °C, 1H NMR (300 MHz, CDCl3) δ 7.22 – 7.06 (m, 7H), 6.95 (s, 1H), 6.84 (d,
13
J = 8.8 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.83 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H); C
NMR (75 MHz, CDCl3) δ 161.87, 158.45, 134.74, 131.81, 130.76, 128.27, 128.13, 126.89, 125.77,
124.17, 120.85, 112.97, 59.66, 55.17, 37.56, 13.89; IR (neat) 1689 cm-1; HRMS (ES, M+Na) m/z
calcd for C21H21NO3 358.1414 found 358.1432.
4.1.43 4-(4-Bromophenyl)-3-(4-methoxyphenyl)-1-methylpyrrole-2-carboxylic acid ethyl ester
(12h) in a one-pot reaction. This material was prepared in a manner identical to the previous
example (12a) with the exception that 2-(4-bromophenyl)-3-dimethylamino-1-(4-methoxyphenyl)
propenone was used as the vinylogous amide in which case a brown solid (0.500 g, 87%) was
obtained. An analytical sample was prepared via flash chromatography on a Biotage Isolera system
using a hexane/ethyl acetate gradient, yielding a pale yellow solid, which displayed the following
properties: mp 148-149 °C; 1H NMR (300 MHz, CDCl3 ) δ 7.29 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.7
Hz, 2H), 6.99-6.90 (m, 3H), 6.85 (d, J = 8.7 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 3.84 (s,
3H), 1.03 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.73, 158.51, 133.67, 131.68, 131.20,
130.60, 129.60, 127.82, 126.61, 122.95, 121.02, 119.66, 113.04, 59.72, 55.19, 37.60, 13.83; IR
(neat) 1685 cm-1; HRMS (ES, M+Na) m/z calcd for C21H20NO3Br 436.0519 found 436.0488.
4.1.44 4-(4-Chlorophenyl)-3-(4-methoxyphenyl)-1-methylpyrrole-2-carboxylic acid ethyl ester
(12i) by a one-pot reaction. This material was prepared in a manner identical to the previous
example (12a) with the exception that 2-(4-chlorophenyl)-3-dimethylamino-1-(4-methoxyphenyl)-
propenone was used as a the vinylogous amide in which case a brown solid (0.535 g, 91%) was
obtained. An analytical sample was prepared via flash chromatography on a Biotage Isolera system
using a hexane/ethyl acetate gradient, which yielded a yellow solid, which displayed the following
1
properties: mp 134-135 °C; H NMR (300 MHz, CDCl3) δ 7.19-7.08 (m, 4H), 7.00 (d, J = 8.5 Hz,
2H), 6.93 (s, 1H), 6.85 (d, J = 8.5 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 3.83 (s, 3H), 1.03
(t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.74, 158.50, 133.20, 131.68, 131.55, 130.63,
18

ACCEPTED MANUSCRIPT
129.25, 128.26, 127.85, 126.64, 122.96, 120.98, 113.03, 59.71, 55.19, 37.59, 13.82; IR (neat) 1685
cm-1; HRMS (ES, M+Na) m/z calcd for C21H20NO3Cl 392.1024 found 392.1037.
4.1.45 4-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)-1-methylpyrrole-2-carboxylic acid ethyl
ester (12j) in a one-pot reaction. This material was prepared in a manner identical to the previous
example (12a) with the exception that 3-dimethylamino-2-(3,4-dimethoxyphenyl)-2-(4-
methoxyphenyl)-propenone was used as the vinylogous amide in which case a brown solid (0.450 g,
91%) was obtained. An analytical sample was prepared via flash chromatography on a Biotage
Isolera system using a hexane/ethyl acetate gradient, which yielded a yellow solid, which displayed
1
the following properties: mp 102-104 °C; H NMR (500 MHz, CDCl3) δ 7.15 (d, J = 8.7 Hz, 2H),
6.94 (s, 1H), 6.86 (d, J = 8.7 Hz, 2H), 6.75 (broad s, 2H), 6.52 (broad s, 1H), 4.10 (q, J = 7.1 Hz,
13
2H), 4.00 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.55 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H); C NMR (75
MHz, CDCl3) δ 161.82, 158.40, 148.33, 147.18, 131.79, 130.53, 128.55, 127.49, 126.29, 123.85,
120.68, 119.81, 113.00, 111.80, 111.08, 59.61, 55.78, 55.35, 55.26, 37.51, 13.82; IR (neat) 1680
cm-1; HRMS (ES, M+Na) m/z calcd for C23H25NO5 418.1625 found 418.1656.
4.1.46 4-(2,3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)-1-methylpyrrole-2-carboxylic acid
ethyl ester (12k) in a one pot reaction. This material was prepared in a manner identical to the
previous example (12a) with the exception that 3-dimethylamino-2-(2,3,4-dimethoxyphenyl)-2-(4-
methoxyphenyl)propenone (0.323g, 0.87 mmol) was used as the vinylogous amide in which case an
orange solid (0.280 g, 76%) was obtained. An analytical sample was prepared via flash
chromatography on a Biotage Isolera system using a hexane/ethyl acetate gradient and a yellow
1
solid was obtained, which displayed the following properties: mp 58-60 °C; H NMR (300 MHz,
CDCl3) δ 7.11 (d, J = 8.9 Hz, 2H), 6.98 (s, 1H), 6.79 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.6 Hz, 1H),
6.46 (d, J = 8.6 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.80 (s,
3H), 3.60 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.89, 158.19, 152.22,
151.67, 142.19, 131.67, 128.55, 128.41, 125.99, 121.18, 119.79, 119.36, 112.68, 106.78, 60.78,
60.40, 59.59, 55.85, 55.15, 37.58, 13.89; IR (neat) 1685 cm-1; HRMS (ES, M+Na) m/z calcd for
C24H27NO6 448.1731 found 448.1725.
4.1.47 1-Benzyl-4-(4-methoxyphenyl)-3-methylpyrrole-2-carboxylic acid ethyl ester (12l) by a
one-pot reaction. Into a 100 mL round bottom flask equipped with magnetic stir bar and reflux
condenser was added 4-dimethlamino-3-(4-methoxyphenyl)-but-3-en-2-one (0.500 g, 2.23 mmol),
N-benzylglycine ethyl ester (0.881 g, 4.56 mmol), and acetic acid (20 mL). The reaction mixture
was heated at reflux overnight, cooled, and the solvent was removed in vacuo. The crude mixture
was then filtered through a short plug of silica with a 20:80 mixture of ethyl acetate:hexane. The
solvent was removed in vacuo to yield a brown oil (0.489 g, 61% yield). An analytical sample was
prepared via automated flash chromatography to yield a brown solid, which exhibited the following
properties: mp 54-56˚C; 1H NMR (500 MHz, CDCl3) δ 7.33 (t, J = 10.0 Hz, 2H), 7.26-7.30 (m, 3H),
7.15 (d, J = 10.0 Hz, 2H), 6.95 (d, J = 10.0 Hz, 2H), 6.87 (s, 1H), 5.56 (s, 2H), 4.28 (q, J = 7.1 Hz,
2H), 3.85 (s, 3H), 2.42 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.99,
158.22, 138.55, 129.76, 128.55, 127.58, 127.35, 127.28, 126.82, 126.37, 125.21, 120.10, 113.84,
59.68, 55.29, 52.72, 14.37, 12.51; IR (neat) 1693 cm-1; HRMS (ES, M+Na) m/z calcd for
C22H23NO3 372.1570 found 372.1581.
4.1.48 1-Benzyl-3-(3,4-dimethoxyphenyl)-4-p-tolylpyrrole-2-carboxylic acid ethyl ester (12m)
by a one-pot reaction. This material was prepared in a manner identical to the previous example
(12l) with the exception that 1-(3,4-dimethoxyphenyl)-3-dimethylamino-2-p-tolyl-propenone was
used as the vinylogous amide in which case a yellow solid (0.440 g, 60% yield) was obtained,
1
which displayed the following properties: mp 44-46 ˚C; H NMR (500 MHz, CDCl3) δ 7.37 (t, J =
19

ACCEPTED MANUSCRIPT
7.4 Hz, 2H), 7.31 (d, J = 7.4 Hz, 1H), 7.26 (d, J = 7.4 Hz, 2H), 7.03 (s, 1H), 7.00 (broad s, 4H), 6.85
– 6.78 (m, 3H), 5.61 (s, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.77 (s, 3H), 2.29 (s, 3H), 0.98
13
(t, J = 7.1 Hz, 3H).; C NMR (75 MHz, CDCl3) δ 161.68, 147.99, 147.78, 138.09, 135.41, 131.56,
131.09, 128.81, 128.66, 128.57, 127.92, 127.52, 127.19, 125.96, 124.65, 123.06, 120.36, 114.41,
110.43, 59.69, 55.81,52.72, 29.70, 21.02, 13.82; IR (neat) 1693 cm-1. HRMS (ES, M+Na) m/z calcd
for C29H29NO4 478.1989 found 478.2026.
4.1.49 1-Benzyl-3,4-bis-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (12e) by a
one-pot reaction. This material was prepared in a manner identical to the previous example (12l)
with the exception that 3-dimethylamino-1,2-bis-(4-methoxyphenyl)-propenone was used as the
vinylogous amide in which case a yellow solid (0.340 g, 58 % yield) was obtained and displayed a
proton NMR spectrum identical to the pyrrole prepared by the stepwise process: (500 MHz, CDCl3)
δ 7.36 (t, J = 10.0 Hz, 2H), 7.31 (t, J =10.0 Hz, 1H), 7.25 (d, J = 10.0 Hz, 2H), 7.16 (d, J = 10.0
Hz, 2H), 7.02 (d, J = 10.0 Hz, 2H), 6.99 (s, 1H), 6.85 (d, J = 10.0 Hz, 2H), 6.74 (d, J = 10.0 Hz,
2H), 5.61 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 0.96 (t, J = 7.1 Hz, 3H).
4.1.50 1-Benzyl-3-(4-methoxyphenyl)-4-p-tolylpyrrole-2-carboxylic acid ethyl ester (12f) in a
one-pot fashion. This material was prepared in a manner identical to the previous example (12l)
(12l) with the exception that 3-dimethylamino-1-(4-methoxyphenyl)-2-p-tolyl-propenone was used
as the vinylogous amide in which case a yellow solid (0.502 g, 67% yield) was obtained, which was
identical by 1H NMR analysis to 1-benzyl-3-(4-methoxyphenyl)-4-p-tolyl-1-1H-pyrrole-2-
carboxylic acid ethyl ester prepared via the stepwise process: 1H NMR (300 MHz, CDCl3 ) δ 7.42 –
7.29 (m, 3H), 7.25 (d, J = 7.2 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.01 (s, 1H), 6.99 (s, 4H), 6.85 (d, J
= 8.7 Hz, 2H), 5.61 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.29 (s, 3H), 0.96 (t, J = 7.1 Hz,
3H).
4.1.51. 4-(4-Methoxyphenyl)-1,3-dimethylpyrrole-2-carboxylic acid ethyl ester (12a) from 2-(4-
methoxyphenyl)-3-oxo-butyraldehyde (11). Into a 100 mL round bottom flask equipped with a
magnetic stir bar and a reflux condenser was placed 2-(4-methoxyphenyl)-3-oxo-butyraldehyde
(0.482 g, 2.51 mmol), sarcosine ethyl ester hydrochloride (0.963 g, 6.27 mmol), and glacial acetic
acid (15 mL). The reaction mixture heated at reflux overnight and the crude reaction mixture was
diluted with ethyl acetate (35 mL), washed with saturated aqueous sodium bicarbonate (3 x 20 mL)
and brine (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated
in vacuo and then filtered through a short plug of silica using a 35:65 mixture of ethyl
acetate:hexane (100 mL). The eluent was concentrated in vacuo to yield a brown oil (0.377 g, 55%)
and an analytical sample was prepared via flash chromatography on a Biotage Isolera system using
1
a hexane/ethyl acetate gradient, which yielded a yellow solid. This material was identical by H
NMR to 4-(4-methoxyphenyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (12a)
prepared via the stepwise route.
4.1.52 (E/Z) 3-Chloro-3-(4-methoxyphenyl)-2-p-tolyl-propenal (13c). Into a 100 ml round
bottom flask equipped with a magnetic stir bar was placed 3-dimethylamino-1-(4-methoxyphenyl)-
2-p-tolyl-propenone (3.69 g, 12.5 mmol), anhydrous dichloromethane (30 ml) and phosphorous
oxychloride (1.17 ml, 12.5 mmol) was added dropwise to the stirred solution and the reaction
mixture was stirred overnight at room temperature. The reaction mixture was quenched by addition
of saturated aqueous, sodium bicarbonate (20 ml) and the biphasic mixture was stirred for 30
minutes. The phases were separated and the aqueous phase was extracted with additional
dichloromethane (2 x 15 ml) and the combined organic phases were filtered through a short plug of
silica with a 30:70 mixture of ethyl acetate:hexane. The organic phase was then concentrated in
vacuo to yield an orange solid (3.362 g, 94 % yield), which by 1H NMR was a 4:1 mixture of E:Z
20

ACCEPTED MANUSCRIPT
isomers. The crude product was separated into the two isomers by flash chromatography with a
hexane/ethyl acetate gradient in which case the following materials were obtained: (E isomer, 13c-
1
1): white solid; 117-118 °C; H NMR (300 MHz, CDCl3) δ 9.69 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H),
7.28 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H), 2.42 (s,
3H).; 13C NMR (75 MHz, CDCl3) δ 190.06, 161.87, 154.98, 140.03, 138.19, 132.14, 131.39,
129.76, 129.00, 128.11, 113.99, 55.53, 21.38.; IR (neat) 1665 cm-1. HRMS (ES, M+Na) calcd for
C17H15O2Cl 309.0653 found 309.0657. (Z isomer, 13c-2): yellow oil; bp 109-110 °C @ 0.300 torr;
1H NMR (300 MHz, CDCl3) δ 10.58 (s, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 6.90
(d, J = 8.9 Hz, 2H), 6.73 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H), 2.32 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 191.58, 160.82, 150.27, 137.69, 136.37, 131.58, 131.25, 130.46, 129.52, 129.09, 113.37, 55.28,
21.24.; IR (neat) 1676 cm-1; HRMS (ES, M+Na) calc for C17H15O2Cl 309.0653 found 309.0647.
4.1.53 3-(4-Methoxyphenyl)-4-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (12c) from the
E-chloroenal isomer (13c-1). Into a nitrogen flushed 3-neck, round bottom flask equipped with a
magnetic stir bar, and a reflux condenser was placed (E)-3-chloro-3-(4-methoxyphenyl)-2-p-
tolylpropenal (0.500 g, 1.65 mmol), glycine ethyl ester HCl (.346 g, 2.48 mmol), 4A molecular
sieves (10 g), and anhydrous DMF (60 ml). The reaction mixture was heated at reflux for 4 hours,
cooled to room temperature, and the solvent was removed in vacuo. The crude solid was dissolved
in a minimal amount of dichloromethane and filtered through a short plug of silica with a 50:50
mixture of ethyl acetate:hexane. The solvent was removed in vacuo to yield a brown solid (0.488 g,
83% yield), which exhibited the following properties:82-83 °C; 1H NMR (500 MHz, CDCl3) δ 9.16
(s, 1H), 7.22 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 7.03 (s, 4H), 6.86 (d, J = 8.7 Hz, 2H),
13
4.22 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.31 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).; C NMR (75 MHz,
CDCl3) δ 161.43, 158.55, 135.51, 131.97, 131.83, 129.06, 128.92, 128.21, 126.83, 126.57, 120.46,
119.85, 113.02, 60.16, 55.16, 21.09, 14.20.; IR (neat) 3346 and 1689 cm-1; HRMS (ES, M+Na)
calcd for C21H21NO3 358.1414 found 358.1424.
4.1.54 3-(4-Methoxyphenyl)-4-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (12c) from the
Z-chloroenal isomer (13c-2). This material was prepared in a manner identical to the previous
example (13c-1) with the exception that (Z)-3-chloro-3-(4-methoxyphenyl)-2-p-tolyl-propenal was
used as the starting material in which case a brown solid (0.062 g, 68 % yield) was obtained, which
1
was identical by H NMR to 3-(4-methoxyphenyl)-4-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl
ester prepared from (E) 3-chloro-3-(4-methoxyphenyl)-2-p-tolyl-propenal.
4.1.55 3,4-Bis(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (12n) from the
chloroenal isomer mix. Into a 100 ml round bottom flask equipped with a magnetic stir bar was
added 3-dimethylamino-1,2-bis-(4-methoxyphenyl)propenone (0.800 g, 2.57 mmol) and anhydrous
dichloromethane (20 ml). To the stirred solution was added phosphorusoxy chloride (0.251 mL,
2.70 mmol) dropwise. The reaction mixture was stirred at room temperature overnight and
quenched by addition of saturated aqueous sodium bicarbonate (20 mL). The biphasic mixture was
stirred for 30 minutes, the phases were separated and the aqueous phase was extracted with
dichloromethane (2 x 15 mL). The combined organic phases were filtered through a short plug of
silica using a 30:70 mixture of ethyl acetate:hexane (100 ml). The eluent was concentrated in vacuo
to yield a white solid (0.705 g, 91% yield). A portion of this crude material (0.604 g, 2.00 mmol),
glycine ethyl ester hydrochloride (0.418 g, 3.00 mmol), 4A molecular sieves (10 g) and anhydrous
DMF (60 ml) were added to a nitrogen flushed 250 mL, 3-neck round bottom flask equipped with a
reflux condenser and a magnetic stir bar. The mixture was heated at reflux overnight before, cooled
to room temperature and the solvent was removed in vacuo. This crude material was then filtered
through a short plug of silica using a 50:50 mixture of ethyl acetate:hexane and the eluent was
concentrated in vacuo to yield a brown solid (0.494 g, 84% yield), which was identical by 1H NMR
21

ACCEPTED MANUSCRIPT
to 3,4-bis-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester previously prepared by our
group1 by a different procedure.
4.1.56 3-(3,4-Dimethoxyphenyl)-4-p-tolyl-1H-pyrrole-2-caboxylic acid ethyl ester (12o) from
the chloroenal isomer mix. This material was prepared in a manner identical to the previous
example (12n) with the exception that 3-dimethylamino-1-(3,4-dimethoxyphenyl)-2-p-
tolylpropenone was used as the vinylogous amide. The crude reaction product was dissolved in
ethyl acetate and passed through a short plug of diatomaceous earth. After concentration of the
filtrate in vacuo an orange solid (.307 g, 59% yield) was obtained, which displayed the following
properties: 60-62 oC; 1H NMR (300 MHz, CDCl3) δ 9.25 (s, 1H), 7.08 (d, J = 5.0 Hz, 1H), 7.03 (s,
4H), 6.87 (dd, J = 5.0 Hz, J = 1.0 Hz, 1H), 6.83 (s, 1H), 6.81(d, J = 1.0 Hz, 1H) , 4.23 (q, J = 7.1
Hz, 2H), 3.91 (s, 3H), 3.73 (s, 3H), 2.34 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).; 13C NMR (75 MHz,
CDCl3) δ 161.07, 147.93, 135.62, 131.61, 129.49, 129.03, 128.85, 128.20, 127.61, 126.80, 123.26,
119.94, 119.78, 114.45, 110.42, 60.11, 55.75, 55.69, 21.03, 14.25.; IR (neat) 1683 cm-`1; HRMS
(ES, M+Na) calcd for C22H23NO4 388.1534 found 388.1519.
4.1.57 3-(4-Methoxyphenyl)-4-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (12p) from the
chloroenal isomer mix. This material was prepared in a manner identical to the previous example
(12n) with the exception that 3-dimethylamino-1-(4-methoxyphenyl)-2-p-tolyl-propenone was used
as the vinylogous amide in which case a brown solid (0.504 g, 85% yield) was obtained, which
displayed the following properties: 82-83 °C; 1H NMR (500 MHz, CDCl3) δ 9.16 (s, 1H), 7.22 (d, J
= 8.7 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 7.03 (s, 4H), 6.86 (d, J = 8.7 Hz, 2H), 4.22 (q, J = 7.1 Hz,
2H), 3.84 (s, 3H), 2.31 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).; 13C NMR (75 MHz, CDCl3) δ 161.43,
158.55, 135.51, 131.97, 131.83, 129.06, 128.92, 128.21, 126.83, 126.57, 120.46, 119.85, 113.02,
60.16, 55.16, 21.09, 14.20.; IR (neat) 1689 cm-1; HRMS (ES, M+Na) calcd. for C21H21NO3
358.1414 found 358.1424.
4.1.58 4-(4-Methoxyphenyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (12q) from the
chloroenal isomer mix. This material was prepared in a manner identical to the previous example
(12n) with the exception that 4-dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one was used as
the vinylogous amide in which case a viscous brown solid (0.219 g, 45% yield) was obtained. An
analytical sample was prepared via a Biotage Isolera automated flash chromatography system in
1
which case a tan solid was obtained and exhibited the following properties: mp 157-159˚C; H
NMR (500 MHz, CDCl3) δ 9.10 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 2.8 Hz, 1H), 6.96 (d,
13
J = 8.7 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.43 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H); C
NMR (75 MHz, CDCl3) δ 161.52, 157.96, 130.07, 128.76, 128.42, 123.44, 120.39, 115.19, 113.96,
60.20, 55.29, 14.50, and 12.71; IR (neat) 1671 cm-1; HRMS (ES, M+Na) m/z calcd for C15H17NO3
282.1101 found 282.1113.
4.1.59 3-(4-Methoxyphenyl)-4-phenyl-1H-pyrrole-2-carboylic acid ethyl ester (12r) from the
chloroenal isomer mix. This material was prepared in a manner identical to the previous example
(12n) with the exception that 3-dimethylamino-1-(4-methoxyxphenyl)-2-phenylpropenone was used
as the vinylogous amide. After purification of the crude product via a Biotage Isolera automated
flash chromatography system a white solid (0.509 g, 86% yield) was obtained, which displayed the
1
following properties: mp 133-134˚C; H NMR (300 MHz, CDCl3) δ 9.19 (s, 1H), 7.27 – 7.11 (m,
7H), 7.10 (d, J = 3.1 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.21
(t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.36, 158.58, 134.74, 131.95, 129.11, 128.33,
128.16, 126.66, 126.62, 125.98, 120.49, 119.94, 113.02, 60.19, 55.17, and 14.18; IR (neat) 1663
cm-1; HRMS (ES, M+Na) m/z calcd for C20H19NO3 344.1252 found 344.1257.
22

ACCEPTED MANUSCRIPT
4.1.60 4-(4-Bromophenyl)-3-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (12s)
from the chloroenal isomer mix. This material was prepared in a manner identical to the previous
example (12n) with the exception that 2-(4-bromophenyl)-3-dimethylamino-1-(4-methoxyphenyl)-
propenone was used as the vinylogous amide in which case a brown solid (0.578 g, 85% yield) was
obtained. An analytical sample was prepared via a Biotage Isolera automated flash chromatography
1
system to yield a tan solid, which displayed the following properties: 141-142 °C; H NMR (300
MHz, CDCl3)) δ 9.41 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 3.1 Hz,
1H), 6.99 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.20
(t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 161.14, 158.71, 133.68, 131.85, 131.28, 129.85,
128.95, 126.15, 125.52, 120.18, 119.95, 113.13, 60.26, 55.17, 14.15.; IR (neat) 1661 cm-1; HRMS
(ES, M+Na) calcd for C20H18NO3Br 422.0362 found 422.0411.
4.1.61 4-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester
(12t) from the chloroenal isomer mix. This material was prepared in a manner identical to the
previous example (12n) with the exception that 3-dimethylamino-1-(3,4-dimethoxyphenyl)-2-p-
tolyl-propenone was used as the vinylogous amide in which case a red-brown solid (0.413 g, 66%
yield) was obtained. An analytical sample was prepared via a Biotage Isolera automated flash
chromatography system to yield a light orange solid which displayed the following properties: 51-
1
53 °C; H NMR (300 MHz, CDCl3) δ 9.25 (s, 1H), 7.23 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 3.0 Hz,
1H), 6.87 (d, J = 8.7 Hz, 2H), 6.80-6.73 (m, 2H), 6.57 (d, J = 1.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H),
13
3.86 (s, 3H), 3.83 (s, 3H), 3.58 (s, 3H), 1.21(t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl3) δ
161.34, 158.56, 148.38, 147.34, 131.95, 128.87, 127.57, 126.98, 126.28, 120.10, 120.01, 119.84,
113.07, 112.01, 111.18, 60.13, 55.80, 55.39, 55.22, 14.15.; IR (neat)1685 cm-1; HRMS (ES, M+Na)
calcd for C22H23NO5 404.1468 found 404.1492.
4.1.62 3,4-Bis-(4-methoxyphenyl)-1-methylpyrrole-2-carboxylic acid ethyl ester (12b) via a
chloroenal intermediate. Into a 100 ml round bottom flask equipped with a magnetic stir bar was
added 3-dimethylamino-1,2-bis-(4-methoxyphenyl)-propenone (0.800 g, 2.57 mmol) and anhydrous
dichloromethane (20 ml). To the stirring solution was added phosphorousoxy chloride (0.251 ml,
0.270 mmol) dropwise. The reaction mixture was stirred at room temperature overnight and
quenched by addition of saturated aqueous sodium bicarbonate (20 mL). The biphasic mixture was
stirred for 30 minutes before the phases were separated and the aqueous phase was extracted with
dichloromethane (2 x 15 mL). The combined organic phases were then filtered through a short plug
of silica using a 3:7 mixture of ethyl acetate:hexane (100 ml). The eluent was concentrated in vacuo
to yield a white solid (0.705 g, 91% yield). A portion of this crude material (0.448 g, 1.48 mmol),
and a magnetic stir bar. The mixture was heated to reflux overnight and allowed to cool to room
temperature. The solvent was removed in vacuo, and the crude material was filtered through a short
plug of silica using a 1:1 mixture of ethyl acetate:hexane (120 ml) and the eluent was sarcosine
ethyl ester (0.341 g, 2.22 mmol), 4 angstrom molecular sieves (10 g) and anhydrous DMF (60 ml)
were added to a nitrogen flushed 250 mL, 3-neck, round bottom flask equipped with a reflux
condenser concentrated in vacuo to yield an orange solid (0.433 g, 80% yield), which was identical
1
by H NMR analysis to 3,4-bis-(4-methoxyphenyl)-1-methylpyrrole-2-carboxylic acid ethyl ester
previously prepared by our group.1
4.1.63 3-(4-Methoxyphenyl)-4-p-tolyl-1-methylpyrrole-2-carboxylic acid ethyl ester (12c) via a
chloroenal intermediate. This material was prepared in a manner identical to the previous example
(12b) with the exception that 3-dimethylamino-1-(4-methoxyphenyl)-2-p-tolyl-propenone was used
as the vinylogous amide in which case a brown solid (0.497 g, 82% yield) was obtained, which was
identical by 1H NMR analysis to 3-(4-methoxyphenyl)-4-p-tolyl-1-methylpyrrole-2-carboxylic acid
1
ethyl ester prepared via the acetic acid cyclization conditions: H NMR (500 MHz, CDCl3) δ 7.14
23

ACCEPTED MANUSCRIPT
(d, J = 8.7 Hz, 2H), 7.03-6.96 (m, 4H), 6.93 (s, 1H), 6.84 (d, J = 8.7 Hz, 2H), 4.10 (q, J = 7.2 Hz,
2H), 3.99 (s, 3H), 3.84 (s, 3H), 2.29 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H).
4.1.64 3-(4-Methoxyphenyl)-1-methyl-4-phenylpyrrole-2-carboxylic acid ethyl ester (12g) via a
chloroenal intermediate. This material was prepared in a manner identical to the previous example
(12b) with the exception that 3-dimethylamino-1-(4-methoxyphenyl)-2-phenyl-propenone was used
as the vinylogous amide to produce a brown oil (0.589 g, 96% yield) that was purified using a
Biotage Isolera flash chromatography system to yield a viscous yellow oil (0.414, 67%), which was
1
identical by H NMR to 3-(4-methoxyphenyl)-1-methyl-4-phenylpyrrole-2-carboxylic acid ethyl
ester prepared via the acetic acid cyclization conditions: 1H NMR (300 MHz, CDCl3) δ 7.22 – 7.06
(m, 7H), 6.95 (s, 1H), 6.84 (d, J = 8.8 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.83 (s, 3H),
1.03 (t, J = 7.1 Hz, 3H)
4.1.65 4-(4-Bromophenyl)-3-(4-methoxyphenyl)-1-methylpyrrole-2-carboxylic acid ethyl ester
(12h) via a chloroenal intermediate. This material was prepared in a manner identical to the
previous example (12b) with the exception that 2-(4-bromophenyl)-3-dimethylamino-1-(4-
methoxyphenyl)-propenone was used as the vinylogous amide in which case an orange solid (0.590
1
g, 73% yield) was obtained, which was identical by H NMR analysis to 4-(4-bromophenyl)-3-(4-
methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester prepared via the acetic acid
cyclization conditions: 1H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.7 Hz,
2H), 6.99-6.90 (m, 3H), 6.85 (d, J = 8.7 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 3.84 (s,
3H), 1.03 (t, J = 7.1 Hz, 3H).
4.1.66 3-(3,4-Dimethoxyphenyl)-4-p-tolyl-1-methylpyrrole-2-carboxylic acid ethyl (12d) ester
via a chloroenal intermediate. This material was prepared in a manner identical to the previous
example (12b) with the exception that 3-dimethylamino-1-(3,4-dimethoxyphenyl)-2-p-tolyl-
propenone was used as the vinylogous amide in which case a red-brown solid was obtained, which
1
was identical by H NMR analysis to 3-(3,4-dimethoxyphenyl)-4-p-tolyl-1-methylpyrrole-2-
1
carboxylic acid ethyl ester prepared via the one-pot acetic acid cyclization conditions: H NMR
(300 MHz, CDCl3) δ 6.98 (s, 4H), 6.90 (s, 1H), 6.83-6.73 (m, 3H), 4.10 (q, J = 7.1 Hz, 2H), 3.95 (s,
3H), 3.88 (s, 3H), 3.74 (s, 3H), 2.27 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H).
4.1.67 1-Benzyl-3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-pyrrole-2-carboxylic acid ethyl
ester (12m). Into a 100 mL round bottom flask equipped with a magnetic stir bar was added 1-(3,4-
dimethoxyphenyl)-3-dimethylamino-2-p-tolyl-propenone (2.642 g, 8.12 mmol) and anhydrous
dichloromethane (32 ml). To the stirred solution was added phosphorous oxychloride (0.805 mL,
1.324 mmol) dropwise. The reaction mixture was stirred at room temperature overnight and
quenched by addition of saturated aqueous sodium bicarbonate solution (34 mL). The biphasic
mixture was stirred for 30 minutes before the phases were separated and the aqueous phase was
extracted with dichloromethane (3 x 15 mL). The combined organic phases were then filtered
through a short plug of silica using a 3:7 mixture of ethyl acetate:hexane (100 mL). The eluent was
concentrated in vacuo to yield an orange solid (1.894 g, 73% yield). A portion of this crude material
(0.490 g, 1.70 mmol), N-benzyl glycine ethyl ester (0.787 g, 4.07 mmol), 4 angstrom molecular
sieves (10 g) and anhydrous DMF (50 ml) were added to a nitrogen flushed 250 mL, 3-neck round
bottom flask equipped with a reflux condenser and a magnetic stir bar. The mixture was heated to
reflux overnight and allowed to cool to room temperature. The solvent was removed in vacuo, the
crude material was diluted with ethyl acetate (20 mL) and then filtered through a short plug of silica
using a 1:1 mixture of ethyl acetate:hexane (150 mL). The eluent was concentrated in vacuo to yield
material, which was dissolved in ethyl acetate (20 mL) and washed with 10% aqueous hydrochloric
acid (1 x 15 mL). The organic phase was dried and concentrated in vacuo to yield a dark yellow
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solid. The solid product was purified using the Isolera flash chromatography system to yield a
1
yellow solid (0.433 g, 60% yield), which displayed the following properties: H NMR (300 MHz,
CDCl3) δ 7.41 – 7.29 (m, 3H), 7.27 – 7.23 (m, 2H), 7.02 (s, 1H), 6.99 (s, 4H), 6.83 – 6.72 (m, 3H),
5.60 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.76 (s, 3H), 2.28 (s, 3H), 0.97 (t, J = 7.1 Hz,
3H) and was identical to the same product obtained via the acetic acid cyclization route.
4.1.68 1-Benzyl-3-(4-methoxyphenyl)-4-p-tolyl-1H-pyrrole-2-carboxylic acid ethyl ester (12f).
This material was prepared in a manner identical to the previous example (12m) with the exception
that 3-dimethylamino-1-(4-methoxyphenyl)-2-p-tolyl-propenone was used as the vinylogous amide.
The crude product was passed through a short plug of silica with 1:3 ethyl acetate:hexane (100 mL)
in which case a light orange solid (.618 g, 69% yield) was obtained and displayed the following
properties: 89-91 oC; 1H NMR (300 MHz, CDCl3 ) δ 7.40 – 7.29 (m, 3H), 7.25 (d, J = 1.7 Hz, 1H),
7.22 (s, 1H), 7.19 – 7.11 (m, 2H), 7.01 (s, 1H), 6.99 (s, 4H), 6.84 (d, J = 8.7 Hz, 2H), 5.60 (s, 2H),
13
4.02 (d, J = 7.1 Hz, 2H), 3.83 (s, 3H), 2.28 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H).; C NMR (75 MHz,
CDCl3) δ 161.70, 158.38, 138.17, 135.36, 131.77, 131.63, 131.11, 128.82, 128.66, 128.30, 127.97,
127.49, 127.13, 126.07, 124.64, 120.41, 112.91, 59.68, 55.19, 52.75, 21.03, 13.73, 1.03.; IR (neat)
1693 cm-1; HRMS (ES, M+Na) calcd for C28H27NO3 448.1883 found 448.1848.
Acknowledgements
We gratefully thank the National Institutes of Health (grant no. R15-CA67236) for support of this research.
Thanks also to the Floyd D. and Elisabeth S. Gottwald endowment for support to JTG. We are also very
appreciative of Mr. Dave Patteson of Advion Inc. for the generous donation of a CMS electrospray mass
spectrometer. Previous grants from the MRI program of the National Science Foundation for the purchase
of a 500 MHz NMR spectrometer (CHE-0116492) and a high-resolution, electrospray mass spectrometer
(CHE-0320669) are also gratefully acknowledged.
References and Notes
1.For an example see Gupton, J.T.; Giglio, B.; Eaton, J.; Rieck, L.; Smith, K.; Keough, M.; Barelli, P.;
Firich, L.; Hempel, J.; Smith, T.: Kanters, R. Tetrahedron, 2009 65, 4283 and references therein.
2. For a few recent examples see: (a) Li, X.; Chen, M.; Xie, X.; Sun, N.; Li, S.; Liu, Y.; Org.Lett. 2015,
17, 2984. (b) Kim, C.; Park, S.; Eom, D.; Seo, B.; Lee, P.; Org. Lett. 2014, 16, 1900. (c) Zheng, J.;
Huang, L.; Huang, C.; Wu, W.; Jiang, H.; J.Org.Chem. 2015, 80 ,1235. (d) Kim, D.; Seo,Y.; Jun, C. ;
Org. Lett. 2015, 17, 3842.
3. For appropriate reviews and articles see: (a) Handy, S.; Zhang, Y. Org. Prep. Proc. Int. 2005, 37,
411. (b) Fernandez, D.; Ahaidar, A.; Danelon, G.; Cironi, P.; Marfil, M.; Perez, O.; Cuevas, C.;
Albericio, F.; Joule, J.; Alvarez, M. Monatsh. Chem. 2004, 135, 615. (c) Bailly, C.; Curr. Med. Chem.–
Anti-Cancer Agents, 2004, 363. (d) Gupton, J., “Pyrrole Natural Products with Antitumor Properties”,
in “Heterocyclic Antitumor Antibiotics: Topics in Heterocyclic Chemistry, Vol.2”, Ed. Lee, M. pp 53-
92, Springer-Verlag, Berlin/Heidelberg, 2006. (e) Fan H.; Peng J.; Hamann M.; Hu J.F. Chem. Rev.
2008, 108, 264. (f) Gupton, J.T.; Yeudall, S.; Telang, N.; Hoerrner, M.; Huff, E.; Crawford, E.;
Lounsbury, K.; Kimmel, M.; Curry, W.; Harison, A.; Juekun, W.; Shimozono, A.; Ortolani, J.;
Lescalleet, Patteson, J.; Moore-Stoll, V.; Rohena, C.; Mooberry, S.; Obaidullah, A.; Kellogg, G.;
Sikorski, J.; Bioorg. Med. Chem. 2017, 25, 3206.
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5. Boger, D.; Boyce, C.; Labroli, M.; Schon, C,; Jin, Q.; J. Am. Chem. Soc.1999, 121, 54.
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Nat. Prod., 2008, 71, 1732.
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7. Gupton, J. T.; Krumpe, K. E.; Burnham, B. S.; Webb, T. M.; Shuford, J. S.; Sikorski, J. A.
Tetrahedron 1999, 55, 14515.
8. Metivier, P.”Friedel-Crafts Acylation”, Eds. Sheldon, R., Bekkum, H. pp. 161-172, Wiley-VCH,
New York, 2001.
9. (a) Effenberger, F.; Sohn, E.; Epple, G.; Chem. Ber.1983, 116, 1195. (b) Keumi, T.; Yoshimura, K.;
Shimada, H.; Kitajima, H.; Bull. Chem. Soc. Jpn. 1988, 44, 455.
10. Abdulla, R.; Brinkmeyer, R.: Abdulla, Tetrahedron 1979, 35, 1675. For a review of vinylogous
amide chemistry see: Elassar, A.Z.; El-Khair, A.; Tetrahedron 2003, 59, 8463.
11. The crude pyrrole product had 1H NMR absorptions identical to a sample prepared by the acetic
acid cyclization route (compound 12a in Table 4).
12. For a review of β-halovinylaldehydes and their synthetic applications see: Brahma, S.; Ray, J.;
Tetrahedron 2008, 64, 2883.
13. Chan, C.K.; Chen, Y.C.; Chen, Y.L.; Chang, M.Y. Tetrahedron 2015, 71, 9187.
14. Yu, J.W.; Mao, S; Wang, Y.Q. Tetrahedron Lett. 2015, 561, 1575.
15. Dolhem, E.; Barhdadi, R.; Folest, J.; Nedelec, J.; Troupel, M. Tetrahedron 2001, 57, 525.
16. Cao, S.; Zhong, S.; Xin, L.; Wan, J.; Wen, C. ChemCatChem. 2015, 7, 1478.
17. The identity of the ketoaldehyde in the crude reaction mixture was established by comparison to an
authentic sample (11)18.
18. An authentic sample of 11 was prepared by hydrolysis of the N-methylglycine exchanged
vinylogous amide (10d). See experimental section 4.1.31.
Graphical Abstract
Further studies on the application of vinylogous amides and β-halovinylaldehydes to the regiospecific
synthesis of unsymmetrical, polyfunctionalized 2,3,4- and 1,2,3,4-substituted pyrroles. John T.
Gupton*, Alex Shimozono, Evan Crawford, Joe Ortolani, Evan Clark, Matt Mahoney, Campbell Heese,
Jeffrey Noble, Carlos Perez Mandry, Rene Kanters, Raymond N. Dominey, Emma W. Goldman, James A.
Sikorski and Daniel C. Fisher.
26