Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of uniquely functionalized pyrroles and quinolones

Article abstract of DOI:10.1016/j.tet.2018.10.078

Pyrroles and quinolones represent core structures, which are routinely found in both natural and synthetic bioactive substances. Consequently, the development of efficient and regiospecific methods for the preparation of such heterocycles with unique functionality is of some importance. We describe herein the regiospecific synthesis of 1,2,3,4-tetrasubstituted pyrroles containing polar substituents and such products are prepared from vinylogous carbamates and vinylogous aminonitriles. We also describe the regiospecific synthesis of 3-aryl containing 1,3,6-trisubstituted quinolones from vinylogous carbamates. The use of an amine exchange reaction to prepare precursors for the pyrrole and quinolone forming cyclizations represents a key factor in the strategy.

Full text of DOI:10.1016/j.tet.2018.10.078

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Application of vinylogous carbamates and vinylogous aminonitriles to
the regiospecific synthesis of uniquely functionalized pyrroles and
quinolones
,
John T. Gupton a *, Evan Crawford a, Matt Mahoney a, Evan Clark a, Will Curry a,
Annie Lane a, Alex Shimozono a, Veronica Moore-Stoll a, Kristen Elofson a, Wen Juekun a,
Micah Newton a, Scott Yeudall a, Elizabeth Jaekle a, Rene Kanters a, James A. Sikorski b
a Department of Chemistry, University of Richmond, Richmond, VA, 23173, USA
b Chemistry and Drug Discovery, Chesterfield, MO, 63005, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrroles and quinolones represent core structures, which are routinely found in both natural and syn-
thetic bioactive substances. Consequently, the development of efficient and regiospecific methods for the
preparation of such heterocycles with unique functionality is of some importance. We describe herein
the regiospecific synthesis of 1,2,3,4-tetrasubstituted pyrroles containing polar substituents and such
products are prepared from vinylogous carbamates and vinylogous aminonitriles. We also describe the
regiospecific synthesis of 3-aryl containing 1,3,6-trisubstituted quinolones from vinylogous carbamates.
The use of an amine exchange reaction to prepare precursors for the pyrrole and quinolone forming
cyclizations represents a key factor in the strategy.
Received 27 September 2018
Received in revised form
26 October 2018
Accepted 31 October 2018
Available online xxx
Keywords:
Vinylogous carbamate
Vinylogous aminonitrile
Pyrrole
© 2018 Elsevier Ltd. All rights reserved.
Quinolone
1. Introduction
groups and hydroxy, acetoxy, amine and amide groups have his-
torically served this function extremely well. We have recently
New and efficient methods for the preparation of pyrrole [1] and
quinolone [2] scaffolds continue to be of significant interest to the
organic chemical community. The need to have ready access to such
materials is the result of their pharmacological properties. A few
notable examples are given in Fig. 1.
Lamellarin D trimethyl ether [3] (1, Fig. 1) represents a potent
anti-proliferative agent that targets topoisomerase 1 and lamellarin
O [4] (2, Fig. 1) functions as an inhibitor of P-glycoprotein efflux
pumps. Ciprofloxacin [5] (3, Fig. 1) is one of the more important
quinolone anti-infective drugs on the commercial market while
Endochin [6] (4, Fig. 1) exhibits significant anti-malarial properties.
All of the substances shown in Fig. 1 contain hydrogen bond donor
and hydrogen bond acceptor sites, which facilitate binding to
appropriate proteins and plays an import role in contributing to
desirable solubility properties [7]. Such pharmaceutical attributes
require the ability to synthesize compounds with polar functional
reported [8] on the amine exchange reaction of vinylogous amides
with glycinate esters, which produced intermediates that were
used
for
the
regiospecific
preparation
of
1,2,3,4-
tetrasubstitutedpyrroles.
We now describe the use of the amine exchange process to
generate similar precursors to 1,2,3,4-tetrasubstituted pyrroles,
which contain the aforementioned polar groups. We also report the
use of the amine exchange process to prepare 3-aryl containing
1,3,6-trisubstituted quinolones, which have recently been
described as novel azaisoflavones [9], function as phytoestrogen
mimetics and are inhibitors [10] of NO production in microglia.
2. Results and discussions
N,N-Dimethylformamide dimethylacetal (DMFA) is a very useful
reagent [11] for the introduction of the vinylogous amide group and
for methylation of carboxylic acids. We anticipated that reacting
DMFA with a series of 2-arylacetic acids would generate the cor-
responding 2-arylvinylogous carbamates. Such substances could
then serve as building blocks for novel pyrrole synthesis and
* Corresponding author.
E-mail address: jgupton@richmond.edu (J.T. Gupton).
https://doi.org/10.1016/j.tet.2018.10.078
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

2
J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
Fig. 1. Biologically active pyrroles and Quinolines.
Table 1
complement our recently reported [8] vinylogous amide studies.
These results are presented in Scheme 1 and Table 1. The requisite
2-arylsubstituted vinylogous carbamates were produced in very
good yield (91e99%) with little if any purification required.
With a variety of vinylogous carbamates in hand, we attempted
to use our recently reported [8] acetic acid mediated condensation
conditions that were previously applied to a series of vinylogous
amides Reaction with sarcosine ethyl ester hydrochloride under
such conditions did not produce the expected pyrrole but did
produce a vinyl acetate (7, Scheme 2). Upon slight modification of
the reaction conditions (Scheme 2) we were able to generate the
vinyl acetate cleanly and in good yield.
Preparation of 2-arylvinylogous carbamates, 6a-g.
Compound Number
Ar
% Yield
6a
6b
6c
6d
6e
6f
4-MeOPh
4-MePh
4-ClPh
91
91
98
97
99
97
92
4-BrPh
3,4-(OMe)2Ph
3,4,5-(OMe)3Ph
Ph
6g
We subsequently decided to employ a different approach, which
involved doing an amine exchange reaction with sarcosine hydro-
chloride and the vinylogous carbamates under milder conditions as
presented in Scheme 3, Table 2.
The reactions as reported in Scheme 3 and Table 2 gave excellent
yields and the crude products were quite pure requiring minimal
purification by flash chromatography. We have had some success in
the past with base-mediated cyclization conditions [12] as applied
to pyrrole synthesis. Consequently, we next attempted the use of
sodium ethoxide in THF at room temperature for the cyclization of
the amine exchanged vinylogous carbamates (8, Scheme 3) and the
results are reported in Scheme 4 and Table 3. Prior to work up of the
reaction mixtures listed in Table 3, all of the reactions were
quenched with acetic anhydride allowing for acylation of the
anionic product formed during the course of the reaction. Conse-
quently the pyrrole forming cyclization with an acylation work up
produced an acetoxy group at the 3-position of the pyrrole [13]. The
3-acetoxypyrroles produced in this manner were quite stable and
exhibited no degradation of their purity over time. The acetoxy
group was chosen, since it has the ability to provide unique func-
tionality, greater molecular polarity and prodrug characteristics [7],
which make it very useful in an SAR guided drug discovery process.
Most of the reaction yields (Table 3) were in a reasonable range
(52e99%) and no extensive optimization studies were subse-
quently conducted. In addition, NOESY NMR analysis was carried
out on compound 9a in Table 3 in order to verify the regiochemical
nature of the various substituents and the results were consistent
with the assigned structure.
Scheme 2. Preparation of Vinyl Acetate.
Scheme 3. Preparation of Amine Exchanged Vinylogous Carbamates.
Table 2
Preparation of amine exchanged vinylogous carbamates, 8a-h.
Compound Number
Ar
R
% Yield
8a
8b
8c
8d
8e
8f
4-MeOPh
4-MePh
4-ClPh
Me
Me
Me
Me
Me
Me
Me
Bz
91
92
99
95
99
94
91
88
4-BrPh
3,4-(OMe)2Ph
3,4,5-(OMe)3Ph
Ph
8g
8h
4-MeOPh
We next turned our attention to developing a method for the
incorporation of an amino/amide group at the 3-position of the
pyrrole [14]. It was anticipated that such a functional group would
provide additional enhancement to the desirable properties pre-
viously described for the acetoxy substituent of pyrrole 9.
Scheme 1. Preparation of 2-Arylvinylogous Carbamates.
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
3
Table 4
Preparation of vinylogous Aminonitriles.11a-g.
Compound Number
Ar
% Yield
11a
11b
11c
11d
11e
11f
4-MeOPh
4-MePh
4-ClPh
4-BrPh
4-FPh
96
95
84
100
95
99
98
Scheme 4. Base Mediated Cyclization of Amine Exchanged Vinylogous Carbamates.
Ph
11g
3,4-(OMe)2Ph
Table 3
Preparation of 1,2,3,4-tetrasubstituted pyrroles with polar 3-acetoxy functionality,
9a-h.
cyclization sequence to prepare the 3-acetoxypyrroles (Scheme 4)
and the 3-aminopyrroles (Scheme 7) suggested there may be
additional applications of this strategy to other important hetero-
cycles. Consequently, we were attracted to the synthesis of quino-
lones [2,9,10] in anticipation that exchange reactions between
anilines and vinylogous carbamates (Scheme 8, Table 7) would be
possible. Application of the glycine/carbamate exchange reaction
(Scheme 3) conditions to an aniline/carbamate exchange (Scheme
8, Table 7) worked quite well (63e93% yields) and the addition of
a small amount of acetic acid to the ethanol mixture significantly
accelerated the reaction rate. The mild acid catalysis is presumably
necessary due to the decreased nucleophilicity of the anilines.
We anticipated our approach would allow us to prepare 3-aryl-
quinolones, which have been identified as novel azaisoflavonoids
and function as phytoestrogen mimics and inhibitors of NO pro-
duction in microglia. During the course of our studies we noticed
that a vinylogous carbamate had been employed by Jamison [5] and
coworkers to prepare the quinolone Ciprofloxacin hydrochloride
(See Fig. 1) in a continuous flow process by a strategy different from
ours.
With a variety of aniline exchanged vinylogous carbamates in
hand we examined the use of triflic anhydride as an acidic mediator
for intramolecular Friedel-Crafts acylation given our recent success
[8] with this reagent. Results of these studies are presented in
Scheme 9 and Table 8.
The triflic anhydride mediated cyclization of the aniline
exchanged vinylogous carbamates (Scheme 9, Table 8) gave quite
good yields of the 3-arylquinolones (59e94%). A base mediated
workup of the crude reaction products with a mixture of aqueous
bicarbonate and THF was employed to convert any triflated pre-
cursors to the desired 3-arylquinolnes. In addition, NOESY NMR
analysis was carried out on one of the quinolones (16a, Table 8) and
the indicated regiochemistry was confirmed.
Compound Number
Ar
R
% Yield
9a
9b
9c
9d
9e
9f
4-MeOPh
4-MePh
4-ClPh
Me
Me
Me
Me
Me
Me
Me
Bz
69
58
59
99
65
52
86
25
4-BrPh
3,4-(OMe)2Ph
3,4,5-(OMe)3Ph
Ph
9g
9h
4-MeOPh
We selected aryl substituted acetonitriles (10, Scheme 5) as our
starting materials given the ability of the cyano group to be
transformed into an amine or amide functionality. Reaction of these
aryl substituted acetonitriles (10, Scheme 5) with DMF acetal gave
excellent yields of the corresponding vinylogous aminonitriles as
presented in Scheme 5 and Table 4.
Since the amine exchange process (Scheme 3) had worked well
for the synthesis of the 3-acetoxypyrroles, we planned to extrap-
olate the strategy to the vinylogous aminonitriles as depicted in
Scheme 6 and Table 5. We had previously used ethanol as the
preferred solvent for such reactions but for the vinylogous ami-
nonitriles this proved unsuccessful. However, utilization of acetic
acid as the solvent gave very good yields and purity (Table 5) of the
desired amine exchanged products (Scheme 6 and Table 5) and
these substances also exhibited good shelf life stability. It is also
noteworthy that we did not observe any acetoxy derivatives under
these reaction conditions as was the case for the vinylogous car-
bamates (Scheme 2) when treated with acetic acid.
Cyclization studies were then carried out on the amine
exchanged vinylogous aminonitriles (Scheme 7, Table 6) and so-
dium hydride was found to be a superior base as compared to so-
dium ethoxide (Scheme 4). The yields for the cyclization reactions
depicted in Scheme 7 and Table 6 were quite reasonable (60e99%).
For examples 13j and 13k the crude reaction products were
quenched with acetic anhydride and methane sulfonic anhydride,
respectively to give amides (71%yield) and sulfonamides (47%yield).
In an analogous manner to the 3-acetoxypyrroles (Scheme 4),
compound 13d in Table 6 was subjected to NOESY NMR analysis
and the regiochemical assignment as depicted in Scheme 7 was
confirmed. These 3-aminopyrroles were also quite stable and
exhibited a very good shelf life.
3. Conclusions
We have described the use of an amine exchange strategy to
couple amines to either vinylogous carbamates or vinylogous
aminonitriles, which allows for base mediated cyclization to the
respective
3-acetoxy
pyrroles
or
3-aminopyrroles/3-
amidopyrroles. The vinylogous carbamates or vinylogous amino-
nitriles are easily prepared in one step from commercially available
arylacetic acids or aryl substituted acetonitriles. The subsequent
conversion of the vinylogous carbamates or vinylogous amino-
nitriles to the requisite pyrroles is accomplished in good overall
yields with polar groups located at the 3-position. The indicated
transformations provide the opportunity to increase both the sol-
ubility and binding properties of bioactive pyrroles by virtue of
additional hydrogen bond donor and hydrogen bond acceptor
groups. In addition the ability to obtain the functionalized pyrroles
in three steps from commercially available starting materials
should prove useful. The use of the amine exchange strategy was
then applied to aniline exchanged vinylogous carbamates, which
The success of the previously described amine exchange/
Scheme 5. Preparation of Vinylogous Aminonitriles
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

4
J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
Scheme 6. Preparation of Amine Exchanged Vinylogous Aminonitriles
Table 7
Table 5
Preparation of aniline exchanged vinylogous carbamates, 15a-j.
Preparation of amine exchanged vinylogous aminonitriles, 12a-i.
Compound Number
Ar
R
Z
% Yield
Compound Number
Ar
R
% Yield
15a
15b
15c
15d
15e
15f
15g
15h
15i
4-MeOPh
4-MePh
4-ClPh
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
MeO
MeO
93
73
81
85
82
63
85
69
81
78
12a
12b
12c
12d
12e
12f
12g
12h
12i
4-MeOPh
4-MePh
4-ClPh
4-BrPh
4-FPh
Me
Me
Me
Me
Me
Me
Me
Bz
87
88
88
91
98
87
92
92
58
4-BrPh
3,4-(OMe)2Ph
3,4,5-(OMe)3Ph
Ph
4-MeOPh
4-MeOPh
4-BrPh
Ph
3,4-(OMe)2Ph
4-MeOPh
4-MePh
Me
Me
Bz
15j
Scheme 7. Base Mediated Cyclization of Amine Exchanged Vinylogous Aminonitriles.
Scheme 9. Prearation of 3-Arylquinolones from Aniline Exchanged Vinylogous
Carbamates.
Table 6
Preparation of 1,2,3,4-tetrasubstituted pyrroles with polar 3-amino and 3-amido
functionality, 13a-k.
Table 8
Preparation of 3-arylquinolones, 16a-j.
Compound Number
Ar
R
Z
% Yield
Compound Number
Ar
R
Z
% Yield
13a
13b
13c
13d
13e
13f
13g
13h
13i
4-MeOPh
4-MePh
4-ClPh
4-BrPh
4-FPh
Me
Me
Me
Me
Me
Me
Me
Bz
H
H
H
H
H
H
H
H
99
74
60
79
75
83
97
63
82
71
47
16a
16b
16c
16d
16e
16f
16g
16h
16i
4-MeOPh
4-MePh
4-ClPh
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
MeO
Br
83
94
90
92
88
83
92
59
74
78
4-Br-Ph
Ph
3,4-(OMe)2Ph
3,4,5-(OMe)3Ph
Ph
4-MeOPh
4-MeOPh
4-MeOPh
3,4-(OMe)2Ph
4-MeOPh
4-MePh
4-MeOPh
4-MeOPh
Bz
Me
Me
H
13j
13k
COCH3
SO2CH3
Me
Me
16j
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 Å 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 in-
strument (both equipped with a silica cartridge). Gradient elution
Scheme 8. Prearation of Aniline Exchanged Vinylogous Carbamates.
cyclized via triflic anhydride to the corresponding 3-
arylquinolones. The rapid two step reaction sequence from the
vinylogous carbamates provides an efficient preparation of the
quinolones by the aniline exchange strategy and should bode well
for use in SAR guided synthesis of novel quinolones containing a 3-
aryl group.
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
5
with ethyl acetate/hexane was accomplished in both instances. The
4.1.5. Z-3-Dimethylamino-2-(3,4-dimethoxyphenyl)acrylic acid
methyl ester (6e)
reaction products were normally eluted within the range of 4e8
column volumes of eluant with a gradient mixture of 60e80% ethyl
acetate in hexane. TLC analyses were conducted on silica plates
with hexane/ethyl acetate as the eluant. All purified reaction
products gave TLC results, flash chromatograms, and 13C NMR
spectra consistent with a sample purity of >95%.
This compound was prepared by procedure 4.1.1 with the
exception that 3,4-dimethoxyphenylaceticacid was used in the re-
action, in which case a 99% yield of an orange solid was obtained,
which exhibited the following properties: mp 102e105 ꢁC; 1H NMR
(CDCl3, 300 MHz) 7.52 (s, 1H), 6.79 (d, J ¼ 8.6 Hz, 1H), 6.70e6.73 (m,
2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.62 (s, 3H) and 2.71 (s, 6H); 13C NMR
(CDCl3, 75 MHz) d 170.7, 149.2, 147.9, 147.6, 129.0, 124.4, 115.5, 110.3,
98.7, 55.8, 55.8, 51.1, 42.8; IR (neat) 1674 and 1594 cmꢂ1; HRMS (ES,
4.1.1. Z-2-(4-Methoxyphenyl)-3-dimethylaminoacrylic acid methyl
ester (6a)
MþH) m/z calcd for C14H20NO4 266.1387 found 266.1390.
Into a 100 mL a round bottom flask equipped with magnetic stir
bar and reflux condenser was added 4-methoxyphenyl acetic acid
(3.0 g, 18.05 mmol), N,N-dimethylformamide dimethyl acetal
(12.91 g, 108 mmol), and dimethylformamide (25 mL). The reaction
mixture was heated to reflux for 4 h and the solvent was removed
in vacuo. To the crude residue was added water (20 mL) and ethyl
acetate (15 mL) and the phases were separated. The aqueous layer
was extracted with additional ethyl acetate (2 ꢀ 15 mL) and the
combined organic layers were washed with aqueous lithium
chloride (20 mL) and dried over anhydrous sodium sulfate. The
drying agent was filtered off and the solvent was removed in vacuo
to give an orange solid (3.85 g, 91% yield), which exhibited the
following properties: mp 63e65 ꢁC; 1H NMR (CDCl3, 500 MHz)
4.1.6. Z-3-Dimethylamino-2-(3,4,5-trimethoxyphenyl)acrylic acid
methyl ester (6f)
This compound was prepared by procedure 4.1.1 with the
exception that (3,4,5-trimethoxyphenyl)acetic acid was used in the
reaction, in which case a 97% yield of an orange solid was obtained,
which exhibited the following properties: mp 110e111 ꢁC; 1H NMR
(acetone-d6, 300 MHz)
d 7.48 (s, 1H), 6.45 (s, 2H), 3.80 (s, 6H), 3.74
(s, 3H), 3.54 (s, 3H) and 2.75 (s, 6H); 13C NMR (CDCl3, 75 MHz)
d
170.3, 152.2, 149.1, 136.6, 131.9, 109.4, 98.8, 60.7, 56.0, 51.0 and
42.7; IR (neat) 1676 and 1593 cmꢂ1; HRMS (ES, MþH) m/z calcd for
C
15H22NO5 calcd for 296.1492 found 296.1484.
d
7.55 (s, 1H), 7.11 (d, J ¼ 8.7 Hz, 2H), 6.84 (d, J ¼ 8.7 Hz, 2H), 3.82 (s,
4.1.7. Z-3-Dimethylamino-2-phenylacrylic acid methyl ester (6g)
This compound was prepared by procedure 4.1.1 with the
exception that phenylacetic acid was used in the reaction, in which
case a 92% yield of a yellow/orange solid was obtained, which
exhibited the following properties: mp 38e40 ꢁC; 1H NMR (CDCl3,
3H), 3.64 (s, 3H) and 2.69 (s, 6H); 13C NMR (CDCl3, 75 MHz)
d
170.7,
158.1, 149.2, 133.0, 128.6, 112.8, 98.4, 55.1, 51.0 and 42.8; IR (neat)
1675 and 1603 cmꢂ1; HRMS (ES, MþH) m/z calcd for C13H18NO3
236.1281 found 236.1301.
300 MHz)
d 7.53 (s, 1H), 7.15e7.27 (m, 5H), 3.53 (s, 3H) and 2.70 (s,
6H); 13C NMR (CDCl3, 75 MHz)
d 170.4, 149.24136.6, 132.1, 127.3,
4.1.2. Z-3-Dimethylamino-2-p-tolylacrylic acid methyl ester (6b)
This compound was prepared by procedure 4.1.1 with the
exception that p-tolylacetic acid was used in the reaction, in which
case a 91% yield of a yellow solid was obtained, which exhibited the
following properties: mp 76e77 ꢁC; 1H NMR (CDCl3, 300 MHz)
126.2, 98.9, 51.0, 42.9; IR (neat) 1679 and 1592 cmꢂ1; HRMS (ES,
MþH) m/z calcd for C12H16NO2 206.1176 found 206.1170.
4.1.8. Z-3-Acetoxy-2-(4-methoxyphenyl) acrylic acid methyl ester
(7)
d
7.56 (s, 1H), 7.10 (s, 4H), 3.64 (s, 3H), 2.69 (s, 6H) and 2.36 (s, 3H);
Into a 20 mL microwave vial equipped with magnetic stir bar
and crimping cap was added 2-(4-methoxy-phenyl)-3-
dimethylaminoacrylic acid methyl ester (580 mg, 2.46 mmol),
acetic acid (7 mL) and acetic anhydride (3 mL). The resulting
mixture was heated in a Biotage Initiator Microwave system for 1 h
at 100 ꢁC. The reaction mixture was diluted with a water (25 mL)/
ethyl acetate (20 mL) mixture and the phases were separated. The
aqueous phase was extracted with additional ethyl acetate
(2 ꢀ 20 mL) and the combined organic phases were washed with
saturated, aqueous sodium bicarbonate and dried over anhydrous
sodium sulfate. The drying agent was filtered off and the solvent
was removed in vacuo to give a yellow oil (572 mg, 92.7% yield). An
analytical sample was prepared by flash chromatography on a
Biotage Isolera system, resulting in an oil, which exhibited the
following properties: bp 150 ꢁC at 0.330 torr; 1H NMR (CDCl,
13C NMR (CDCl3, 75 MHz)
d 170.7, 149.2, 135.7, 133.4, 131.9, 128.1,
98.8, 51.0, 42.9 and 21.2; IR (neat) 1686 and 1584 cmꢂ1; HRMS (ES,
MþH) m/z calcd for C13H18NO2 220.1332 found 220.1307.
4.1.3. Z-2-(4-Chlorophenyl)-3-dimethylaminoacrylic acid methyl
ester (6c)
This compound was prepared by procedure 4.1.1 with the
exception that 4-chlorophenylacetic acid was used in the reaction,
in which case a 98% yield of a pale yellow solid was obtained, which
exhibited the following properties: mp 74e76 ꢁC; 1H NMR
(acetone-d6, 300 MHz)
d
7.57 (s, 1H), 7.29 (d, J ¼ 8.6 Hz, 2H), 7.17 (d,
J ¼ 8.6 Hz), 3.54 (s, 3H), and 2.74 (s, 6H); 13C NMR (CDCl3, 75 MHz)
d
170.2, 149.5, 135.2, 133.3, 132.0, 127.5, 97.6, 51.1, 43.1; IR (neat)
1665 and 1609 cmꢂ1; HRMS (ES, MþH) m/z calcd for C12H15ClNO2
500 MHz)
d
8.45 (s, 1H), 7.30 (d, J ¼ 8.8 Hz, 2H), 6.94 (d, J ¼ 8.8 Hz,
240.0786 found 240.0766.
2H), 3.85 (s, 3H), 3.82 (s, 3H) and 2.18 (s, 3H); 13C NMR (CDCl3,
75 MHz)
d 167.3, 166.9, 159.2, 143.8, 131.1, 123.8, 117.6, 113.4, 55.2,
4.1.4. Z-2-(4-Bromophenyl)-3-dimethylaminoacrylic acid methyl
ester (6)
52.0 and 20.6; IR (neat) 1776 and 1710 cmꢂ1; HRMS (ES, MþNa) m/z
calcd for C13H14O5Na 273.0733 found 273.0752.
This compound was prepared by procedure 4.1.1 with the
exception that 4-bromophenylacetic acid was used in the reaction,
in which case a 97% yield of a yellow solid was obtained, which
exhibited the following properties: mp 94e96 ꢁC; 1H (CDCl3,
4.1.9. 2-(4-Methoxyphenyl)-3-(ethoxycarbonylmethyl-
methylamino)acrylic acid methyl ester (8a)
Into a 20 mL microwave vial equipped with a magnetic stir bar
and crimping cap was added 2-(4-methoxyphenyl)-3-
dimethylaminoacrylic acid methyl ester (1.07 g, 4.55 mmol), sar-
cosine ethyl ester hydrochloride (2.10 g, 13.64 mmol), and ethanol
(20 mL). The resulting mixture was heated in a Biotage Initiator
microwave system for 2 h at 100 ꢁC. The solvent was removed in
500 MHz)
d
7.57 (s, 1 H), 7.41 (d, J ¼ 8.4 Hz, 2 H), 7.08 (d, J ¼ 8.4 Hz,
2 H), 3.64 (s, 3 H) and 2.70 (s, 6 H); 13C NMR (CDCl3, 75 MHz) 170.0,
149.5, 135.7, 133.7, 130.5, 120.2, 97.7, 51.1 and 43.2; IR (neat) 1670
and 1603 cm-1; HRMS (ES, MþH) m/z calcd for C12H15BrNO2
284.0281 found 284.0256.
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

6
J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
vacuo and the crude residue was dissolved in a mixture of water
(25 mL) and ethyl acetate (15 mL) and the phases were separated.
The aqueous phase was extracted with additional ethyl acetate
(2 ꢀ 15 mL) and the combined organic phases were washed with
brine (15 mL), and dried over anhydrous sodium sulfate. The drying
agent was filtered off and the solvent was removed in vacuo to give
a yellow solid (1.27 g, 91% yield), which exhibited the following
characteristics: bp 180 ꢁC @ 0.58 torr; 1H NMR (CDCl3, 500 MHz)
148.6, 148.1, 147.9, 128.2, 124.1, 115.1, 110.5, 101.0, 61.1, 55.8, 51.3,
42.2 and 14.0; IR (neat) 1732 and 1686 cmꢂ1; HRMS (ES, MþNa) m/z
calcd for C17H23NO6Na 360.1418 found 360.1389.
4.1.14. 3-(Ethoxycarbonylmethyl-methylamino)-2-(3,4,5-
trimethoxyphenyl) acrylic acid methyl ester (8f)
This compound was prepared by procedure 4.1.9 with the
exception
that
3-dimethylamino-2-(3,4,5-trimethoxyphenyl)
d
7.53 (s, 1H), 7.13 (d, J ¼ 8.4, 2H), 6.84 (d, J ¼ 8.4, 2H), 4.14 (q,
acrylic acid methyl ester was used in the reaction, in which case a
94% yield of a yellow solid was obtained, which exhibited the
following properties: mp 84e85 ꢁC; 1H NMR (CDCl3, 300 MHz)
J ¼ 7.1 Hz, 2H), 3.83 (s, 3H), 3.82 (s, 2H), 3.69 (s, 3H), 2.75 (s, 3H) and
1.26 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 170.5, 169.0,
158.4, 148.5, 132.8,127.9, 113.1, 100.8, 61.2, 56.0, 55.1, 51.3, 42.34 and
d
7.51 (s, 1H), 6.45 (s, 2H), 4.12 (q, J ¼ 7.1 Hz, 2H), 3.87 (s, 2H), 3.86 (s,
3H), 3.85 (s, 6H), 3.68 (s, 3H), 2.82 (s, 3H) and 1.23 (t, J ¼ 7.15 Hz);
13C NMR (CDCl3, 75 MHz)
170.0, 169.1, 152.4, 148.6, 136.9, 131.2,
14.1; IR (neat) 1743 and 1685 cmꢂ1; HRMS (ES, MþH) m/z calcd for
C
16H22NO5 308.1492 found 308.1501.
d
109.0, 101.2, 61.1, 60.8, 56.0, 51.3, 42.5 and 14.05; IR (neat) 1742 and
1693 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C18H25NO7Na 390.1523
found 390.1497.
4.1.10. 3-(Ethoxycarbonylmethyl-methylamino)-2-p-tolylacrylic
acid methyl ester (8b)
This compound was prepared by the procedure 4.1.9 with the
exception that 3-dimethylamino-2-p-tolylacrylic acid methyl ester
was used in the reaction, in which case a 92% yield of a pale yellow
solid was obtained, which exhibited the following properties: mp
4.1.15. 3-(Ethoxycarbonylmethyl-methylamino)-2-phenylacrylic
acid methyl ester (8g)
This compound was prepared by procedure 4.1.9 with the
exception that 3-dimethylamino-2-phenylacrylic acid methyl ester
was used in the reaction, in which case a 91% yield of a yellow solid
was obtained, which exhibited the following properties: mp
51e52 ꢁC; 1H NMR (CDCl3, 500 MHz)
d 7.52 (s, 1H), 7.09 (s, 4H), 4.12
(q, J ¼ 7.15 Hz, 2H), 3.66 (s, 2H), 3.63 (s, 3H), 2.74 (s, 3H), 2.35 (s, 3H)
and 1.24 (t, J ¼ 7.15 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 170.4, 169.0,
148.4, 136.2, 132.7, 131.7, 128.3, 101.1, 61.1, 55.9, 51.3, 42.4, 21.2, 14.1;
41e43 ꢁC; 1H NMR (CDCl3, 500 MHz)
d 7.54 (s, 1H), 7.19e7.31 (m,
IR (neat) 1745 and 1681 cmꢂ1; HRMS (ES, MþH) m/z calcd for
5H), 4.13 (q, J ¼ 7.1 Hz, 2H), 3.66 (s, 2H), 3.64 (s, 3H), 2.73 (s, 3H) and
C
16H22NO4 292.1543 found 292.1512.
1.24 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 170.2, 168.9,
148.5, 135.8, 131.9, 127.6, 126.7, 101.3, 61.2, 56.0, 51.3, 42.4 and 14.1;
4.1.11. 2-(4-Chlorophenyl)-3-(ethoxycarbonylmethyl-methylamino)
acrylic acid methyl ester (8c)
IR (neat) 1746 and 1680 cmꢂ1; HRMS (ES, MþH) m/z calcd for
C15H20NO4 278.1387 found 278.1405.
This compound was prepared by procedure 4.1.9 with the
exception that 2-(4-chlorophenyl)-3-dimethylaminoacrylic acid
methyl ester was used in the reaction, in which case a 99% yield of
an orange solid was obtained that exhibited the following proper-
4.1.16. 3-(Benzylethoxycarbonylmethylamino)-2-(4-
methoxyphenyl)acrylic acid methyl ester (8h)
Into a 20 mL microwave vial equipped with a magnetic stir bar
and crimping cap was added 2-(4-methoxyphenyl)-3-
dimethylaminoacrylic acid methyl ester (521 mg, 2.21 mmol), N-
benzylglycine ethyl ester (1.07 g, 5.54 mmol), triflouroacetic acid
(505 mg, 4.43 mmol) and ethanol (10 mL). The resulting mixture
was heated in a Biotage Initiator microwave system for 2 h at
100 ꢁC. The solvent was removed in vacuo, the crude residue was
dissolved in a water (25 mL)/ethyl acetate (15 mL) mixture and the
phases were separated. The aqueous phase was extracted with
additional ethyl acetate (2 ꢀ 15 mL) and the combined organic
phases were washed with brine (15 mL), and dried over anhydrous
sodium sulfate. The drying agent was filtered off and the solvent
was removed in vacuo to give a crude residue (1.35 g). The crude
residue was purified via flash chromatography with a Biotage Iso-
lera system to give a white solid (752 mg, 88% yield), which
exhibited the following properties: mp 69e71 ꢁC; 1H NMR (CDCl3,
ties: mp 70e72 ꢁC; 1H NMR (CDCl3, 500 MHz)
d 7.54 (s, 1H), 7.27 (d,
J ¼ 8.5, 2H), 7.17 (d, J ¼ 8.5, 2H), 4.15 (q, J ¼ 7.1 Hz, 2H), 3.70 (s, 2H),
3.65 (s, 3H), 2.74 (s, 3H) and 1.27 (t, J ¼ 7.1, 3H); 13C NMR (CDCl3,
75 MHz)
d 169.8, 168.8, 148.9, 134.4, 133.2, 132.6, 127.7, 100.1, 61.3,
53.6, 51.3, 42.4 and14.1; IR (neat) 1747 and 1681 cmꢂ1; HRMS (ES,
MþH) m/z calcd for C15H19ClNO4 312.0997 found 312.0986.
4.1.12. 2-(4-Bromophenyl)-3-(ethoxycarbonylmethyl-
methylamino)acrylic acid methyl ester (8d)
This compound was prepared by procedure 4.1.9 with the
exception that 2-(4-bromophenyl)-3-dimethylaminoacrylic acid
methyl ester was used in the reaction, in which case a 95% yield of
an orange solid was obtained, which exhibited the following
properties: mp 83e85 ꢁC; 1H NMR (CDCl3, 500 MHz)
d 7.54 (s, 1H),
7.42 (d, J ¼ 8.4 Hz, 2H), 7.11 (d, J ¼ 8.4 Hz, 2H), 4.15 (q, J ¼ 7.15 Hz,
2H), 3.70 (s, 2H), 3.65 (s, 3H), 2.74 (s, 3H) and 1.27 (t, J ¼ 7.15 Hz,
500 MHz)
d
7.77 (s, 1H), 7.30e7.36 (m, 3H), 7.19 (d, J ¼ 6.6 Hz, 2H),
3H); 13C NMR (CDCl3, 75 MHz)
d
169.7, 168.8, 148.9, 134.9, 133.6,
7.12 (d, J ¼ 8.7 Hz, 2H), 6.82 (d, J ¼ 8.7 Hz, 2H), 4.34 (s, 2H), 4.05 (q,
130.7, 120.7, 100.0, 61.3, 56.4, 51.3, 42.44 and 14.08; IR (neat) 1748
and 1692 cmꢂ1; HRMS (ES, MþH) m/z calcd for C15H19BrNO4
356.0492 found 356.0503.
J ¼ 7.15 Hz, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 3.52 (s, 2H) and 1.19 (t,
J ¼ 7.15 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 170.5, 168.9, 158.5,
148.3, 136.3, 132.7, 128.8, 127.9, 127.8, 127.7, 113.3, 101.1, 61.0, 59.0,
55.1, 51.4, 50.0, 14.0; IR (neat) 1751 and 1689 cmꢂ1; HRMS (ES,
MþH) m/z calcd for C22H26NO5 384.1805 found 384.1828.
4.1.13. 3-(Ethoxycarbonylmethyl-methylamino)-2-(3,4-
dimethoxyphenyl)acrylic acid methyl ester (8e)
This compound was prepared by procedure 4.1.9 with the
exception that 3-dimethylamino-2-(3,4-dimethoxyphenyl)acrylic
acid methyl ester was used in the reaction, in which case a 99% yield
of an orange solid was obtained, which exhibited the following
4.1.17. 3-Acetoxy-4-(4-methoxphenyl)-1-methyl-1H-pyrrole-2-
carboxylic acid ethyl ester (9a)
Into a 3-neck round bottom flask equipped with a magnetic
stirring bar, reflux condenser, and under a nitrogen atmosphere
was added sodium hydride (262 mg, 10.9 mmol), anhydrous
ethanol (523 mg, 11.3 mmol), and anhydrous tetrahydrofuran
(50 mL). The resulting mixture was stirred at room temperature for
properties: mp 88e91 ꢁC; 1H NMR (CDCl3, 500 MHz)
d 7.52 (s, 1H),
6.81 (d, J ¼ 8.7 Hz, 1H), 6.74e6.77 (m, 2H), 4.12 (q, J ¼ 7.1 Hz, 2H),
3.91 (s, 3H), 3.89 (s, 3H), 3.67 (s, 2H), 3.65 (s, 3H), 2.77 (s, 3H) and
1.24 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d
170.3, 169.0,
30 min
and
2-(4-methoxyphenyl)-3-(ethoxycarbonylmethyl-
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
7
methylamino)-acrylic acid methyl ester (840 mg, 2.73 mmol) was
added and the reaction mixture stirred for 4 h. Acetic anhydride
(2.23 mg, 21.9 mmol) was added and the reaction mixture stirred
for an additional 12 h and quenched with 60 mL of water. The
aqueous mixture was extracted with ethyl acetate (3 ꢀ 20 mL) and
the combined organic phases were dried over anhydrous sodium
sulfate. The drying agent was removed by filtration and the solvent
was removed in vacuo to give a crude residue. The crude residue
was purified via a Biotage Isolera system to give a yellow/orange
solid (548 mg, 69% yield), which exhibited the following properties:
reaction, in which case a yellow/orange solid (65% yield) was ob-
tained, which exhibited the following properties: mp 108e109 ꢁC;
1H NMR (CDCl3, 300 MHz)
d 6.98e6.95 (m, 2H), 6.86e6.88 (m, 2H),
4.30 (q, J ¼ 7.2 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H). 2.30 (s,
3H) and 1.36 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3, 75 Hz)
d 169.2,
160.2, 149.01, 148.0, 137.0,125.1, 124.6,119.3, 116.9, 113.7, 111.6, 110.5,
59.9, 55.9, 55.8, 37.9, 20.8 and14.34; IR (neat) 1768 and 1690 cmꢂ1
;
HRMS (ES, MþNa) m/z calcd for C18H21NO6Na 370.1261 found
370.1232.
mp 72e73 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.34 (d, J ¼ 8.7 Hz, 2H),
4.1.22. 3-Acetoxy-1-methyl-4-(3,4,5-trimethoxyphenyl)-1H-
pyrrole-2-carboxylic acid ethyl ester (9f)
6.91 (d, J ¼ 8.7 Hz, 2H), 6.85 (s, 1H), 4.30 (q, J ¼ 7.2 Hz, 2H), 3.92 (s,
3H), 3.82 (s, 3H), 2.30 (s, 3H), and 1.35 (t, J ¼ 7.2 Hz, 3H); 13C NMR
This compound was prepared by procedure 4.1.17 with the
(CDCl3, 75 MHz) d 169.3,160.2,158.5,138.7,128.0,124.8, 124.6,116.7,
exception
3-(ethoxy-carbonylmethyl-methylamino)-2-(3,4,5-
114.2, 113.7, 59.9, 55.2, 37.9, 20.8 and 14.4; IR (neat) 1762 and
1694 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C17H19NO5Na 340.1155
found 340.1166.
trimethoxyphenyl)acrylic acid methyl ester was used in the reac-
tion, in which case a yellow/orange solid (52% yield) was obtained,
which exhibited the following properties: mp 129e131 ꢁC; 1H NMR
(CDCl3, 300 MHz)
d
6.89 (s, 1H), 6.66 (s, 2H), 4.30 (q, J ¼ 7.1 Hz, 2H),
4.1.18. 3-Acetoxy-1-methyl-4-p-tolyl-1H-pyrrole-2-carboxylic acid
ethyl ester (9b)
3.95 (s, 3H), 3.88 (s, 9H). 2.30 (s, 3H) and 1.36 (t, J ¼ 7.1 Hz, 3H); 13
C
NMR (CDCl3, 75 MHz)
d 169.1, 160.2, 153.4, 138.6, 137.1, 127.8, 124.7,
This compound was prepared by procedure 4.1.17 with the
117.1, 113.9, 104.3, 60.9, 60.0, 56.1, 38.0, 20.8 and 14.4; IR (neat)
1756, and 1685 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C19H23NO7Na
400.1367 found 400.1394.
exception
3-(ethoxycarbonylmethyl-methylamino)-2-p-tolyla-
crylic acid methyl ester was used in the reaction, in which case a
58% purified yield of an off-white solid was obtained, which
exhibited the following properties: mp 79e81 ꢁC; 1H NMR (CDCl3,
300 MHz)
d
7.33 (d, J ¼ 8.2 Hz, 2H), 7.18 (d, J ¼ 8.2 Hz, 2H), 6.88 (s,
4.1.23. 3-Acetoxy-1-methyl-4-phenyl-1H-pyrrole-2-carboxylic acid
ethyl ester (9g)
1H), 4.31 (q, J ¼ 7.2 Hz, 2H), 3.93 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H) and
1.37 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3,75 MHz)
d 169.2,160.3,138.8,
This compound was prepared by procedure 4.1.17 with the
136.2,129.4,129.3,126.7, 124.7, 116.9, 113.8, 59.9, 38.0, 21.1, 20.8 and
exception
3-(ethoxycarbonylmethyl-methylamino)-2-
14.4; IR (neat) 1761 and 1686 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
phenylacrylic acid methyl ester was used in the reaction, in
which case an off-white solid (86% yield) was obtained, which
exhibited the following properties: mp 74e75 ꢁC; 1H NMR (CDCl3,
C
17H19NO4Na 324.1206 found 324.1154.
4.1.19. 3-Acetoxy-4-(4-chlorophenyl)-1methyl-1H-pyrrole-2-
carboxylic acid ethyl ester (9c)
300 MHz)
d
7.44 (d, J ¼ 9.0 Hz, 2H), 7.37 (t, J ¼ 9.0 Hz, 2H), 7.28 (t,
J ¼ 9.0 Hz, 1H), 6.91 (s, 1H), 4.31 (q, J ¼ 7.2 Hz, 2H), 3.95 (s, 3H), 2.31
(s, 3H) and 1.37 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 169.2,
This compound was prepared by procedure 4.1.17 with the
exception 2-(4-chlorophenyl)-3-(ethoxy-carbonylmethyl-methyl-
amino)acrylic acid methyl ester was used in the reaction, in which
case a yellow/orange solid (59% yield) was obtained, which
exhibited the following properties: mp 96e98 ꢁC; 1H NMR (CDCl3,
160.2, 138.9,132.3,128.7, 126.8,126.5,124.89, 117.0, 113.9, 60.0, 38.0,
20.8 and 14.4; IR (neat) 1764 and 1679 cm-1; HRMS (ES, MþNa) m/z
calcd for C16H17NO4Na 310.1050 found 310.1038.
500 MHz)
d
7.36 (d, J ¼ 10.0 Hz, 2H), 7.33 (d, J ¼ 10.0 Hz, 2H), 6.90 (s,
1H), 4.31 (q, J ¼ 7.15 Hz, 2H), 3.95 (s, 3H), 2.31 (s, 3H) and 1.37 (t,
4.1.24. 3-Acetoxy-1-benzyl-4-(4-methoxyphenyl)-1H-pyrrole-2-
carboxylic acid ethyl ester (9h)
J ¼ 7.15 Hz, 3H); 13C NMR (CDCl3, 75 Hz)
d 169.1, 160.1, 138.8, 132.4,
130.8, 128.8, 128.0, 124.7, 115.9, 114.1, 60.1, 38.1, 20.8 and 14.4; IR
(neat) 1751 and 1693 cmꢂ1; HRMS (ES, MþH) m/z calcd for
C16H17NO4Cl 322.0841 found 322.0881.
Into a 3-neck round bottom flask equipped with a magnetic
stirring bar, reflux condenser and under a nitrogen atmosphere was
added sodium hydride (245 mg, 1.02 mmol), anhydrous ethanol
(490 mg, 1.07 mmol), anhydrous tetrahydrofuran (25 mL) and the
mixture was stirred at room temperature for 30 min. 3-(Benzyle-
4.1.20. 3-Acetoxy-4-(4-bromophenyl)-1methyl-1H-pyrrole-2-
carboxylic acid ethyl ester (9d)
thoxycarbonylmethylamino)-2-(4-methoxyphenyl)acrylic
acid
This compound was prepared procedure 4.1.17 with the excep-
tion 2-(4-bromophenyl)-3-(ethoxy-carbonylmethyl-methylamino)
acrylic acid methyl ester was used in the reaction, in which case an
off-white solid was obtained (99% yield), which exhibited the
following properties: mp 108e110 ꢁC; 1H NMR (CDCl3, 500 MHz)
methyl ester was added and the resulting reaction mixture was
stirred for 4 h at room temperature. Acetic anhydride was then
added (2.08 g, 20.4 mmol) to the reaction mixture and stirring was
continued at room temperature for 12 additional hours. The reac-
tion was quenched with 30 mL of brine, extracted with ethyl acetate
(3 ꢀ 15 mL) and dried over anhydrous sodium sulfate. The drying
agent was removed by filtration and the solvent was removed in
vacuo to give an orange/brown residue The crude residue was pu-
rified via a Biotage Isolera flash system to give a yellow solid
(245 mg, 25% yield), which exhibited the following characteristics:
d
7.49 (d, J ¼ 8.5 Hz, 2H), 7.30 (d, J ¼ 8.5 Hz, 2H), 6.90 (s, 1H), 4.31 (q,
J ¼ 7.2 Hz), 4.13 (s, 3H), 2.31 (s, 3H) and 1.37 (t, J ¼ 7.2 Hz);13C NMR
(CDCl3, 75 Hz)
d 169.1, 160.1, 138.7, 131.8, 131.3, 128.3, 124.6, 120.4,
115.9, 114.2, 60.1, 38.1, 20.8 and 14.4; IR (neat) 1768 and 1693 cmꢂ1
;
HRMS (ES, MþH) m/z calcd for C16H17NO4Br 366.0335 found
366.0347.
mp 72e74 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 7.40e7.30 (m, 5H), 7.17
(d, J ¼ 9.0 Hz, 2H), 6.88e6.94 (m, 3H), 5.55 (s, 2H), 4.25 (q, J ¼ 7.1 Hz,
2H), 3.83 (s, 3H), 2.30 (s, 3H) and 1.29 (t, J ¼ 7.1 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) 169.0, 160.0, 158.5, 139.2, 137.5, 128.7, 128.0, 127.6,
127.0, 124.7, 123.9, 117.4, 114.2, 113.5, 60.0, 55.3, 53.1, 20.8 and 14.3;
IR (neat) 1772 and 1693 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
4.1.21. 3-Acetoxy-1-methyl-4-(3,4-dimethoxyphenyl)-1H-pyrrole-
2-carboxylic acid ethyl ester (9e)
This compound was prepared by procedure 4.1.17 with the
exception
3-(ethoxycarbonylmethyl-methylamino)-2-(3,4-
dimethoxyphenyl)acrylic acid methyl ester was used in the
C23H23NO5Na 416.1468 found 416.1494.
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

8
J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
4.1.25. Z-3-Dimethylamino-2-(4-methoxyphenyl)acrylonitrile
(11a)
(m, 4H), 7.10e7.17 (m, 1H), 6.91 (s, 1H) and 3.24 (s, 6H); 13C NMR
(CDCl3, 75 MHz) d 149.8, 136.6, 128.7, 125.1, 124.0, 121.0 and 43.2; IR
To a round bottom flask, equipped with a reflux condenser and a
magnetic stirring bar, was added 4-methoxybenzyl acetonitrile
(0.5 g, 3.40 mmol), N,N-dimethylformamide dimethyl acetal
(1.630 g, 13.6 mmol), and DMF (15 mL). The reaction mixture was
refluxed for 4 h and diluted with aqueous lithium chloride (30 mL).
The mixture was extracted with ethyl acetate (3 ꢀ 20 mL) and
washed with aqueous lithium chloride (30 mL). The solution was
dried over anhydrous sodium sulfate and the solvent was removed
in vacuo to give an orange solid (0.660 g, 96% yield), which
exhibited the following properties: mp 60e62 ꢁC; 1H NMR (CDCl3,
(neat) 2187 and 1614 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
C11H12N2Na 195.0893 found 195.0886.
4.1.31. Z-2-(3,4-Dimethoxyphenyl)-3-dimethylaminoacrylonitrile
(11g)
This compound was prepared by procedure 4.1.25 with the
exception that 3,4-dimethoxyphenylacetonitrile was used in the
reaction in which case a brown solid (98% yield) was obtained,
which exhibited the following properties: mp 88e91 ꢁC; 1H NMR
(CDCl3, 500 MHz)
d 6.83 (broad m, 1H), 6.82e6.83 (m, 2H), 6.80 (s,
300 MHz)
d
7.24 (d, J ¼ 8.8 Hz, 2H), 6.87 (d, J ¼ 8.8 Hz, 2H), 6.78 (s,
1H), 3.91 (s, 3H), 3.88 (s, 3H) and 3.23 (s, 6H); 13C NMR (CDCl3,
1H), 3.81 (s, 3H), and 3.22 (s, 6H); 13C NMR (CDCl3, 75 MHz)
d
157.7,
75 MHz)
d 149.4, 149.1, 147.0, 129.8, 121.3, 116.3, 111.8, 108.3, 56.0,
149.1, 129.2, 125.5, 121.3, 114.2, 55.4 and 42.4; IR (neat) 2178 and
1620 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C12H14N2ONa 225.0998
found 225.0938.
55.9, 42.4; IR (neat) 2187 and 1617 cmꢂ1; HRMS (ES, MþH) m/z
calcd for C13H17N202 233.1285 found 233.1256.
4.1.26. Z-3-Dimethylamino-2- p-tolylacrylonitrile (11b)
4.1.32. {[2-Cyano-2-(4-methoxyphenyl)vinyl]methylamino}acetic
acid ethyl ester (12a)
This compound was prepared by procedure 4.1.25 with the
exception that 4-methylphenylacetonitrile was used in the reac-
tion, in which case a 95% yield of a solid was obtained, which
exhibited the following properties: mp 84e87 ꢁC; 1H NMR (CDCl3,
Into a round bottom flask, equipped with a reflux condenser and
magnetic stirring bar, was added 3-dimethyl-amino-2-(4-
methoxyphenyl)acrylonitrile (0.685 g, 3.39 mmol), sarcosine ethyl
ester hydrochloride (1.561 g, 10.2 mmol), and acetic acid (15 mL).
The reaction mixture was heated at reflux for 6 h and diluted with
water (30 mL). The aqueous layer was extracted with ethyl acetate
(3 ꢀ 15 mL) and the combined organic layers were washed with
saturated aqueous sodium bicarbonate and dried over anhydrous
sodium sulfate. After removing the drying agent by filtration, the
solvent was concentrated in vacuo and the crude residue was pu-
rified via a Biotage Isolera flash system to give an orange solid
(0.929 g, 87% yield), which exhibited the following characteristics:
300 MHz)
d
7.22 (d, J ¼ 8.3 Hz, 2H), 7.12 (d, J ¼ 8.3 Hz, 2H), 6.89 (s,
1H), 3.23 (s, 6H), and 2.33 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d
149.4,
134.8, 133.7, 129.9, 124.1, 121.2, 42.5 and 20.8; IR (neat) 2176 and
1620 cmꢂ1; HRMS (ES, MþH) m/z calcd for C12H15N2 187.1230 found
187.1213.
4.1.27. Z-2-(4-Chlorophenyl)-3-dimethylaminoacrylonitrile (11c)
This compound was prepared by procedure 4.1.25 with the
exception that 4-chlorophenylacetonitrile was used in the reaction,
in which case a solid (84% yield) was obtained, which exhibited the
following properties: mp 73e75 ꢁC; 1H NMR (CDCl3, 500 MHz)
mp 78e79 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.25 (d, J ¼ 8.8 Hz, 2H),
6.86 (d, J ¼ 8.8 Hz, 2H), 6.76 (s, 1H), 4.29 (q, J ¼ 7.1, 2H), 4.13 (s, 2H),
d
7.27 (d, J ¼ 9.1 Hz, 2H), 7.24 (d, J ¼ 9.1 Hz, 2H), 6.89 (s, 1H) and 3.26
3.81 (s, 3H), 3.29 (s, 3H), and 1.34 (t, J ¼ 7.1, 3H); 13C NMR (CDCl3,
(s, 6H); 13C NMR (CDCl3, 75 MHz)
d
149.8, 135.2, 131.1, 128.7, 125.1,
75 MHz) d 168.7, 158.0, 148.6, 128.6, 126.0, 120.3, 114.2, 79.4, 61.8,
120.7 and 42.6; IR (neat) 2187 and 1633 cmꢂ1; HRMS (ES, MþNa)
m/z calcd for C11H11N2ClNa 229.0503 found 229.0460.
56.4, 55.4, 41.4 and 14.2; IR (neat) 2181 and 1736 cmꢂ1; HRMS (ES,
MþNa) m/z calcd for C15H18N2O3Na 297.1210 found 297.1198.
4.1.28. Z-2-(4-Bromophenyl)-3-dimethylaminoacrylonitrile (11d)
This compound was prepared by procedure 4.1.25 with the
exception that 4-bromophenylacetonitrile was used in the reaction,
in which case a solid (100% yield) was obtained, which exhibited
the following properties: mp 84e86 ꢁC; 1H NMR (CDCl, 500 MHz)
4.1.33. {[2-Cyano-2-p-tolylvinyl]methylamino}acetic acid ethyl
ester (12b)
This compound was prepared by procedure 4.1.32 with the
exception that 3-dimethylamino-2-p-tolylacrylonitrile was used in
the reaction, in which case a solid (88% yield) was obtained, which
exhibited the following properties: mp 84e85 ꢁC; 1H NMR
d
7.41 (d, J ¼ 8.6 Hz, 2H), 7.18 (d, J ¼ 8.6 Hz, 2H), 6.89 (s, 1H) and 3.23
(s, 6H); 13C NMR (CDCl3, 75 MHz)
d 149.8, 135.7, 131.7, 125.4, 120.6,
(acetone-d6, 300 MHz)
d
7.23 (d, J ¼ 8.3 Hz, 2H), 7.12 (d, J ¼ 8.3 Hz,
118.4 and 31.4; IR (neat) 2184 and 1617 cmꢂ1; HRMS (ES, MþNa) m/
z calcd for C11H11N2BrNa 272.9998 found 272.9950.
2H), 6.84 (s,1H), 4.29 (q, J ¼ 7.1, 2H), 4.13 (s, 2H), 3.30 (s, 3H), 2.33 (s,
3H) and 1.34 (t, J ¼ 7.1, 3H); 13C NMR (CDCl3, 75 MHz)
d 168.9, 149.7,
134.5, 133.8, 129.2, 123.8, 119.9, 77.9, 60.9, 56.3, 40.1, 19.9 and 13.6;
4.1.29. Z-2-(4-Fluorophenyl)-3-dimethylaminoacrylonitrile (11e)
This compound was prepared by procedure 4.1.25 with the
exception that 4-flourophenylacetonitrile was used in the reaction,
in which case a solid (95% yield) was obtained, which exhibited the
following properties: mp 52e53 ꢁC; 1H NMR (CDCl3, 500 MHz)
IR (neat) 2181 and 1739 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
C15H18N2O2Na 281.1260 found 281.1247.
4.1.34. {[2-(4-Chlorophenyl)-2-cyanovinyl]methylamino}acetic
acid ethyl ester (12c)
d
7.23e7.28 (m, 2H), 6.99 (t, J ¼ 8.7 Hz, 2H), 6.81 (s, 1H) and 3.23 (s,
6H); 13C NMR (CDCl3, 75 MHz)
d
160.81 (d, J ¼ 243.9 Hz), 149.8,
This compound was prepared by procedure 4.1.32 with the
exception that 2-(4-chlorophenyl)-3-dimethylamino-acrylonitrile
was used in the reaction, in which case a solid (88% yield) was
obtained, which exhibited the following properties: mp
132.8 (d, J ¼ 3.0 Hz), 125.6 (d, J ¼ 7.5 Hz), 121.1115.4 (d, J ¼ 21.8 Hz),
75.8 and 42.4; IR (neat) 2185 and 1610 cmꢂ1; HRMS (ES, MþH) m/z
calcd for C11H12N2F 191.0979 found 191.0984.
102e104 ꢁC; 1H NMR (acetone-d6; 300 MHz)
d 7.42 (s, 1H), 7.37 (d,
4.1.30. Z-3-Dimethylamino-2-phenylacrylonitrile (11f)
J ¼ 8.3 Hz, 2H), 7.32 (d, J ¼ 8.3 Hz, 2H), 4.26 (s, 2H), 4.22 (q, J ¼ 7.1,
This compound was prepared by procedure 4.1.25 with the
exception that phenylacetonitrile was used in the reaction, in which
case a solid was obtained (99% yield), which exhibited the following
2H), 3.37 (s, 3H) and 1.28 (t, J ¼ 7.1, 3H); 13C NMR (CDCl3, 75 MHz)
d;
168.44, 149.5, 134.67 131.2, 128.8, 125.6, 119.7, 78.6, 61.9, 56.4, 41.5
and 14.1; IR (neat) 2187 and 1749 cmꢂ1; HRMS (ES, MþH) m/z calcd
for C14H16N2O2Cl 279.0895 found 279.0904.
properties: mp 73e75 ꢁC; 1H NMR (CDCl3, 500 MHz)
d 7.34e7.29
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
9
4.1.35. {[2-(4-Bromophenyl)-2-cyanovinyl]methylamino}acetic
acid ethyl ester (12d)
This compound was prepared by procedure 4.1.32 with the
exception that 2-(4-bromophenyl)-3-dimethylaminoacrylonitrile
was used in the reaction, in which case a solid (91% yield) was
obtained, which exhibited the following properties: mp
in vacuo. The crude residue (0.624 g, 92% yield) was purified using a
Biotage Isolera flash chromatography system to give a pale yellow
solid, which exhibited the following properties: mp 93e94 ꢁC; 1H
NMR (CDCl3, 500 MHz)
d
7.41 (t, J ¼ 10.0 Hz, 2H), 7.36 (t,
J ¼ 10.0 Hz Hz, 1H), 7.30 (d, J ¼ 10.0 Hz, 2H), 7.27 (d, J ¼ 10.0 Hz, 2H),
6.97 (s, 1H), 6.88 (d, J ¼ 10.0 Hz, 2H), 4.63 (s, 2H), 4.27 (q, J ¼ 7.1 Hz,
2H), 4.24 (s, 2H), 3.82 (s, 3H),1.32 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3,
112e114 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.42 (d, J ¼ 8.7 Hz, 2H),
7.20 (d, J ¼ 8.7 Hz, 2H), 6.87 (s, 1H), 4.30 (q, J ¼ 7.1, 2H), 4.17 (s, 2H),
75 MHz) d 168.8, 158.1, 148.2, 135.4, 129.0, 128.5, 128.4, 128.0, 126.0,
3.32 (s, 3H) and 1.34 (t, J ¼ 7.1, 3H); 13C NMR (CDCl3, 75 MHz)
119.9, 114.2, 79.5, 61.8, 59.4, 55.3, 50.9 and 14.1; IR (neat) 2176 and
d
168.4, 149.4, 135.1, 131.7, 125.9, 119.6, 119.2, 78.78, 61.9, 56.4, 41.7
1741 cmꢂ1
373.1523, found 373.1515.
;
HRMS (ES, MþNa) m/z calcd for C21H22N2O3Na
and 14.1; IR (neat) 2186 and 1740 cmꢂ1; HRMS (ES, MþNa) m/z
calcd for C14H15N2O2BrNa 345.0209 found 345.0218.
4.1.40. [Benzyl(2-cyano-2-p-tolylvinyl)amino]acetic acid ethyl ester
(12i)
4.1.36. {[2-Cyano-2-(4-fluorophenyl)vinyl]methylamino}acetic acid
ethyl ester (12e)
This compound was prepared by procedure 4.1.32 with the
exception that 2-(4-flourophenyl)-3-dimethylamino-acrylonitrile
was used in the reaction, in which case a solid (98% yield) was
obtained, which exhibited the following properties: mp 83e84 ꢁC;
This compound was prepared by procedure 4.1.39 with the
exception that 3-dimethylamino-2-p-tolylacrylonitrile and N-
benzyl glycine were used in the reaction, in which case a 58% yield
of a solid was obtained, which exhibited the following properties:
mp 76e78 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 7.44e7.35 (m, 3H),
1H NMR (CDCl3, 300 MHz)
d
7.37 (dd, J ¼ 8.7, 5.2 Hz, 2H), 7.00 (t,
7.31e7.28 (m, 2H), 7.24 (d, J ¼ 8.3 Hz, 2H), 7.13 (d, J ¼ 7.8 Hz, 2H),
J ¼ 8.7 Hz, 2H), 6.80 (s, 1H), 4.29 (q, J ¼ 7.1 Hz, 2H), 4.15 (s, 2H), 3.30
7.05 (s, 1H), 4.63 (s, 2H), 4.31e4.23 (m, 4H), 2.34 (s, 3H) and 1.31 (t,
(s, 3H) and1.34 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d
168.5,
J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 168.7, 148.7, 135.5, 133.1,
1295, 129.0, 128.4, 128.1, 124.3, 119.9, 79.55, 61.8, 59.5, 51.1, 20.9 and
161.2 (d, J ¼ 245.1 Hz), 149.4, 132.1 (d, J ¼ 3.2 Hz), 126.1 (d,
J ¼ 7.8 Hz), 120.0,115.5 (d, J ¼ 21.7 Hz), 78.7, 61.9, 56.3, 41.5, and14.1;
IR (neat) 2186 and 1744 cmꢂ1;HRMS (ES, MþNa) m/z calcd for
14.2; IR (neat) 2180 and 1741 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
C21H22N2O2Na 357.1573 found 357.1583.
C
14H15N2O2FNa 285.1010 found 285.1013.
4.1.41. 3-Amino-4-(4-methoxyphenyl)-1-methyl-1H- pyrrole-2-
carboxylic acid ethyl ester (13a)
4.1.37. [(2-Cyano-2-phenylvinyl-methylamino)]acetic acid ethyl
ester (12f)
This compound was prepared by procedure 4.1.32 with the
exception that 3-dimethylamino-2-phenylacrylonitrile was used in
the reaction, in which case a solid (87% yield) was obtained, which
exhibited the following properties: mp 60e62 ꢁC; 1H NMR
Into a 3-neck round bottom flask, equipped with a magnetic
stirring bar and under an inert atmosphere, were added sodium
hydride (0.219 g, 0.00547 mol) and anhydrous THF (20 mL).{[2-
Cyano-2-(4-methoxyphenyl)vinyl]methylamino}acetic acid ethyl
ester (0.600 g, 0.00219 mol) was added drop wise in THF and the
reaction mixture stirred at room temperature for 12 h. The reaction
was quenched with brine, extracted with ethyl acetate (3 ꢀ 15 mL)
and dried over anhydrous sodium sulfate. The ethyl acetate extract
was filtered and concentrated in vacuo to give a give pale yellow
solid (0.591 g, 99% yield), which exhibited the following properties:
(acetone-d6, 500 MHz)
d
7.38 (d, J ¼ 7.5 Hz, 2H), 7.35 (s, 1H), 7.32 (t,
J ¼ 7.5 Hz, 2H), 7.13 (t, J ¼ 7.5 Hz, 1H), 4.36 (s, 2H), 4.23 (q, J ¼ 7.1 Hz,
2H), 3.36 (s, 3H) and 1.34 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3;,
75 MHz)
d 168.9150.2, 136.7, 128.6, 125.0, 123.8, 119.8, 77.9, 60.9,
56.3, 40.2 and 13.6; IR (neat) 2182 and 1724 cmꢂ1; HRMS (ES,
MþNa) m/z calcd for C14H16N2O2Na 267.1104 found 267.1098.
mp 48e49 ꢁC; 1H NMR (CDCl3, 500 MHz)
d
7.36 (d, J ¼ 8.7, 2H), 6.96
(d, J ¼ 8.7 Hz, 2H), 6.64 (s, 1H), 4.60 (s, 2H), 4.36 (q, J ¼ 7.1, 2H), 3.85
4.1.38. {[2-Cyano-2-(3,4-dimethoxyphenyl)vinyl]methylamino}
acetic acid ethyl ester (12g)
(s, 3H), 3.83 (s, 3H) and 1.41 (t, J ¼ 7.1, 3H); 13C NMR (CDCl3, 75 MHz)
d
162.1158.0, 128.4, 127.1, 126.5, 114.4, 111.7, 107.6, 59.3, 55.3, 37.4
This compound was prepared by procedure 4.1.32 with the
and 14.7; IR (neat) 3420, 3322 and 1650 cmꢂ1; HRMS (ES, MþH) m/
z calcd for C15H19N2O3 275.1390 found 275.1395.
exception
that
2-(3,4-dimethoxyphenyl)-3-
dimethylaminoacrylonitrile was used in the reaction, in which
case a solid (92% yield) was obtained, which exhibited the following
properties: bp 130 ꢁC, 0.305 torr; 1H NMR (CDCl3, 500 MHz)
4.1.42. 3-Amino-1-methyl-4-p-tolyl-1H- pyrrole-2-carboxylic acid
ethyl ester (13b)
d
6.80e6.88 (m, 3H), 6.78 (s, 1H), 4.30 (q, J ¼ 7.1 Hz, 2H), 4.15 (s, 2H),
This compound was prepared by procedure 4.1.41 with the
exception that 3-{[2-cyano-2-p-tolylvinyl]methyl-amino}acetic
acid ethyl ester was used in the reaction, in which case a 74% yield
of a solid was obtained, which exhibited the following properties:
3.92 (s, 3H), 3.88 (s, 3H), 3.25 (s 3H) and 1.35 (t, J ¼ 7.1 Hz, 3H); 13
C
NMR (CDCl3, 75 MHz) d 168.7, 149.2, 148.8, 147.6, 129.2, 121.0, 116.9,
111.6, 108.8, 79.6, 61.8, 56.3, 56.0, 55.9, 41.5 and 14.2; IR (neat) 2190
and 1740 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C16H20N2O4Na
327.1315 found 327.1309.
mp 69e70 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.34 (d, J ¼ 8.1 Hz, 2H),
7.22 (d, J ¼ 8.1 Hz, 2H), 6.67 (s, 1H), 4.64 (s, 2H), 4.36 (d, J ¼ 7.1 Hz,
2H), 3.83 (s, 3H), 2.38 (s, 3H) and 1.40 (t, J ¼ 7.1 Hz, 3H); 13C NMR
4.1.39. {Benzyl-[2-cyano-2-(4-methoxyphenyl)vinyl]amino}acetic
acid ethyl ester (12h)
(CDCl3, 75 MHz) d 161.7, 141.3, 134.7, 131.7, 129.3, 127.5, 126.5, 111.2,
107.3, 58.6, 36.7, 20.2 and 14.1; IR (neat) 3469, 3367 and 1642 cmꢂ1
;
Into a round bottom flask, equipped with a reflux condenser and
magnetic stirring bar, was added 3-dimethylamino-2-(4-
methoxyphenyl)acrylonitrile (1.00 g, 0.0043 mol), N-benzyl
glycine (1.64 g, 0.0085 mol), and acetic acid (20 mL). The reaction
mixture was heated at reflux for 6 h and diluted with water (30 mL).
The aqueous layer was extracted with ethyl acetate (3 ꢀ 15 mL) and
the combined organic layers were washed with saturated aqueous
sodium bicarbonate until gas evolution ceased. The organic phase
was dried over anhydrous sodium sulfate, filtered and concentrated
HRMS (ES, MþH) m/z calcd for C15H19N2O2 259.1441, found
259.1437.
4.1.43. 3-Amino-4-(4-chlorophenyl)-1-methyl-1H- pyrrole-2-
carboxylic acid ethyl ester (13c)
This compound was prepared by procedure 4.1.41 with the
exception that 3-{[2-(4-chlorophenyl)-2-cyanovinyl]methylamino}
acetic acid ethyl ester used in the reaction, in which case a 60% yield
of a solid was obtained, which exhibited the following properties:
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

10
J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
mp 69e70 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.37 (broad s, 4H), 6.68
4.1.48. 3-Amino-1-benzyl-4-(4-methoxyphenyl)-1H-pyrrole-2-
carboxylic acid ethyl ester (13h)
(s, 1H), 4.63 (s, 2H), 4.36 (q, J ¼ 7.1 Hz, 2H), 3.83 (s, 3H), and1.40 (t,
J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d
162.1, 140.3, 132.6, 131.6,
This compound was prepared by procedure 4.1.41 with the
129.1, 128.2, 127.1, 110.8, 107.9, 59.4, 37.6 and 14.6; IR (neat) 3458,
3347 and 1641 cmꢂ1; HRMS (ES, MþH) m/z calcd for C14H16N2O2Cl
279.0895 found 279.0920.
exception
that
{benzyl-[2-cyano-2-(4-methoxyphenyl)vinyl]
amino}acetic acid ethyl ester was used in the reaction, in which
case a 63% yield of a solid was obtained, which exhibited the
following properties: bp 111 ꢁC at 0.385 torr; 1H NMR (CDCl3,
300 MHz)
d
7.38 (d, J ¼ 8.7 Hz, 2H), 7.34e7.23 (m, 3 H), 7.14 (d,
4.1.44. 3-Amino-4-(4-bromophenyl)-1-methyl-1H- pyrrole-2-
carboxylic acid ethyl ester (13d)
J ¼ 8.0 Hz, 2H), 6.96 (d, J ¼ 8.7 Hz, 2H), 6.76 (s, 1H), 5.42 (s, 2H), 4.68
(broad s, 2H), 4.27 (q, J ¼ 7.1 Hz, 2H), 3.85 (s, 3H) and 1.27 (t,
This compound was prepared by procedure 4.1.41 with the
exception that {[2-(4-bromophenyl)-2-cyanovinyl]methylamino}
acetic acid ethyl ester was used in the reaction, in which case a 79%
yield of a solid was obtained, which exhibited the following prop-
J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 161.9, 158.1, 141.0, 138.8,
128.5, 128.4, 127.2, 126.8, 126.6, 126.4, 114.1, 112.5, 107.0, 59.3, 55.3,
52.8 and 14.5; IR (neat) 3480, 3349 and 1664 cmꢂ1; HRMS (ES,
MþH) m/z calcd for C21H23N2O3 351.1703 found 351.1709.
erties: mp 79e80 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.51 (d, J ¼ 8.6 Hz,
2 H), 7.32 (d, J ¼ 8.6 Hz, 2H), 6.68 (s, 1H), 4.63 (s, 2H), 4.36 (q,
4.1.49. 3-Amino-1-benzyl-4-p-tolyl-1H-pyrrole-2-carboxylic acid
ethyl ester (13i)
J ¼ 7.1 Hz, 2H), 3.83 (s, 3H) and 1.41 (t, J ¼ 7.1 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) d 162.0, 140.3, 133.1, 131.9, 128.4, 127.1, 119.4, 110.7,
This compound was prepared by procedure 4.1.41 with the
exception that [benzyl(2-cyano-2-p-tolylvinyl)amino]-acetic acid
ethyl ester was used in the reaction, in which case an 82% yield of a
solid was obtained, which exhibited the following properties: bp
107.9, 59.4, 37.6 and 14.7; IR (neat) 3429, 3334 and 1653 cmꢂ1
;
HRMS (ES, MþH) m/z calcd for C14H16N2O2Br 323.0390 found
323.0405.
92 ꢁC at 0.365 torr; 1H NMR (CDCl3, 300 MHz)
d
7.36 (d, J ¼ 7.2 Hz,
4.1.45. 3-Amino-4-(4-fluorophenyl)-1-methyl-1H- pyrrole-2-
carboxylic acid ethyl ester (13e)
2H), 7.23e7.31 (m, 3H), 7.21 (d, J ¼ 7.2 Hz, 2H), 7.13 (d, J ¼ 7.2 Hz,
2H), 6.80 (s, 1H), 5.43 (s, 2H), 4.72 (s, 2H), 4.27 (q, J ¼ 7.1 Hz, 2H),
2.39 (s, 3H) and 1.28 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
This compound was prepared by procedure 4.1.41 with the
exception that {[2-cyano-2-(4-fluorophenyl)-vinyl]methylamino}
acetic acid ethyl ester was used in the reaction, in which case a 75%
yield of a solid was obtained, which exhibited the following prop-
d
161.9, 141.2, 138.8, 135.7, 131.0, 129.7, 128.5, 127.2, 127.1, 126.6,
112.7, 107.0, 59.3, 52.9, 21.2 and 14.6; IR (neat) 3472, 3368 and
1660 cmꢂ1; HRMS (ES, MþH) m/z calcd for C21H23N2O2 335.1754
found 335.1735.
erties: mp 57e59 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 7.39 (dd,
J ¼ 8.9 Hz, J ¼ 5.4 Hz, 2H), 7.09 (t, J ¼ 8.9 Hz, 2H), 6.65 (s, 1H), 4.62
(broad s, 2H), 4.37 (q, J ¼ 7.1 Hz, 2H), 3.83 (s, 3H) and 1.40 (t,
4.1.50. 3-Acetylamino-4-(4-methoxyphenyl)-1-methyl-1H-
pyrrole-2-carboxylic acid ethyl ester (13j)
J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 162.1, 161.3 (d,
J ¼ 247.5 Hz), 140.2, 130.1 (d, J ¼ 3.8 Hz), 128.6 (d, J ¼ 7.5 Hz), 127.1,
115.7 (d, J ¼ 21.0 Hz), 111.0, 107.7, 59.4, 37.5 and 14.7; IR (neat) 3403
and 1659 cmꢂ1; HRMS (ES, MþH) m/z calcd for C14H16N2O2F
263.1190 found 263.1176.
This compound was prepared by procedure 4.1.41 with the
exception that {[2-cyano-2-(4-methoxy-phenyl)vinyl]methyl-
amino}acetic acid ethyl ester was used in the reaction. In addition,
acetic anhydride (3.5 eq.) was added to the reaction mixture fol-
lowed by two additional hours of stirring prior to reaction workup,
in which case a 71% yield of a solid was obtained. This material
exhibited the following properties: mp 133e136 ꢁC; 1H NMR
4.1.46. 3-Amino-4-phenyl-1-methyl-1H- pyrrole-2-carboxylic acid
ethyl ester (13f)
(CDCl3, 300 MHz)
d
7.26 (d, J ¼ 8.7 Hz, 2H), 6.86 (d, J ¼ 8.7 Hz, 2H),
This compound was prepared by procedure 4.1.41 with the
exception that [(2-cyano-2-phenylvinyl)methylamino]- acetic acid
ethyl ester was used in the reaction, in which case an 83% yield of a
solid was obtained, which exhibited the following properties: mp
6.76 (s, 1H), 4.26 (q, J ¼ 7.1 Hz, 2H), 4.13 (s, 3H), 3.81 (s, 3H), 3.29 (s,
3H) and 1.34 (t, J ¼ 7.1 Hz, 3H); 13C NMR (acetone-d6, 75 MHz)
d
168.8, 160.7, 158.3, 128.2, 126.7, 125.5, 121.4, 117.9, 113.6, 59.3, 54.6,
36.9, 22.4 and 13.8; IR (neat) 3258, 1685 and 1650 cmꢂ1; HRMS (ES,
36e38 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.45 (d, J ¼ 8.3 Hz, 2H), 7.41
MþNa) m/z calcd for C17H20N2O4Na 339.1515 found 339.1519.
(t, J ¼ 8.3 Hz, 2H), 7.25 (t, J ¼ 8.3 Hz, 1H), 6.70 (s, 1H), 4.67 (broad s,
2H), 4.37 (q, J ¼ 7.1 Hz, 2H), 3.84 (s, 3H) and 1.41 (t, J ¼ 7.1 Hz, 3H);
4.1.51. 3-Methanesulfonylamino-4-(4-methoxyphenyl)-1-methyl-
1H- pyrrole-2-carboxylic acid ethyl ester (13k)
13C NMR (CDCl3, 75 MHz)
d 162.2, 140.4, 134.2, 128.9, 127.3, 127.0,
125.9, 111.9107.7, 59.3, 37.5 and 14.7; IR (neat) 3413, 3334 and
1651 cmꢂ1; HRMS (ES, MþH) m/z calcd for C14H17N2O2 245.1285
found 245.1279.
Into a 3-neck round bottom flask, equipped with a magnetic
stirring bar and under an inert atmosphere, was added sodium
hydride (0.110 g, 0.00457 mol), ethanol (0.220 g, 0.00471 mol) and
anhydrous THF (30 mL). The reaction mixture stirred for 30 min and
cooled in an ice bath.{[2-Cyano-2-(4-methoxyphenyl)vinyl]meth-
ylamino}acetic acid ethyl ester (0.250 g, 0.00091 mol) in a minimal
amount of dry THF was slowly added to the reaction mixture and
the resulting solution was stirred for 4 h. Methane sulfonic anhy-
dride (0.960 g, 0.00349) in a minimal amount of dry THF was added
dropwise and the resulting reaction mixture stirred for 12 h. The
reaction was quenched with brine (20 mL), extracted with ethyl
acetate (3 ꢀ 15 mL), dried over anhydrous sodium sulfate and
concentrated in vacuo to give a crude residue. The crude residue
was purified using a Biotage Isolera flash chromatography system
to produce a brown solid (0.150 g, 47% yield), which exhibited the
following properties: mp 139e141 ꢁC; 1H NMR (CDCl3, 300 MHz)
4.1.47. 3-Amino-4-(3,4-dimethoxyphenyl)-1-methyl-1H- pyrrole-
2-carboxylic acid ethyl ester (13g)
This compound was prepared by procedure 4.1.41 with the
exception that {[2-cyano-2-(3,4-dimethoxyphenyl)vinyl]methyl-
amino}acetic acid ethyl ester was used in the reaction, in which
case a 97% yield of a solid was obtained, which exhibited the
following properties: mp 107e109 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.00e6.96 (m, 2H), 6.93 (d, J ¼ 8.7 Hz,1H), 6.66 (s, 1H), 4.62 (broad
s, 2H), 4.37 (q, J ¼ 7.1 Hz, 2H), 3.92 (s, 6H), 3.84 (s, 3H) and 1.41 (t,
J ¼ 7.1 Hz, 3H). 13C NMR (CDCl3,75 MHz)
d 162.2, 149.3, 147.6, 140.1,
127.1, 126.9, 119.5, 111.9, 111.87, 110.8, 107.7, 59.3, 56.0, 55.9, 37.4 and
14.7; IR (neat) 3437, 3354 and 1663 cmꢂ1; HRMS (ES, MþNa) m/z
calcd for C16H20N2O4Na 327.1315, found 327.1311.
d
7.47 (d, J ¼ 9.0 Hz, 2H), 6.94 (d, J ¼ 9.0 Hz, 2H), 6.79 (s, 1H), 4.41 (q,
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
11
J ¼ 7.1 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 2.60 (s, 3H) and 1.44 (q,
z calcd for C18H19BrNO2 360.0594 found 360.0614.
J ¼ 7.1 Hz, 2H); 13C NMR (CDCl3; 75 MHz)
d 160.9, 158.7, 129.4, 126.4,
125.7, 125.2, 121.4, 117.3, 114.0, 60.7, 55.2, 40.3, 38.0 and14.3; IR
4.1.56. 2-(3,4-Dimethoxyphenyl)-3-(methyl-p-tolylamino)acrylic
acid methyl ester (15e)
(neat) 3266 and 1695 cmꢂ1; HRMS (ES, MþNa) m/z calcd for
C
16H20N2O5SNa 375.0985 found 375.0982.
This compound was prepared by procedure 4.1.52 with the
exception that 2-(3,4-dimethoxyphenyl)-3-dimethylaminoacrylic
acid methyl ester was used in the reaction, in which case an 82%
yield of an orange solid was obtained, which exhibited the
following properties: mp 110e112 ꢁC; 1H NMR (CDCl3, 300 MHz)
4.1.52. 2-(4-Methoxyphenyl)-3-(methyl-p-tolylamino)acrylic acid
methyl ester (15a)
To a round bottom flask, equipped with a reflux condenser and a
magnetic stirring bar, was added 3-dimethyl-amino-2-(4-
methoxyphenyl)acrylic acid methyl ester (1.0 g, 0.00425 mol), N-
methyl p-toluidine (1.03 g, 0.0085 mol), ethanol (20 mL), and acetic
acid (0.5 mL). The reaction mixture was refluxed overnight and the
solvent was removed in vacuo. Water (20 mL) and ethyl acetate
(15 mL) were added to the reaction mixture and the phases were
separated. The aqueous layer was extracted with additional ethyl
acetate (3 ꢀ 15 mL) and the combined organic phases were washed
with aqueous 1% HCl (20 mL) followed by a wash with saturated
aqueous sodium bicarbonate (20 mL). The resulting organic phase
was dried over anhydrous sodium sulfate and concentrated in vacuo
to give a yellow solid (1.24 g, 93% yield), which exhibited the
following characteristics: mp 86e88 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.94 (s, 1H), 7.12 (d, J ¼ 8.6 Hz, 2H), 7.00 (d, J ¼ 8.6 Hz, 2H),
6.74e6.84 (m, 3H), 3.90 (s, 3H), 3.87 (s, 3H), 3.72 (s, 3H), 2.89 (s, 3H)
and 2.33 (s, 3H); 13C NMR (CDCl3, 75 MHz)
170.3, 148.1, 147.9,
d
145.3, 145.1, 133.5, 129.7, 128.6, 123.9, 119.7, 144.8, 110.5, 105.3, 55.9,
55.8, 51.5, 38.6 and 20.6; IR (neat) 1690 cmꢂ1; HRMS (ES, MþH) m/z
calcd for C20H24NO4 342.1700 found 342.1707.
4.1.57. 3-(Methyl-p-tolylamino)-2-(3,4,5-trimethoxyphenyl)acrylic
acid methyl ester (15f)
This compound was prepared by procedure 4.1.52 with the
exception
that
3-dimethylamino-2-(3,4,5-trimethoxyphenyl)
acrylic acid methyl ester was used in the reaction, in which case a
63% yield of a yellow solid was obtained, which exhibited the
following properties: mp 116e117 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.94 (s, 1H), 7.14 (m, 4H), 6.99 (d, J ¼ 8.7 Hz, 2H), 6.85 (d, J ¼ 8.7 Hz,
2H) 3.83 (s, 3H), 3.71 (s, 3H), 2.87 (s, 3H) and 2.33 (s, 3H); 13C NMR
(CDCl3, 75 MHz) 170.4, 158.4, 145.3, 145.1133.4, 132.4, 129.7, 128.3,
119.7, 113.1, 105.4, 55.2, 51.5, 38.7 and 20.6; IR (neat) 1692 cmꢂ1
d
7.93 (s, 1H), 7.11 (d, J ¼ 8.4 Hz, 2H), 6.98 (d, J ¼ 8.4 Hz, 2H), 6.43 (s,
2H), 3.86 (s, 3H), 3.83 (s, 6H), 3.73, (s, 3H), 2.97 (s, 3H) and 2.32 (s,
3H); 13C NMR (CDCl3; 75 MHz)
170.0, 152.4, 145.4, 144.8, 136.9,
d
;
d
HRMS (ES, MþH) m/z calcd for C19H22NO3 312.1594 found 312.1586.
133.7, 131.4, 129.6, 120.1, 108.9, 105.0, 60.8, 56.1, 51.5, 39.2 and 20.6;
IR (neat) 1685 cmꢂ1; HRMS (ES, MþH) m/z calcd for C21H26NO5
372.1805 found 372.1806.
4.1.53. 3-(Methyl-p-tolylamino)-2-p-tolylacrylic acid methyl ester
(15b)
This compound was prepared by procedure 4.1.52 with the
exception that 3-dimethylamino-2-p-tolyl-acrylic acid methyl ester
was used in the reaction, in which case a 73% yield of a pale yellow
solid was obtained, which exhibited the following properties: mp
4.1.58. 3-(Methyl-p-tolylamino)-2-phenylacrylic acid methyl ester
(15g)
This compound was prepared by procedure 4.1.52 with the
exception that 3-dimethylamino-2-phenylacrylic acid methyl ester
was used in the reaction, in which case an 85% yield of a pale yellow
solid was obtained, which exhibited the following properties: mp
105e108 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.95 (s, 1H), 7.17e7.11 (m,
6H), 7.00 (d, J ¼ 8.5 Hz, 2H), 3.71 (s, 3H), 2.86 (s, 3H), 2.37 (s, 3H) and
2.34 (s, 3H); 13C NMR (CDCl3, 75 MHz)
170.4, 145.3, 145.2, 136.3,
d
95e97 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.97 (s, 1H), 7.21e7.35 (m,
5H), 7.12 (d, J ¼ 8.5 Hz, 2H), 7.00 (d, J ¼ 8.5 Hz, 2H), 3.71 (s, 3H), 2.85
(s, 3H) and 2.33 (s, 3H); 13C NMR (CDCl3, 75 MHz)
170.1, 145.5,
133.4, 133.1, 131.3, 129.7, 128.4, 119.7, 105.7, 51.2, 38.7, 21.3 and 20.6;
IR (neat) 1685 cmꢂ1; HRMS (ES, MþH) m/z calcd for C19H22NO2
296.1645 found 296.1639.
d
145.1, 136.2, 133.6, 131.5, 129.8, 127.6, 126.7, 119.9, 105.7, 51.5, 39.0
and 20.7; IR (neat) 1687 cmꢂ1; HRMS (ES, MþH) m/z calcd for
4.1.54. 2-(4-Chlorophenyl)-3-(methyl-p-tolyamino)acrylic acid
methyl ester (15c)
C18H20NO2 282.1489 found 282.1500.
This compound was prepared by procedure 4.1.52 with the
exception that 2-(4-chlorophenyl)-3-dimethyl-aminoacrylic acid
methyl ester was used in the reaction, in which case an 81% yield of
a yellow solid was obtained, which exhibited the following prop-
4.1.59. 3-(Ethyl-p-tolylamino)-2-(4-methoxyphenyl)acrylic acid
methyl ester (15h)
This compound was prepared by procedure 4.1.52 with the
exception that N-ethyl p-toluidine was used in the reaction, in
which case a 69% yield of a yellow oil was obtained, which
exhibited the following properties: bp 126 ꢁC at 0.970 torr; 1H NMR
erties: mp 97e99 ꢁC; 1H NMR (CDCl3, 300 MHz)
d
7.95 (s, 1H), 7.24
(d, J ¼ 8.6 Hz, 2 H), 7.09e7.15 (m, 4H), 6.96 (d, J ¼ 8.6 Hz, 2H), 3.71 (s,
3H), 2.92 (s, 3H) and 2.33 (s, 3H); 13C NMR (CDCl3, 75 MHz)
169.8,
d
(CDCl3, 300 MHz) d 7.85 (s, 1H), 7.01e7.07 (m, 4H), 6.90 (d,
146.0, 144.6, 134.6, 134.0, 132.7, 132.4, 129.7, 127.7, 120.3, 103.9, 51.5,
J ¼ 9.0 Hz, 2H), 6.76 (d, J ¼ 9.0 Hz, 2H), 3.79 (s, 3H), 3.69 (s, 3H), 3.43
39.8 and 20.7; IR (neat) 1685 cmꢂ1; HRMS (ES, MþH) m/z calcd for
(q, J ¼ 6.0 Hz, 2H), 2.29 (s, 3H) and 0.96 (t, J ¼ 6.0 Hz, 3H); 13C NMR
C
18H19ClNO2 316.1099 found 316.1108.
(CDCl3, 75 MHz) d 170.4, 158.2, 145.0, 143.2, 133.9, 132.0, 129.5,
128.2, 121.8, 113.1, 104.1, 55.1, 51.4, 46.2, 20.7 and 13.5; IR (neat)
1688 cmꢂ1; HRMS (ES, MþH) m/z calcd for C20H24NO3 326.1751
found 326.1759.
4.1.55. 2-(4-Bromophenyl)-3-(methyl-p-tolylamino)acrylic acid
methyl ester (15d)
This compound was prepared by procedure 4.1.52 with the
exception that 2-(4-bromophenyl)-3-dimethyl-aminoacrylic acid
methyl ester was used in the reaction, in which case an 85% yield of
a yellow solid was obtained, which exhibited the following prop-
4.1.60. 2-(4-Methoxyphenyl)-3-[(4-methoxyphenyl)methylamino]
acrylic acid methyl ester (15i)
This compound was prepared by procedure 4.1.52 with the
exception that 4-methoxyphenyl N-methyl aniline was used in the
reaction, in which case a 91% yield of a yellow solid was obtained,
which exhibited the following properties: mp 112e114 ꢁC; 1H NMR
erties: mp 102e103 ꢁC; 1H NMR (CDCl3, 300 MHz)
d 7.95 (s, 1H),
7.39 (d, J ¼ 8.5 Hz, 2H), 7.06e7.11 (m, 4H), 6.96 (d, J ¼ 8.5 Hz, 2H),
3.71 (s, 3H), 2.93 (s, 3H) and 2.33 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d
169.6, 145.9, 144.6, 135.1, 134.1, 133.0, 130.6, 129.7, 120.5, 120.4,
(CDCl3; 300 MHz)
J ¼ 9.0 Hz, 2H), 6.81e6.84 (m, 4H), 3.83 (s, 3H), 3.80 (s, 3H), 3.70 (s,
d
7.87 (s, 1H), 7.12 (d, J ¼ 9.0 Hz, 2H), 7.01 (d,
103.9, 51.4, 40.0 and 20.6; IR (neat) 1685 cmꢂ1; HRMS (ES, MþH) m/
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

12
J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
3H) and 2.89 (s, 3H); 13C NMR (CDCl3; 75 MHz)
d
170.5, 158.3, 156.5,
(neat) 1615 cmꢂ1; HRMS (ES, MþH) m/z calcd for C17H15NOCl
145.9, 141.1, 132.4, 128.2, 121.9, 114.3, 113.0, 104.2, 55.6, 55.2, 51.4
284.0837 found 284.0839.
and 39.7; IR (neat) 1688 cmꢂ1; HRMS (ES, MþH) m/z calcd for
C
19H22NO4 328.1543 found 328.1542.
4.1.65. 3-(4-Bromophenyl)-1,6-dimethyl-1H-quinolin-4-one (16d)
This compound was prepared by procedure 4.1.62 with the
exception that 2-(4-bromophenyl)-3-(methyl-p-tolylamino)acrylic
acid methyl ester was used in the reaction, in which case a 92% yield
of a white solid was obtained, which exhibited the following
4.1.61. 3-[(4-Bromophenyl)methylamino]-2-(4-methoxyphenyl)
acrylic acid methyl ester (15j)
This compound was prepared by procedure 4.1.52 with the
exception that 4-bromophenyl N-methyl aniline was used in the
reaction, in which case a 78% yield of a yellow solid was obtained,
which exhibited the following properties: mp 112e114 ꢁC; 1H NMR
properties: mp 179e180 ꢁC; 1H NMR (CDCl3; 300 MHz)
d
8.36
(broad s, 1H), 7.67 (s, 1H), 7.51e7.60 (m, 5H), 7.34 (d, J ¼ 6.0 Hz, 1H),
3.86 (s, 3H) and 2.52 (s, 3H); 13C NMR (CDCl3; 75 MHz)
175.4,
d
(CDCl3; 300 MHz)
d
7.88 (s, 1H), 7.41 (d, J ¼ 8.8 Hz, 2H), 7.12 (d,
142.1, 138.1, 134.6, 133.9, 133.5,131.3, 130.2, 127.1, 126.9, 120.8, 120.3,
115.1, 40.7 and 21.0; IR (neat) 1614 cmꢂ1; HRMS (ES, MþH) m/z
calcd for C17H15NOBr 328.0332 found 328.0317.
J ¼ 8.8 Hz, 2H), 6.93 (d, J ¼ 8.8 Hz, 2H), 6.85 (d, J ¼ 8.8 Hz, 2H), 3.83
(s, 3H), 3.73 (s, 3H) and 2.89 (s, 3H); 13C NMR (CDCl3; 75 MHz)
d
169.9, 158.6, 146.0, 144.1, 132.1, 132.0, 127.7, 120.6, 116.1, 113.3,
107.8, 55.2, 51.6 and 38.5; IR (neat) 1687 cmꢂ1; HRMS (ES, MþH) m/
z calcd for C18H19NO3Br 376.0543 found 376.0557.
4.1.66. 3-(3,4-Dimethoxyphenyl)-1,6-dimethyl-1H-quinolin-4-one
(16e)
This compound was prepared by procedure 4.1.62 with the
exception that 2-(3,4-dimethoxyphenyl)-3-(methyl-p-tolylamino)
acrylic acid methyl ester. was used in the reaction, in which case an
88% yield of a yellow solid was obtained, which exhibited the
following properties: mp 157e159 ꢁC; 1H NMR (CDCl3; 300 MHz)
4.1.62. 1,6-Dimethyl-3-(4-Methoxyphenyl)-1H-quinolin-4-one
(16a)
To a round bottom flask, equipped with a glass stopper and a
magnetic stirring bar, was added 2-(4-methoxyphenyl)-3-(methyl-
p-tolylamino)acrylic acid methyl ester (0.400g, 0.00128 mol), triflic
anhydride (0.00256 mol) and anhydrous dichloromethane (20 mL).
The reaction mixture was allowed to stir overnight and the solvent
was removed in vacuo. To the crude residue was added 30 mL of a
50:50 mixture of THF and saturated aqueous sodium carbonate. The
crude reaction mixture was heated at reflux for one hour, cooled to
room temperature and water (20 mL) and ethyl acetate (15 mL)
were added to the mixture. The phases were separated and the
aqueous layer was extracted with additional ethyl acetate
(3 ꢀ 15 mL) followed by a brine (15 mL) extraction. The combined
organic phases were dried over anhydrous sodium sulfate and
concentrated in vacuo to yield an off white solid (0.297 g, 83% yield),
which exhibited the following properties: mp 154e156 ꢁC; 1H NMR
d
8.39 (d, J ¼ 3.0 Hz, 1H), 7.70 (s, 1H), 7.53 (dd, J ¼ 9.0, J ¼ 3.0 Hz, 1H),
7.48 (d, J ¼ 3.0 Hz, 1H), 7.35 (d, J ¼ 9.0 Hz, 1H), 7.12 (dd, J ¼ 9.0,
J ¼ 3.0 Hz, 1H), 6.94 (d, J ¼ 9.0 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.88
(s, 3H) and 2.52 (s, 3H); 13C NMR (CDCl3; 75 MHz)
d 175.8, 148.6,
148.18, 141.9, 138.0, 133.6, 133.3, 128.6, 127.0, 126.8, 121.2, 120.3,
115.0, 112.6, 111.2, 56.0, 40.6 and 20.9; IR (neat) 1572 cmꢂ1; HRMS
(ES, MþH) m/z calcd for C19H20NO3 310.1438 found 310.1440.
4.1.67. 1,6-Dimethyl-3-(3,4,5-trimethoxyphenyl)-1H-quinolin-4-
one (16f)
This compound was prepared by procedure 4.1.62 with the
exception
that
3-(methyl-p-tolylamino)-2-(3,4,5-trimethoxy-
phenyl)acrylic acid methyl ester was used in the reaction, in which
case an 83% yield of a yellow solid was obtained, which exhibited
the following properties: mp 210e211 ꢁC; 1H NMR (CDCl3;
(CDCl3;300 MHz)
d
8.38 (d, J ¼ 1.5 Hz, 1H), 7.66e7.62 (m, 3H), 7.52
(dd, J ¼ 8.6 Hz, J ¼ 1.5 Hz, 1H), 7.34 (d, J ¼ 8.6 Hz, 2H), 6.98 (d,
J ¼ 8.6 Hz, 2H), 3.86 (s, 6H) and 2.52 (s, 3H); 13C NMR (CDCl3;
300 MHz)
d
8.40 (d, J ¼ 3.0 Hz, 1H), 7.71 (s, 1H), 8.40 (dd, J ¼ 9.0,
75 MHz)
d
175.8, 158.7, 141.7, 138.1, 133.5, 133.3, 129.7, 128.1, 127.0,
J ¼ 3.0 Hz, 1H), 7.36 (d, J ¼ 9.0 Hz, 1 H), 6.96 (s, 2H), 3.93 (s, 6H), 3.90
126.9, 121.4, 114.9, 113.8, 55.3, 40.6 and 20.9; IR (neat) 1617 cmꢂ1
;
(s, 3H), 3.89 (s, 3H) and 2.52 (s, 3H); 13C NMR (CDCl3; 75 MHz)
HRMS (ES, MþH) m/z calcd for C18H18NO2 280.1332 found 280.1335.
d
175.6, 153.0, 142.2, 138.0, 137.3, 133.8, 133.5, 131.3, 127.1, 126.8,
121.3, 155.1, 106.1, 60.8, 56.2, 40.7 and 20.9; IR (neat) 1582 cmꢂ1
;
4.1.63. 1,6-Dimethyl -3-p-tolyl-1H-quinolin-4-one (16b)
HRMS (ES, MþH) m/z calcd for C20H22NO4 340.1543 found 340.1547.
This compound was prepared by procedure 4.1.62 with the
exception that 3-(methyl-p-tolylamino)-2-p-tolylacrylic acid
methyl ester was used in the reaction, in which case a 94% yield of a
white solid was obtained, which exhibited the following proper-
4.1.68. 1,6-dimethyl-3-phenyl-1H-quinolin-4-one (16g)
This compound was prepared by procedure 4.1.62 with the
exception that 3-(methyl-p-tolylamino)-2-phenylacrylic acid
methyl ester was used in the reaction, in which case a 92% yield of a
yellow solid was obtained, which exhibited the following proper-
ties: mp 160e163 ꢁC; 1H NMR (CDCl3; 300 MHz)
1H), 7.68 (s, 1H), 7.60 (d, J ¼ 6.0 Hz, 2H), 7.52 (dd, J ¼ 6.0 Hz,
J ¼ 1.5 Hz, 1 H), 7.33 (d, J ¼ 6.0 Hz, 1H), 7.25 (d, J ¼ 6.0 Hz, 2H), 3.86
(s, 3H), 2.52 (s, 3H) and 2.40 (s, 3H); 13C NMR (CDCl3; 75 MHz)
d
8.33 (d, J ¼ 1.5 Hz,
ties: mp 150e151 ꢁC; 1H NMR (CDCl3; 300 MHz)
d
1H NMR (CDCl3;
300 MHz)
J ¼ 2.0 Hz,1H), 7.43 (t, J ¼ 6.0 Hz, 2H), 7.32e7.37 (m, 2H), 3.87 (s, 3H)
and 2.52 (s, 3H); 13C NMR (CDCl3; 75 MHz)
175.7, 142.4, 138.0,
d
8.39 (broad s, 1H), 7.69e7.71 (m, 3H), 7.53 (dd, J ¼ 9.0,
d
175.7, 142.1, 138.0, 136.5, 133.4, 133.2, 132.7, 128.9, 128.4, 127.0,
126.8, 121.4, 115.1, 40.6, 21.2 and 20.9; IR (neat) 1614 cmꢂ1; HRMS
d
(ES, MþH) m/z calcd for C18H18NO 264.1383 found 264.1377.
135.7, 133.6, 133.3, 128.6, 128.2, 127.0, 126.8, 126.6, 121.3, 115.2, 40.6
and 21.0; IR (neat) 1609 cmꢂ1; HRMS (ES, MþH) m/z calcd for
4.1.64. 3-(4-Chlorophenyl)-1,6-dimethyl-1H-quinolin-4-one (16c)
This compound was prepared by procedure 4.1.62 with the
exception that 2-(4-chlorophenyl)-3-(methyl-p-tolylamino)acrylic
acid methyl ester was used in the reaction, in which case a 90% yield
of a white solid was obtained, which exhibited the following
C17H16NO 250.1226 found 250.1221.
4.1.69. 1-Ethyl-3-(4-methoxyphenyl)-6-methyl-1H-quinolin-4-one
(16h)
This compound was prepared by procedure 4.1.62 with the
properties: mp 173e174 ꢁC; 1H NMR (CDCl3; 300 MHz)
d
8.36 (d,
exception
that
3-(ethyl-p-tolylamino)-2-(4-methoxy-phenyl)
J ¼ 1.5 Hz, 1H), 7.66 (s. 1H), 7.63 (d, J ¼ 6.0 Hz, 2H), 7.53 (dd,
acrylic acid methyl ester was used in the reaction, in which case a
59% yield of a yellow oil was obtained, which exhibited the
following properties: bp 202 ꢁC @ 0.92 torr; 1H NMR (CDCl3;
J ¼ 6.0 Hz, J ¼ 1.5 Hz, 1H), 7.32e7.38 (m, 3H), 3.86 (s, 3H) and 2.51 (s,
3H); 13C NMR (CDCl3; 75 MHz)
d 175.4, 142.2, 138.0, 134.2, 133.8,
133.5, 132.4, 129.7, 128.2, 127.0, 126.6, 119.9, 115.2, 40.7 and 21.0; IR
300 MHz)
d
8.39 (d, J ¼ 2.0 Hz, 1H), 7.70 (s, 1H), 7.65 (d, J ¼ 9.0 Hz,
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078

J.T. Gupton et al. / Tetrahedron xxx (xxxx) xxx
13
2H), 7.50 (dd, J ¼ 9.0, J ¼ 2.0 Hz, 1H), 7.37 (d, J ¼ 9.0 Hz, 1H), 6.98 (d,
(CHE-0320669) are also gratefully acknowledged.
J ¼ 9.0 Hz, 2H), 4.24 (q, J ¼ 6.0 Hz, 2H), 3.86 (s, 3H), 2.51 (s, 3H) and
1.54 (t, J ¼ 6.0 Hz, 3H); 13C NMR (CDCl3; 75 MHz)
d 175.1, 158.7,
Appendix A. Supplementary data
140.6, 136.9, 133.2, 133.1, 129.7, 128.3, 127.4, 127.1, 121.5, 114.9, 113.7,
55.3, 48.0, 20.9 and 15.6; IR (neat) 1608 cmꢂ1; HRMS (ES, MþH) m/z
calcd for C19H20NO2 294.1489 found 294.1452.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2018.10.078.
4.1.70. 6-Methoxy-3-(4-methoxyphenyl)-1-methyl-1H-quinolin-4-
one (16i)
References
This compound was prepared by procedure 4.1.62 with the
exception
that
2-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-
[1] For some recent examples see: (a) X. Xu, M. Ratnikov, P. Zavalij, M. Doyle,
Org.Lett. 13 (2011) 6122;
methylamino]acrylic acid methyl ester was used in the reaction, in
which case a 74% yield of a pale yellow solid was obtained, which
exhibited the following properties: mp 158e160 ꢁC; 1H NMR
(b) X. Li, M. Chen, X. Xie, N. Sun, S. Li, Y. Liu, Org. Lett. 17 (2015) 2984;
(c) C. Kim, S. Park, D. Eom, B. Seo, P. Lee, Org. Lett. 16 (2014) 190;
(d) J. Zheng, L. Huang, C. Huang, W. Wu, H. Jiang, J. Org. Chem. 80 (2015) 1235;
(e) D. Kim, Y. Seo, C. Jun, Org. Lett. 17 (2015) 3842;
(CDCl3; 300 MHz)
d
7.98 (d, J ¼ 2.8 Hz,1H), 7.65 (d, J ¼ 9.0 Hz, 2H),
(f) X. Zhang, X. Xu, G. Chen, W. Yi, Org. Lett. 18 (2016) 4864;
(g) C. Bailly, Curr. Med. Chem. Anti Canc. Agents (2004) 363;
(h) J. Gupton, Pyrrole natural products with antitumor properties, in: M. Lee
(Ed.), Heterocyclic Antitumor Antibiotics: Topics in Heterocyclic Chemistry,
vol. 2, Springer-Verlag, Berlin/Heidelberg, 2006, pp. 53e92.
[2] For some recent examples see: (a) J. Wu, Y. Zhou, T. Wu, Y. Zhou, C.H. Chiang,
A. Lei, Org. Lett. 19 (2017) 6432;
7.64 (s, 1H), 7.37 (d, J ¼ 9.0 Hz, 1H), 7.29 (dd, J ¼ 9.0 Hz, J ¼ 2.8 Hz,
1H), 6.98 (d, J ¼ 9.0 Hz, 2H), 3.95 (s, 3H) and 3.85 (s, 6 H) 13C NMR
(CDCl3; 75 MHz) d 175.2,158.7, 156.4,141.2,134.6,129.7,128.3,128.1,
122.6120.1, 116.7, 113.7, 106.6, 55.8, 55.3 and 40.8; IR (neat)
1609 cmꢂ1; HRMS (ES, MþNa) m/z calcd for C18H17NO3Na 296.1281
found 296.1281.
(b) X. Xu, X. Zhang, Org. Lett. 19 (2017) 4984;
(c) J. Pinto, V. Silva, A.M.G. Silva, L. Santos, A.M.S. Silva, J. Org. Chem. 80 (2015)
6649;
4.1.71. 6-Bromo-3-(4-methoxyphenyl)-1-methyl-1H-quinolin-4-
one (16j)
This compound was prepared by procedure 4.1.62 with the
exception
methoxyphenyl)acrylic acid methyl ester was used in the reac-
tion, in which case a 78% yield of a yellow solid was obtained, which
exhibited the following properties: mp 195e197 ꢁC; 1H NMR
(d) T. Zhao, B. Xu, Org. Lett. 12 (2010) 212;
(e) A. Nilsen, G. Miley, I. Forquer, M. Mather, K. Katneni, Y. Li, S. Pou,
A. Pershing, A. Stickles, E. Ryan, J. Kelly, J. Doggett, K. White, D. Hinrichs,
R. Winter, S. Charman, L. Zakharov, I. Bathurst, J. Burrows, A. Vaidya, M. Riscoe,
J. Med. Chem. 57 (2014) 3818;
that
3-[(4-bromophenyl)methylamino]-
2-(4-
(f) X. Xu, R. Sun, S. Zhang, X. Zhang, W. Yi, Org. Lett. 20 (2018) 1893;
(g) R. Manetsch, R. Cross, J. Org. Chem. 75 (2010) 8654.
[3] C. Dialer, D. Imbri, S. Hansen, T. Opatz, J. Org. Chem. 80 (2015) 11605.
[4] X. Huang, X. Xiao, Y. Zhang, T. Talele, A. Salim, Z. Chen, R. Capon, Mar. Drugs 12
(2014) 3818.
[5] H. Lin, C. Dai, T. Jamison, K. Jensen, Angew. Chem. Int. Ed. 56 (2017) 8870.
[6] J. Maignan, C. Lichorowic, J. Giarusso, L. Blake, D. Casandra, T. Mutka,
A. LaCrude, J. Burrows, J. Willis, P. Willis, D. Kyle, R. Manetsch, J. Med. Chem.
59 (2016) 6943.
(CDCl3; 300 MHz)
d
8.58 (d, J ¼ 2.0 Hz, 1H), 7.63 (dd, J ¼ 9.0 Hz,
J ¼ 2.0 Hz,1H), 7.56 (s,1H), 7.54 (d, J ¼ 9.0 Hz, 2H), 7.20 (d, J ¼ 9.0 Hz,
1H), 6.90 (d, J ¼ 9.0 Hz, 2H) and 3.81 (s, 3H) and 3.75 (s, 3H); 13C
NMR (CDCl3; 75 MHz) d 174.5, 158.8, 142.2, 138.5, 134.6, 129.7, 129.5,
128.2, 127.4, 121.9, 117.3, 117.1, 113.7, 55.3 and 40.67; IR (neat)
1577 cmꢂ1; HRMS (ES, MþH) m/z calcd for C17H15NO2Br 344.0281
found 344.0284.
[7] G. Patrick, An Introduction to Medicinal Chemistry, fifth ed., Oxford Univ.
Press, Oxford, U.K., 2013, pp. 258e264. Ch. 14.
[8] J. Gupton, A. Shimozono, E. Crawford, J. Ortolani, E. Clark, M. Mahoney,
C. Heese, J. Noble, C. Perez Mandry, R. Kanters, R. Dominey, E. Goldman,
J. Sikorski, D. Fisher, Tetrahedron 74 (2018) 2650.
[9] H. Gim, H. Li, S. Jumg, Y. Park, J. Ryu, K. Chung, R. Jeon, Eur. J. Med. Chem. 85
(2014) 107.
Acknowledgements
[10] G. Jin, S. Ha, H. Park, B. Kang, S. Kim, H. Kim, J. Ryu, R. Jeon, Biorg. Med. Chem.
Lett. 18 (2008) 4092.
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. Pre-
vious grants from the MRI program of the National Science Foun-
dationn for the purchase of a 500 MHz NMR spectrometer (CHE-
0116492) and a high-resolution, electrospray mass spectrometer
[11] R. Abdulla, R. Brinkmeyer, Tetrahedron 35 (1979) 1675.
[12] J. Gupton, B. Giglio, J. Eaton, E. Rieck, K. Smith, M. Keough, P. Barelli, L. Firich,
J. Hempel, T. Smith, R. Kanters, Tetrahedron 65 (2009) 4283.
[13] For similar 3-acetoxy nitrogen heterocycles see E. Edstrom, T. Yu, Tetrahedron
35 (1994) 6985.
[14] For similar 3-aminopyrroles see; (a) M. Doyle, P. Truong, M. Mandler, Tetra-
hedron Lett 56 (2015) 3042;
(b) X. Lei, L. Li, Y.P. He, Y. Tang, Org. Lett. 17 (2015) 5224;
(c) Y. Wang, A. Lei, Y. Tang, Chem. Commun. 51 (2015) 4507.
Please cite this article as: J.T. Gupton et al., Application of vinylogous carbamates and vinylogous aminonitriles to the regiospecific synthesis of
uniquely functionalized pyrroles and quinolones, Tetrahedron, https://doi.org/10.1016/j.tet.2018.10.078