Synthesis and reactivity of 2-thionoester pyrroles: A route to 2-formyl pyrroles

Article abstract of DOI:10.1039/c9ra07527e

2-Functionalised pyrroles exhibit considerable synthetic utility. Herein, the synthesis and reactivity of 2-thionoester (-C(S)OR) pyrroles is reported. 2-Thionoester pyrroles were synthesised using a Knorr-type approach from aliphatic starting materials. 2-Thionoester pyrroles were reduced to the corresponding 2-formyl pyrroles, or the deuterated formyl variant, in one step using RANEY nickel, thereby removing the need for the much-utilised hydrolysis/decarboxylation/formylation steps that are typically required to convert Knorr-type 2-carboxylate pyrroles into 2-formyl pyrroles. 2-Thionoester pyrroles proved tolerant of typical functional group interconversions for which the parent 2-carboxylate pyrroles have become known.

Full text of DOI:10.1039/c9ra07527e

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Synthesis and reactivity of 2-thionoester pyrroles:
a route to 2-formyl pyrroles†
Cite this: RSC Adv., 2019, 9, 31773
Min Joon Kim, Sophie M. Gaube, Michael H. R. Beh, Craig D. Smith
*
and Alison Thompson
2-Functionalised pyrroles exhibit considerable synthetic utility. Herein, the synthesis and reactivity of 2-
thionoester (–C(S)OR) pyrroles is reported. 2-Thionoester pyrroles were synthesised using a Knorr-type
approach from aliphatic starting materials. 2-Thionoester pyrroles were reduced to the corresponding 2-
formyl pyrroles, or the deuterated formyl variant, in one step using RANEY® nickel, thereby removing the
need for the much-utilised hydrolysis/decarboxylation/formylation steps that are typically required to
convert Knorr-type 2-carboxylate pyrroles into 2-formyl pyrroles. 2-Thionoester pyrroles proved tolerant
of typical functional group interconversions for which the parent 2-carboxylate pyrroles have become
known.
Received 15th August 2019
Accepted 20th September 2019
DOI: 10.1039/c9ra07527e
rsc.li/rsc-advances
2-Formyl pyrroles are critical to the synthesis of (poly)pyrroles secondary metabolites in marine bacteria and plants.9,12,13 In
such as porphyrins and BODIPYs courtesy of their availability particular, we noticed a role for thiophilic reagents in the
from widely used Knorr-type syntheses, and their robust and reduction of 2-thioester pyrroles14–17 induced by RANEY®
reliable reactivity.1 However, attempts to reduce the 2-carbox- nickel.14,15,18
ylate functionality of Knorr-type pyrroles with H-DIBAL are
We thus explored the reactivity of 2-thionoester pyrroles with
unfruitful, which is unsurprising considering the doubly- RANEY® nickel, taking advantage of the availability of RANEY®
vinylogus carbamate character of the ester (Fig. 1, top). nickel as a slurry in water. O-Ethyl 2-thionoester pyrrole 1a,
Instead, transformation to 2-formyl pyrroles typically entails initially prepared via treatment of the corresponding 2-carbox-
hydrolysis of the 2-carboxylate functionality,2,3 followed by ylate pyrrole with Lawesson's reagent,9 was reacted with excess
decarboxylation and nally formylation.4–7 Alternatively, reduc- 2800 RANEY® nickel to provide the 2-formyl pyrrole 2a in 67%
tion of the 2-carboxylate functionality to the corresponding isolated yield (Table 1, entry 1). To commence the reaction,
alcohol, followed by oxidation back to the desired aldehyde,8 a slurry of RANEY® nickel in water and acetone was activated
also provides the requisite 2-formyl pyrrole. In addition to the via heating at reux temperature for an hour before 1a was
inevitably poor atom economy that results from such circui- added. Although the purpose of the activation step is unclear,
tousness, these reactions can be low yielding and necessitate
harsh conditions. The potential of utilising new reactivity at the
2-position of pyrroles opens new synthetic opportunities in
pyrrole chemistry that build on traditional approaches.9 Herein,
we report the one-step reduction of 2-thionoester pyrroles to
provide 2-formyl pyrroles, and explore the stability of 2-thio-
noester pyrroles under conditions typically used for the
synthetic manipulation of Knorr-type pyrroles.
2-Thionoester pyrroles, which bear the –C(S)OR functional
group at the 2-position, have not been studied in detail despite
the fact that thionoesters are more electrophilic compared to
the corresponding “all-oxygen ester” functional groups
(–CO2R).10,11 In contrast, 2-thioester pyrroles (–C(O)SR) have
been thoroughly evaluated as such species are common
Department of Chemistry, Dalhousie University, P. O. Box 15000, Halifax, NS, B3H
4R2, Canada. E-mail: Alison.Thompson@dal.ca
† Electronic supplementary information (ESI) available: Experimental details
Fig. 1 Conversion of Knorr-type pyrroles to 2-formyl pyrroles.
RSC Adv., 2019, 9, 31773–31780 | 31773
including synthetic procedures and NMR spectra. See DOI: 10.1039/c9ra07527e
This journal is © The Royal Society of Chemistry 2019

View Article Online
RSC Advances
Paper
Table 1 Reduction of 2-carboxylate pyrroles to 2-formyl pyrroles
using RANEY® nickel
avenues to try to understand the atom efficiency of the reaction,
as well as the source of the formyl hydrogen atom. First,
although we did not attempt to dry the pyrophoric reductant,
water from the commercially available RANEY® nickel slurry
was manually removed by pipette. Acetone was then added, and
the slurry shaken. Aer being allowed to settle, the liquid was
removed once again. This process was repeated several times so
as to produce a slurry of RANEY® nickel in wet acetone. The
reaction of pyrrole 1e with this acetone-based slurry resulted in
only trace amounts of 2e suggesting that the water within the
slurry is critical to the formation of the aldehyde. To investigate
whether deuterium27,28 could be introduced into the 2-formyl
moiety, a slurry of RANEY® nickel in D2O was prepared through
removal/addition as above, with the added sonication step aer
each addition. The solvent removal/addition and sonicator
wash cycle was repeated 10 times to ensure efficient exchange.
Reaction of the deuterated slurry with pyrrole 1e, in acetone,
resulted in formation of the deuterated aldehyde i.e. R–C(O)D,
2e0 in moderate yield (Table 1, entry 6). Interestingly, without
the use of sonication a 3 : 1 mixture of the deuterated and
undeuterated aldehydes was recovered, again indicating the
critical role of the slurry water to the reductive capability of the
RANEY® nickel.
Entry
Substrate
R1
R2
Yield of 2 (%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
–H
–Me
–Et
–Ph
Et
Et
Et
Et
67
52
63
45
–C(O)CH3
–Me
–(CH2)4CH3
–(CH2)2C(O)OCH3
Et
44b (46c)
45d
70
Bn
Bn
Bn
1g
1h
12
a
b
c
Isolated yield. 15% starting material recovered. Deuterated 2e0
using RANEY® nickel in D2O slurry. d Expected product is 2b.
this procedure is documented alongside the success of W2
RANEY® nickel in the desulfurisation of a 2-thioester pyrrole.19
We found that this activation step was essential for success of
our desired reduction using currently commercially available
2800 RANEY® nickel, which is different from W2 RANEY®
nickel. Aer the starting material has been fully consumed, the
reaction mixture was ltered through a short pad of silica to
remove the spent RANEY® nickel and thus enable isolation of
the desired aldehyde. Execution of the reaction under an
atmosphere of hydrogen did not improve the yield,18,20–22 sup-
porting the synergy of the thiophilicity and hydride content of
the RANEY® nickel, and we were unable to reduce the stoichi-
ometry without signicant detriment to yield (see ESI†). Simi-
larly, dissolution of the substrate in acetone was key to success,
as the use of other water-miscible solvents (methanol, ethanol,
tetrahydrofuran and isopropanol),23 all previously reported as
suitable for reactions involving RANEY® nickel, resulted only in
isolation of starting material. Furthermore, treatment of 1a with
nickel boride returned only starting material.24
Although yields were moderate (Table 1), the one-step
desulfurative reduction of 2-thionoester pyrroles to 2-formyl
pyrroles is more streamlined than the common hydrolysis/
decarboxylation/formylation route shown in Fig. 1. The one-
step synthesis of 2-formyl pyrroles from O-ethyl 2-thionoester
pyrroles in reasonable yield was successful for substrates
bearing unsubstituted positions (1a, Table 1, entry 1) as well as
those with alkyl (entries 2 and 3) and aryl (entry 4) substituents.
Similarly, the incorporation of a conjugated keto-substituent
was tolerated (entry 5). The reduction of O-benzyl 2-thio-
noester pyrroles was also successful (entries 6–9). Long-chain
substituents were tolerated (entry 7), but incorporation of an
alkyl ester functionality served to reduce the efficacy of the
desired thionoester reduction using RANEY® nickel (entry 8).
Although a complete mechanism for desulfurisation by
RANEY® nickel remains unclear,25,26 we explored a number of
The manner by which RANEY® nickel effects desulfurative
reduction has been long debated.25,26,29 Assuming a radical
mechanism, we used two radical clocks/traps in the hopes of
intercepting radical intermediate species (Fig. 2).30,31 However,
in neither case was trapping observed with reduction of 1a
serving to return the 2-formyl pyrrole 2a (50–60% yield) no
matter whether large excess of a cyclopropane were present or
not. However, in light of the large excess of RANEY® nickel
used, we maintain that a radical mechanism is most likely for
the reduction. In contrast, reaction of 1a with RANEY® nickel in
the presence of 50 eq. TEMPO resulted in the isolation of only
7% 2a. However, no trapped products could be identied via
either mass spectrometry or NMR spectroscopy.32,33
With the one-step reduction to form 2-formyl pyrroles in
hand, we sought a practical synthesis of 2-thionoester pyrroles
that did not entail thionation of 2-carboxylate pyrroles. We thus
turned our attention to the preparation of 2-thionoester
pyrroles from aliphatic materials, modelling the Knorr
synthesis by incorporation of thionoester functionality. Reac-
tion of potassium ethyl xanthogenate and chloroacetone,
following modied literature methods,34,35 gave 3 (Scheme 1),
and then extrusion of sulfur produced the desired acetothioa-
cetate 4. Treatment with sodium nitrite gave the oxime 5, which
could be isolated and characterised although the typical
procedure entailed treating the crude material with 2,4-penta-
nedione and zinc powder to provide O-ethyl 2-thionoester
Fig. 2 Cyclopropane radical clocks and TEMPO.
31774 | RSC Adv., 2019, 9, 31773–31780
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
treatment of 1e with borane cleanly reduced the acyl group to
give the corresponding ethyl derivative 1c, no matter whether
borane were generated in situ (Method A) or used as reagent
(Method B). 2-Thionoester 1c mirrored the reactivity of 2-
carboxylate pyrroles in the preparation of dipyrrins, thereby
providing 7. Similarly, treatment of 1e with base effected
hydrolysis and decarboxylation to give 8, and treatment with
acid resulted in deacylation to render 1a. However, reaction of
pyrrole 1e with CAN or Pb(OAc)4 returned the corresponding
ester (–CO2R) with no sign of the desired oxidation of the 5-
methyl group, clearly presenting a limitation as none of the
desired 5-formyl species was produced.
Scheme 1 Knorr-type synthesis of o-ethyl 2-thionoester pyrrole.
In conclusion, an alternative route to 2-formyl pyrroles has
been achieved via development of a modied Knorr procedure
to produce 2-thionoester pyrroles, followed by the use of
RANEY® nickel to promote reduction of the thionoester moiety
to an aldehyde. The tolerance and utility of 2-thionoester
pyrroles in reactions that are in widespread use within dipyrrin
and porphyrin chemistry were investigated. Given the circui-
tousness nature of the synthesis of 2-formyl pyrroles of this
genre and for these applications, the synthesis and use of 2-
thioester pyrroles is presented as a viable alternative to the
specialised manipulation of traditional Knorr-type 2-carbox-
ylate pyrroles.
pyrrole 1e. As with traditional Knorr-type syntheses,36 by-
products accompanied the desired pyrrole: 6 is the ester
(–CO2R) variant of 1e; and 1a is produced as a consequence of
deacylation. As such, the basic Knorr conditions were modied
using various stoichiometries of sodium carbonate, tripotas-
sium phosphate and sodium acetate salts to assert that the use
of sodium carbonate resulted in the highest yield (33%) of the
desired 2-thionoester pyrrole 1e. Cognisant that a Knorr-type
synthesis of 2-carboxylate pyrroles yields 30–60% of the
desired product on the same scale, this synthetic approach to 2-
thionoester pyrroles is in keeping with the most prevalent of the
routes to functionalised pyrroles.37,38 The corresponding benzyl
Experimental section
General information
thionoester pyrrole was synthesised following
a similar
approach, but originating with the reaction of CS2 with benzyl
alcohol in the presence of potassium hydroxide to produce the
required potassium O-benzyl carbonodithioate starting
material.
In order to probe the utility of 2-thionoester pyrroles beyond
their conversion to 2-formyl pyrroles, we explored the potential
of 1e as a substrate for the most common reactions that utilise
2-carboxylate pyrrole analogues. As shown in Scheme 2,
˚
Anhydrous solvents, silica 40–63 mm 60 A and reagents were
purchased and used as received. NMR spectra were obtained
using 300 or 500 MHz instruments using CDCl3 or DMSO as
solvents and are reported in part per million (ppm). Internal
1
solvents were referenced at 7.26 ppm for H and at 77.16 ppm
1
for 13C when using CDCl3, and at 2.50 ppm for H when using
DMSO-d6. Coupling constants (J) are given in Hertz (Hz). Mass
spectra were obtained using a time-of-ight ion trap instrument
Scheme 2 Reactions of 2-thionoester pyrrole 1e.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 31773–31780 | 31775

View Article Online
RSC Advances
Paper
operating in ESI+/ꢀ mode. Flash chromatography was per-
formed using Silicycle ultra-pure silica (230–400 mm). Pyrroles
1a, 1b, 1e, and 1f were prepared according to literature proce-
dure involving Lawesson's reagent.9 Compound 3 was prepared
according to the literature method.39 RANEY® nickel used
was W. R. Grace Grade 2800 (CAS# 7440-02-0), purchased in the
form of a slurry in water with the nickel composition stated as
equal to or greater than 89%. Before each use, the bottle con-
taining the RANEY® nickel slurry was thoroughly shaken before
aliquots were drawn out quickly with a pipette in order to enable
efficient transfer of the slurried material to a reaction ask.
General procedure for synthesising 2-formyl pyrroles from 2-
thionoester pyrroles (GP1)
Slurried RANEY® nickel (2 mL containing water and RANEY®
nickel) was suspended in acetone, and the mixture was heated
at reux temperature for 1 hour. 2-Thionoester pyrrole 1 (0.47
mmol) was dissolved in acetone (10 mL), and the resulting
solution was added to the reaction mixture containing RANEY®
nickel in acetone held at reux temperature. The reaction
mixture was heated at reux temperature for 2 hours, with
stirring under nitrogen gas. Analysis using thin layer chroma-
tography showed the complete consumption of starting mate-
rial and the appearance of the product at lower Rf. The reaction
mixture was allowed to cool to room temperature and then
ltered through a short pad of silica, washing with acetone (500
mL). The ltrate was concentrated under vacuum, diluted with
ethyl acetate and washed with brine. The organic layer was then
dried using anhydrous sodium sulfate, and the solvent was
removed through use of a rotary evaporator to yield a dark
greenish brown solid. The crude product was puried via
column chromatography over silica, eluting with 40% ethyl
acetate/hexanes.
O-Ethyl 4-ethyl-3,5-dimethyl-1H-pyrrole-2-carbothioate (1c)
According to the literature method,40 the title compound was
obtained as a yellow solid (0.63 g, 60%). Mp 66–68 ꢁC; 1H-NMR
(500 MHz, CDCl3): d 9.08 (broad s, 1H), 4.66 (q, 2H, J ¼ 7.0 Hz),
2.36 (q, 2H, J ¼ 7.5 Hz), 2.27 (s, 3H), 2.21 (s, 3H), 1.46 (t, 3H, J ¼
7.0 Hz), 1.04 (t, 3H, J ¼ 7.5 Hz); 13C NMR (125 MHz, CDCl3):
d 199.5, 134.2, 128.7, 126.0, 66.5, 17.2, 15.4, 14.3, 12.0, 11.9, one
carbon signal missing; HRMS-ESI (m/z): [M + Na]+ calculated for
C
11H17NNaOS, 234.0923; found 234.0931.
General procedure for radical studies (GP2)
O-Ethyl 3,5-dimethyl-4-phenyl-1H-pyrrole-2-carbothioate (1d)
According to the literature method,40 the title compound was
obtained as a yellow solid (0.76 g, 39%). Mp 89–92 ꢁC; 1H-NMR
(300 MHz, CDCl3): d 9.31 (broad s, 1H), 7.39–7.45 (m, 2H), 7.29–
7.34 (m, 1H), 7.22–7.25 (m, 2H), 4.71 (q, 2H, J ¼ 6.9 Hz), 2.30 (s,
3H), 2.26 (s, 3H), 1.49 (t, 3H, J ¼ 6.9 Hz); 13C NMR (125 MHz,
CDCl3): d 200.0, 134.5, 134.3, 130.2, 129.0, 128.4, 126.6, 124.8,
66.8, 14.3, 12.9, 12.5, one carbon signal missing; HRMS-ESI (m/
z): [M + Na]+ calculated for C15H17NNaOS, 282.0923; found
282.0923.
Following GP1, the radical clock or TEMPO was added along
with 2-thionoester pyrrole 1a. Each reaction was run in parallel
with a reference reaction prepared by GP1 using the same batch
of RANEY® nickel. Cyclopropyl phenyl ketone: 500 equiva-
lencies of the radical clock were added with 1a, and the product
2a was isolated in 55% (in absence of a radical clock: 53%).
Diethyl cyclopropane-1,1-dicarboxylate: 200 equivalencies of the
radical clock were added with 1a, and the product 2a was iso-
lated in 64% (in absence of a radical clock: 58%). TEMPO: 50
equivalencies of TEMPO were added with 1a, and the product 2a
was isolated in 7% (in absence of a radical trap: 37%).
O-Benzyl 3,5-dimethyl-4-pentyl-1H-pyrrole-2-carbothioate (1g)
According to the literature method,40 the title compound was
obtained as a yellow oil (0.53 g, 50%). 1H-NMR (300 MHz,
CDCl3): d 9.13 (broad s, 1H), 7.35–7.49 (m, 5H), 5.70 (s, 2H), 2.34
(t, 2H, J ¼ 7.2 Hz), 2.24 (s, 3H), 2.22 (s, 3H), 1.42 (quin., 2H, J ¼
7.2 Hz), 1.28–1.35 (m, 4H), 0.91 (t, 3H, J ¼ 7.2 Hz); 13C NMR (125
MHz, CDCl3): d 198.7, 136.2, 135.0, 129.1, 128.6, 128.4, 128.2,
127.0, 124.7, 72.0, 31.7, 30.5, 23.9, 22.7, 14.2, 12.4, 12.0; HRMS-
ESI (m/z): [M + Na]+ calculated for C19H25NNaOS, 338.1549;
found 338.1545.
2-Formyl-3,5-dimethylpyrrole (2a)
Following GP1, the title compound was obtained as a beige solid
(67%). Mp 87–88 ꢁC; 1H-NMR (300 MHz, CDCl3): d 10.16
(broad s, 1H), 9.43 (s, 1H), 5.82 (m, 1H), 2.29 (s, 3H), 2.27 (s, 3H);
13C NMR (125 MHz, CDCl3): d 176.0, 138.7, 134.9, 128.9, 112.1,
13.3, 10.7; HRMS-ESI (m/z): [M + Na]+ calculated for C7H9NNaO,
146.0576; found 146.0576.
2-Formyl-3,4,5-trimethylpyrrole (2b) from 1b
Following GP1, the title compound was obtained as a beige solid
(52%). Mp 142–145 ꢁC; 1H-NMR (300 MHz, CDCl3): d 9.99
(broad s, 1H), 9.44 (s, 1H), 2.24 (s, 6H), 1.91 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 175.6, 136.2, 132.9, 127.9, 118.3, 11.7, 9.0,
8.5; HRMS-ESI (m/z): [M + Na]+ calculated for C8H11NNaO,
160.0733; found 160.0731.
O-Benzyl 3,5-dimethyl-4-methylpropionic-1H-pyrrole-2-
carbothioate (1h)
According to the literature method,40 the title compound was
obtained as a yellow solid (0.45 g, 43%). Mp 98–100 ꢁC; 1H-NMR
(500 MHz, CDCl3): d 9.11 (broad s, 1H), 7.33–7.45 (m, 5H), 5.67
(s, 2H), 3.65 (s, 3H), 2.69 (t, 2H, J ¼ 7.5 Hz), 2.41 (t, 2H, J ¼ 7.5
Hz), 2.23 (s, 3H), 2.23 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 198.9, 173.4, 136.1, 135.0, 128.6, 128.4, 128.3, 126.1, 122.2,
4-Ethyl-2-formyl-3,5-dimethylpyrrole (2c)
72.2, 51.7, 34.8, 19.5, 12.3, 11.9, one carbon signal missing; Following GP1, the title compound was obtained as a beige solid
HRMS-ESI (m/z): [M + Na]+ calculated for C18H21NNaO3S, (63%). Mp 98–100 ꢁC; 1H-NMR (300 MHz, CDCl3): d 10.03
354.1134; found 354.1127.
(broad s, 1H), 9.45 (s, 1H), 2.38 (q, 2H, J ¼ 7.5 Hz), 2.27 (s, 3H),
31776 | RSC Adv., 2019, 9, 31773–31780
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
2.26 (s, 3H), 1.06 (t, 3H, J ¼ 7.5 Hz); 13C NMR (125 MHz, CDCl3): (br s, 1H), 9.45 (s, 1H), 3.66 (s, 3H), 2.72 (t, 2H, J ¼ 7.0 Hz), 2.44
d 175.8, 136.0, 132.4, 128.1, 125.1, 17.2, 15.3, 11.7, 9.0; HRMS- (t, 2H, J ¼ 7.5 Hz), 2.27 (s, 3H), 2.26 (s, 3H); 13C NMR (125 MHz,
ESI (m/z): [M + Na]+ calculated for C9H13NNaO, 174.0889; CDCl3): d 176.0, 173.4, 135.9, 132.3, 128.1, 121.1, 51.8, 34.7,
found 174.0889.
19.4, 11.7, 8.9; HRMS-ESI (m/z): [M + Na]+ calculated for
11H15NNaO3, 232.0944; found 232.0946.
C
2-Formyl-3,5,-dimethyl-4-phenylpyrrole (2d)
O-Ethyl acetothioacetate (4)
Following GP1, the title compound was obtained as a beige solid
1
ꢁ
(45%). Mp 148–150 C; H-NMR (300 MHz, DMSO-d6): d 11.77 The title compound was synthesised following a modied
(br s, 1H), 9.56 (s, 1H), 7.39–7.44 (t, 2H), 7.25–7.31 (m, 3H), 2.25 literature procedure.34 A solution of S-acetonyl O-ethyl dithio-
(s, 3H), 2.21 (s, 3H); 13C NMR (125 MHz, CDCl3): d 176.6, 135.6, carbonate 3 39 (31.4 g, 176 mmol) in anhydrous Et2O (70 mL)
134.3, 131.7, 130.0, 128.5, 128.4, 126.7, 125.6, 12.4, 9.6; HRMS- was added drop-wise over 20 minutes to a suspension of NaH
ESI (m/z): [M + Na]+ calculated for C13H13NNaO, 222.0889; found (60% in oil, 10.7 g, 268 mmol) in anhydrous Et2O (350 mL) at
222.0887.
10 ꢁC, with stirring under nitrogen. Aer 10 minutes, the
mixture was poured into aqueous K2HPO4 solution (0.91 M, 390
mL) and stirred. The ethereal layer was separated and the
aqueous layer was extracted with Et2O (3 ꢂ 200 mL). The
combined organic extracts were washed with brine (300 mL),
dried over anhydrous MgSO4 and concentrated in vacuo. The
crude product was puried via fractional vacuum distillation
(heated at 140–150 ꢁC), using a water-fed aspirator (ꢃ25–60
mmHg), and the desired product was collected at 84 ꢁC as
a yellow liquid (14.1 g, 55%). The product was present in both
enol and keto forms with an approximate 3 : 1 enol–keto ratio,
according to the 1H NMR spectrum. 1H-NMR (300 MHz, CDCl3):
d 13.75 (s, 1H), 5.67 (s, 1H), 4.54 (q, J ¼ 7.1 Hz, 0.7H), 4.47 (q, J ¼
7.1 Hz, 2H), 3.89 (s, 0.7H), 2.26 (s, 1H), 2.03 (s, 3H), 1.41 (t, J ¼
7.1 Hz, 1H), 1.38 (t, J ¼ 7.1 Hz, 3H), in accordance with litera-
ture.34 However, the literature34 reports a 4 : 1 enol–keto ratio.
4-Acetyl-2-formyl-3,5-dimethylpyrrole (2e)
Following GP1, the title was compound was prepared as a beige
solid (44%). Mp 168–170 ꢁC; 1H-NMR (300 MHz, CDCl3): d 9.89
(br s, 1H), 9.65 (s, 1H), 2.58 (s, 3H), 2.57 (s, 3H), 2.46 (s, 3H); 13
C
NMR (125 MHz, CDCl3): d 195.0, 177.7, 142.6, 134.2, 128.4,
123.9, 31.4, 15.4, 11.5; HRMS-ESI (m/z): [M + Na]+ calculated for
C9H11NNaO2, 188.0682; found 188.0681.
4-Acetyl-2-formyl-d-3,5-dimethylpyrrole (2e0)
To a slurry of RANEY® nickel (2 mL containing water and
RANEY® nickel), deuterium oxide (5 mL portion) was added.
The reaction vessel was stirred and sonicated at room temper-
ature for 30 seconds, and the solvent was decanted. The
exchange/wash cycle was repeated 10 times. Aer a nal wash,
deuterium oxide (2 mL) and acetone (10 mL) were added. GP1
was followed to obtain the title compound as a beige solid
(46%). Mp 1H-NMR (300 MHz, CDCl3): d 9.69 (br s, 1H), 2.58 (s,
3H), 2.57 (s, 3H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 195.0, 177.4 (t), 142.6, 134.2, 128.3, 123.9, 31.4, 15.5, 11.6;
HRMS-ESI (m/z): [M + Na]+ calculated for C9H10DNNaO2,
189.0745; found 189.0736.
O-Ethyl 2-oximinoacetothioacetate (5)
The title compound was synthesised following a modied
literature procedure.41 The resulting product mixture was
poured into distilled water (25 mL) and extracted into CH2Cl2 (3
ꢂ 10 mL). The combined organic fractions were washed with
saturated NaHCO3, dried over anhydrous sodium sulfate and
concentrated in vacuo to yield the product as a bright yellow
solid (277 mg, 23%). Mp 75–77 ꢁC; 1H-NMR (300 MHz, CDCl3):
d 8.13 (s, 1H), 4.66 (q, J ¼ 7.1 Hz, 2H), 2.42 (s, 3H), 1.45 (t, J ¼
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 204.6, 193.5, 155.0,
68.5, 26.0, 13.6; HRMS-ESI (m/z): [M + Na]+ calculated for C6-
H9NO3SNa, 198.0195; found 198.0189.
2-Formyl-3,5-dimethylpyrrole (2b) from 1f
Following GP1, the title compound was prepared (45%). 1H-
NMR (300 MHz, CDCl3): d 9.86 (broad s, 1H), 9.42 (s, 1H), 2.23
(s, 6H), 1.91 (s, 3H) matching the data given above for this
compound.
O-Ethyl 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carbothioate (1e)
2-Formyl-3,5-dimethyl-4-pentylpyrrole (2g)
The title compound was synthesised following a modied
literature procedure typically used for Knorr-type synthesis of 2-
carboxylate pyrroles.41 A solution of sodium nitrite (530 mg, 7.67
mmol) in distilled water (1.9 mL) was added drop-wise to
a solution of O-ethyl acetothioacetate (4) (1.02 g, 6.98 mmol) in
AcOH (1.6 mL) at 0 ꢁC. The reaction mixture was stirred at room
temperature and monitored via thin layer chromatography until
the starting material was consumed. Aer 45 minutes, the
resulting mixture containing crude O-ethyl 2-oximinoaceto-
thioacetate (5) was transferred to a dropping funnel and added
drop-wise to a slurry of 2,4-pentanedione (0.71 mL, 6.98 mmol),
Following GP1, the title compound was obtained as a beige solid
1
ꢁ
(70%). Mp 70–71 C; H-NMR (300 MHz, CDCl3): d 9.87 (br s,
1H), 9.47 (s, 1H), 2.37 (t, 2H, J ¼ 7.5 Hz), 2.28 (s, 3H), 2.27 (s,
3H), 1.45 (quin., 2H, J ¼ 7.5. Hz), 1.28–1.38 (m, 4H), 0.92 (t, 3H, J
¼ 7.0 Hz); 13C NMR (125 MHz, CDCl3): d 175.8, 135.6, 132.3,
128.0, 123.6, 31.8, 30.4, 23.9, 22.7, 14.2, 11.8, 9.0; HRMS-ESI (m/
z): [M + Na]+ calculated for C12H19NNaO, 216.1359; found
216.1362.
2-Formyl-3,5-dimethyl-4-methylpropionic pyrrole (2h)
Following GP1, the title was compound was obtained as a beige Na2CO3 (1.63 g, 15.3 mmol) and AcOH (10 mL). At the same
solid (12%). Mp 128–129 ꢁC; 1H-NMR (500 MHz, CDCl3): d 9.82 time, Zn dust (0.958 g, 14.6 mmol) was slowly added to the
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 31773–31780 | 31777

View Article Online
RSC Advances
Paper
slurry. The rate of addition and an ice-bath were used to keep combined organic fractions were washed with saturadted
ꢁ
the temperature below 30 C. Aer the addition was complete, NaHCO3 (10 mL) and brine (10 mL), dried over anhydrous
the reaction mixture was stirred at room temperature and Na2SO4 and concentrated in vacuo. The crude mixture was
monitored via thin layer chromatography. Aer 30 minutes the puried via column chromatography on silica, eluting with 3%
resulting mixture was poured into distilled water (150 mL) and EtOAc/hexanes to afford the desired product as a crystalline
then ltered through Celite, washing with CH2Cl2 until the yellow solid (325 mg, 61%). Characterisation data matched that
washings were colorless.40 The ltrate was extracted with provided above.
CH2Cl2 (3 ꢂ 100 mL). The combined organic fractions were
washed with saturated NaHCO3 (150 mL) and brine (150 mL),
then dried over anhydrous Na2SO4 and the solvent evaporated in
vacuo. The resulting residue was puried via column chroma-
tography on silica, eluting with a gradient of 5–20% EtOAc/
hexanes, yielding the desired product as a yellow solid (0.53 g,
1,3,7,9-Tetramethyl-2,8-diethyl-5-H-4,6-dipyrrin
hydrobromide (7)
Pyrrole 1c (64 mg, 0.3 mmol) was added to formic acid (0.29 mL)
and the resulting mixture heated to reux temperature before
HBr (0.096 mL, 0.84 mmol) was added. The reaction mixture
was stirred for an hour at reux temperature. Then, the mixture
was allowed to cool down to room temperature and was kept in
the fridge for 2 days. The precipitate was collected and washed
1
ꢁ
33%). Mp 109–111 C; H-NMR (500 MHz, CDCl3): d 9.41 (br s,
1H), 4.68 (q, J ¼ 7.1 Hz, 2H), 2.58 (s, 3H), 2.52 (s, 3H), 2.45 (s,
3H), 1.49 (t, J ¼ 7.1 Hz, 3H), in accordance with literature.9
1
with ether to obtain a red-orange solid (49 mg, 49%). H-NMR
(300 MHz, CDCl3): d 12.92 (br s, 2H), 7.02 (s, 1H), 2.66 (s, 6H),
3-Acetyl-2,4-dimethyl-1H-pyrrole (8) from 1e
To a solution of ground KOH (252 mg, 4.50 mmol) in ethylene 2.42 (q, J ¼ 7.6 Hz, 4H), 2.26 (s, 6H), 1.07 (t, J ¼ 7.6 Hz, 6H), in
glycol (1.6 mL) was added 1e (507 mg, 2.25 mmol). The reaction accordance with literature.42
ꢁ
mixture was heated at 160 C, with stirring, for 1 hour, moni-
toring via thin layer chromatography (40% EtOAc/hexanes).
Water (5 mL) was then added and the mixture was extracted
into CH2Cl2 (3 ꢂ 5 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo to yield the
desired product as an off-white solid (269 mg, 87%). H-NMR
(500 MHz, CDCl3): d 7.93 (br s, 1H), 6.36 (s, 1H), 2.50 (s, 3H),
2.42 (s, 3H), 2.27 (s, 3H), in accordance with literature.41
O-Ethyl 3,5-dimethyl-1H-pyrrole-2-carbothioate (1a) from 1e
The title compound was synthesised following a modied
literature procedure.43 Ethylene glycol (1.5 mL), para-toluene
sulfonic acid (16 mg, 0.08 mmol) and 1e (174 mg, 0.77 mmol)
were added to a 2 mL microwave vial equipped with a stir bar.
The vial was sealed and the mixture was pre-stirred for 1 minute
then heated for 2 minutes at 100 ꢁC in a laboratory microwave.
Once allowed to cool to room temperature, the vial was
unsealed. Water (5 mL) was added and the mixture was
extracted into CH2Cl2 (3 ꢂ 5 mL). The combined organic frac-
1
O-Ethyl 4-ethyl-3,5-dimethyl-1H-pyrrole-2-carbothioate (1c)
from 1e
ꢁ
Method 1. To a cooled solution (ꢀ10 C ice per salt) of 1e tions were dried over anhydrous Na2SO4 and then concentrated
(496 mg, 2.20 mmol) in THF (4 mL) was added NaBH4 (184 mg, in vacuo. The crude mixture was puried via column chroma-
4.40 mmol), and then BF3$OEt2 (750 mL). The resulting mixture tography on silica, eluting with 5% EtOAc/hexanes to yield the
1
was stirred for 50 minutes at ꢀ10 ꢁC, monitoring usingꢁ TLC desired product as a yellow solid (95 mg, 67%). H-NMR (300
(20% EtOAc/hexanes). 0.5 M HCl (5 mL) was added at 0 C to MHz, CDCl3): d 9.09 (br s, 1H), 5.85 (s, 1H), 4.65 (q, J ¼ 7.1 Hz,
quench the reaction. Water (10 mL) was added and the mixture 2H), 2.30 (s, 3H), 2.25 (s, 3H), 1.46 (t, J ¼ 7.1 Hz, 3H), in
was extracted into Et2O (3 ꢂ 10 mL). The combined organic accordance with literature.9
fractions were washed with brine (15 mL), dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude mixture was
puried via column chromatography on silica, eluting with 5%
EtOAc/hexanes to yield the desired product as a crystalline
yellow solid (388 mg, 83%). Mp 63–64 C; H-NMR (500 MHz,
CDCl3): d 9.07 (br s, 1H), 4.66 (q, J ¼ 7.1 Hz, 2H), 2.37 (q, J ¼
7.6 Hz, 2H), 2.26 (s, 3H), 2.21 (s, 3H), 1.46 (t, J ¼ 7.1 Hz, 3H), 1.04
(t, J ¼ 7.6 Hz, 3H); 13C-NMR{1H} (125 MHz, CDCl3): d 199.5,
134.2, 128.7, 125.9, 122.1, 66.5, 17.2, 15.3, 14.3, 12.0, 11.8;
HRMS-ESI (m/z): [M + Na]+ calculated for C11H17NOSNa,
234.0923; found 234.0914.
Potassium O-benzyl carbonodithioate
The title compound was synthesised following a modied
literature procedure.25 Carbon disulde (17.4 mL, 289 mmol)
and benzyl alcohol (25 mL, 242 mmol) were added to
a suspension of KOH (13.5 g, 242 mmol) in diethyl ether (375
mL). The suspension was stirred at room temperature for 3
hours. The product was collected via suction ltration and
washed with Et2O to yield the desired product as a pale yellow
1
ꢁ
1
solid (34.3 g, 64%). H-NMR (300 MHz, DMSO-d6): d 7.35–7.27
(m, 5H), 5.33 (s, 2H), in accordance with literature.35
Method 2. 1 M BH3$THF (1.9 mL, 1.9 mmol) was added drop-
wiꢁse to a solution of 1e (569 mg, 2.52 mmol) in THF (18 mL) at
0 C, under nitrogen. The reaction mixture was stirred for 18
O-Benzyl acetothioacetate
hours, then quenched by slowly adding distilled water (2 mL), The title compound was synthesised following a modied litera-
5% aq. HCl (10 mL), and stirring for a further 30 minutes at ture procedure.39 A solution of chloroacetone (5.4 mL, 67.4 mmol)
room temperature. Saturated NaCl (10 mL) was added, and the in acetone (34 mL) was added drop-wise to a solution of potassium
resulting mixture was extracted into EtOAc (3 ꢂ 10 mL). The O-benzyl carbonodithioate in acetone (84 mL) at 0 ꢁC over a period
31778 | RSC Adv., 2019, 9, 31773–31780
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
of 10 minutes with stirring. Aer 1 hour, the solvent was removed
in vacuo. The resulting mixture containing S-acetonyl O-benzyl
dithiocarbonate was dissolved in dry Et2O (27 mL) and was added
drop-wise over 20 minutes to a suspension of NaH (60% in oil,
Acknowledgements
This work was supported by the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) courtesy of
a Discovery Grant (AT) and the CREATE Training Program in
BioActives (510963). NSERC (MJK, MHRB), Nova Scotia Grad-
uate (MJK, MHRB) and Laing Undergraduate Research Award
(SMG) scholarships are acknowledged.
ꢁ
3.2 g, 81.0 mmol) in dry Et2O (135 mL) under nitrogen at 10 C.
Aer 10 minutes, the reaction mixture was poured into aqueous
KH2PO4 solution (1.2 M, 200 mL) and stirred at room temperature.
The ethereal layer was separated and the aqueous layer was
extracted with ether (3 ꢂ 100 mL). The combined organic fractions
were washed with brine (150 mL), dried with anhydrous MgSO4
and concentrated in vacuo. The resulting residue was puried via
column chromatography on silica, eluting with 2% ethyl acetate/
hexanes to isolate the desired product as a yellow liquid (1.9 g,
13%). The product was isolated as a mixture containing enol and
keto forms with an approximate 3 : 1 enol–keto ratio according to
the 1H NMR spectrum. 1H-NMR (500 MHz, CDCl3): d 13.70 (s, 1H),
7.40–7.35 (m, 6.9H), 5.76 (s, 1H), 5.51 (s, 0.7H), 5.46 (s, 2H), 3.95 (s,
0.7H), 2.24 (s, 1H), 2.04 (s, 3H); 13C-NMR{1H} (125 MHz, CDCl3):
d 213.1, 208.1, 177.8, 135.4, 134.7, 128.9, 128.8, 128.75, 128.72,
128.6, 128.5, 103.3, 74.7, 70.9, 61.7, 31.1, 29.9, 23.3; HRMS-ESI (m/
z): [M + Na]+ calculated for C11H12O2SNa, 231.0450; found
231.0460.
References
1 J. M. Wood, D. P. Furkert and M. A. Brimble, Nat. Prod. Rep.,
2019, 36, 289–306.
2 L. Knorr, Justus Liebigs Ann. Chem., 1886, 236, 290–314.
3 J. B. Paine III and D. Dolphin, J. Org. Chem., 1985, 50, 5598–
5604.
4 G. Anguera, W. Y. Cha, M. D. Moore, J. T. Brewster,
M. Y. Zhao, V. D. Lynch, D. Kim and J. L. Sessler, Angew.
Chem., Int. Ed., 2018, 57, 2575–2579.
5 S. Neya, T. Yoneda, H. Omori, T. Hoshino, A. T. Kawaguchi
and M. Suzuki, Tetrahedron, 2017, 73, 6780–6785.
6 S. Shah, C. Lee, H. Choi, J. Gautam, H. Jang, G. J. Kim,
Y.-J. Lee, C. L. Chaudhary, S. W. Park, T.-g. Nam, J.-A. Kim
and B.-S. Jeong, Org. Biomol. Chem., 2016, 14, 4829–4841.
7 Y. Yang, S. Chen, L. Liu, S. Li, Q. Zeng, X. Zhao, H. Li,
Z. Zhang, L.-S. Bouchard, M. Liu and X. Zhou, ACS Appl.
Mater. Interfaces, 2017, 9, 23400–23408.
8 A. Tsotinis, P. A. Afroudakis, K. Davidson, A. Prashar and
D. Sugden, J. Med. Chem., 2007, 50, 6436–6440.
9 B. R. Groves, D. A. Smithen, T. S. Cameron and A. Thompson,
RSC Adv., 2016, 6, 69691–69697.
O-Benzyl 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carbothioate
The title compound was synthesised following a modied
literature procedure.41 A solution of NaNO2 (235 mg, 3.41 mmol)
in distilled water (852 mL) was added drop-wise to a solution of
O-benzylꢁ acetothioacetate (645 mg, 3.10 mmol) in AcOH (774
mL) at 0 C. The reaction mixture was stirred at room tempera-
ture and monitored via thin layer chromatography until the
starting material was consumed. The reaction mixture was then
transferred to a dropping funnel and added drop-wise to
a slurry of 2,4-pentanedione (316 mL, 3.10 mmol), Na2CO3
(361 mg, 3.41 mmol) and AcOH (2 mL). At the same time, Zn
dust (11.4 g, 173.9 mmol) was slowly added to the slurry with the
rate of addition and an ice-bath was used to keep the temper-
ature below 30 ꢁC. Aer full addition, the reaction mixture was
stirred at room temperature. The resulting mixture was poured
into distilled water (25 mL) and then ltered through Celite,
washing with CH2Cl2. The ltrate was extracted with CH2Cl2 (3
ꢂ 10 mL). The combined organic fractions were washed with
saturated NaHCO3 (10 mL) and brine (10 mL), then dried over
anhydrous Na2SO4 and evaporated in vacuo. The resulting
residue was puried via column chromatography on silica,
eluting with a gradient of 5–20% ethyl acetate/hexanes, then
washed with pentane (3 ꢂ 25 mL), yielding the desired product
10 M. A. Shalaby and H. Rapoport, J. Org. Chem., 1999, 64, 1065–
1070.
11 T. L. Cottrell, The strengths of chemical bonds, Butterworths
Scientic Publications, London, England, 2nd edn, 1958.
12 A. El Gamal, V. Agarwal, S. Diethelm, I. Rahman,
M. A. Schorn, J. M. Sneed, G. V. Louie, K. E. Whalen,
T. J. Mincer, J. P. Noel, V. J. Paul and B. S. Moore, Proc.
Natl. Acad. Sci. U. S. A., 2016, 113, 3797–3802.
13 C. T. Walsh, S. Garneau-Tsodikova and A. R. Howard-Jones,
Nat. Prod. Rep., 2006, 23, 517–531.
14 T. M. Cresp and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1,
1973, 2961–2971.
15 C. E. Loader and H. J. Anderson, Can. J. Chem., 1969, 46,
3879–3885.
¨
16 B. Fohlisch, D. Abu Bakr and P. Fischer, J. Org. Chem., 2002,
67, 3682–3686.
1
ꢁ
as a yellow solid (168 mg, 19%). Mp 122–124 C; H-NMR (500
MHz, CDCl3): d 9.43 (br s, 1H), 7.45–7.36 (m, 5H), 5.68 (s, 2H),
2.54 (s, 3H), 2.51 (s, 3H), 2.43 (s, 3H); 13C-NMR{1H} NMR (125
MHz, CDCl3): d 200.7, 195.9, 141.0, 135.4, 128.8, 128.62, 128.58,
128.56, 127.1, 125.0, 73.1, 31.6, 15.5, 14.0; HRMS-ESI (m/z): [M +
Na]+ calculated for C16H17NO2SNa, 310.0872; found 310.0869.
17 C. Savarin, J. Srogl and L. S. Liebeskind, Org. Lett., 2000, 2,
3229–3231.
18 R. Mozingo, D. E. Wolf, S. A. Harris and K. Folkers, J. Am.
Chem. Soc., 1943, 65, 1013–1016.
19 E. Bullock, T.-S. Chen and C. E. Loader, Can. J. Chem., 1966,
44, 1007–1011.
20 L. Birry and A. Lasia, J. Appl. Electrochem., 2004, 34, 735–749.
´
´
ˇ
´
21 I. Pogorelic, M. Filipan-Litvic, S. Merkas, G. Ljubic,
Conflicts of interest
´
I. Cepanec and M. Litvic, J. Mol. Catal. A: Chem., 2007, 274,
The authors declare no competing nancial interest.
202–207.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 31773–31780 | 31779

View Article Online
RSC Advances
Paper
22 B. Klenke and I. H. Gilbert, J. Org. Chem., 2001, 66, 2480– 33 X. Zhang, H. Wang and Y. Guo, Rapid Commun. Mass
2483. Spectrom., 2006, 20, 1877–1882.
23 X. Wang and R. Rinaldi, ChemSusChem, 2012, 5, 1455–1466. 34 A. J. Bridges and G. H. Whitham, J. Chem. Soc., Perkin Trans.
24 J. M. Khurana and R. Arora, Synthesis, 2009, 1127–1130. 1, 1975, 1603–1606.
25 H. Hauptmann and W. F. Walter, Chem. Rev., 1962, 62, 347– 35 F. Carta, A. Akdemir, A. Scozzafava, E. Masini and
404. C. T. Supuran, J. Med. Chem., 2013, 56, 4691–4700.
26 J. Rentner, M. Kljajic, L. Offner and R. Breinbauer, 36 L. Knorr, Ber. Dtsch. Chem. Ges., 1884, 17, 1635.
Tetrahedron, 2014, 70, 8983–9027.
37 E. V. Antina, G. B. Guseva, A. E. Loginova, A. S. Semeikin and
27 S. S. Bokatzian-Johnson, M. L. Maier, R. H. Bell, K. E. Alston,
A. I. V'yugin, Russ. J. Gen. Chem., 2010, 80, 2374–2381.
B. Y. Le and E. A. Cioffi, J. Labelled Compd. Radiopharm., 38 H. Fischer, Org. Synth., 1935, 15, 17.
2007, 50, 380–383.
39 M. D. Brown, D. W. Gillon, G. D. Meakins and
28 R. J. Heys, J. Labelled Compd. Radiopharm., 2010, 53, 716–
G. H. Whitham, J. Chem. Soc., Perkin Trans. 1, 1985, 1623–
721.
1626.
29 G. R. Pettit and R. E. Kadunce, J. Org. Chem., 1962, 27, 4566– 40 B. Groves, D. Smithen, S. Cameron and A. Thompson, RSC
4570. Adv., 2016, 6, 69691–69697.
30 A. Call, C. Casadevall, F. Acuna-Pares, A. Casitas and 41 S. Mula, A. K. Ray, M. Banerjee, T. Chaudhuri, K. Dasgupta
J. Lloret-Fillol, Chem. Sci., 2017, 8, 4669–5218.
31 W. Liu, L. Li and C.-J. Li, Nat. Commun., 2015, 6, 6526.
32 P. J. Wright and A. M. English, J. Am. Chem. Soc., 2003, 125,
8655–8665.
and S. Chattopadhyay, J. Org. Chem., 2008, 73, 2146–2154.
42 T. E. Wood, B. Berno, C. S. Beshara and A. Thompson, J. Org.
Chem., 2006, 71, 2964–2971.
43 J. Regourd, I. M. Comeau, C. S. Beshara and A. Thompson, J.
Heterocycl. Chem., 2006, 43, 1709–1714.
31780 | RSC Adv., 2019, 9, 31773–31780
This journal is © The Royal Society of Chemistry 2019