Decarboxylative arylation of substituted pyrroles N -protected with 2-(trimethylsilyl)ethoxymethyl (SEM)

Article abstract of DOI:10.1139/cjc-2017-0402

Palladium-catalyzed decarboxylative arylation is reported using pyrroles N-protected with the 2-(trimethylsilyl)ethoxymethyl (SEM) group and featuring 2-, 3-, and 4-substituents about the pyrrolic framework. In contrast to N-protected pyrroles previously

Full text of DOI:10.1139/cjc-2017-0402

Page 1 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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Carlotta Figliola, Sarah M. Greening, Connor Lamont, Brandon R. Groves and Alison Thompson*
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*Corresponding author: Alison.Thompson@dal.ca
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Department of Chemistry, Dalhousie University, PO BOX 15000, Halifax, NS, B3H 4R2, Canada
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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Dedication
Dedicated to Professor Neil Burford with thanks for teaching us so much.
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Abstract
Palladiumꢀcatalyzed decarboxylative arylation is reported using pyrroles Nꢀprotected with the 2ꢀ
(trimethylsilyl)ethoxymethyl (SEM) group and featuring 2ꢀ, 3ꢀ and 4ꢀsubstituents about the pyrrolic
framework. In contrast to Nꢀprotected pyrroles previously used in decarboxylative arylation, the use of
SEM allows deprotection under mild conditions.
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Keywords
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Pyrroles, decarboxylative arylation, pyrrole Nꢀprotection, SEM, substituted pyrrolic core
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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Introduction
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Considerable effort has addressed the development of efficient synthetic strategies to form (hetero)arylꢀ
(hetero)aryl1ꢀ3 CꢀC bonds that proceed under mild reaction conditions and with high selectivity and
broad tolerance. In this vein, transition metalꢀcatalyzed direct CꢀH arylation has earned significant
attention due to the large variety of tolerated functional groups and high yielding selectivity at low
catalyst loadings.4ꢀ6 More recently, transition metalꢀcatalyzed decarboxylative arylation, using
carboxylic acids as synthetic equivalents of aryl halides, triflates and organometallic species, has been
investigated.7
Pyrroles are a recurrent feature in supramolecular, medicinal and agricultural chemistry.2,8ꢀ10
There are numerous examples of transition metalꢀcatalyzed direct CꢀH and decarboxylative arylation
using pyrroles and various transition metals. In this way, aryl groups have been efficiently adjoined to
the 2ꢀposition of pyrroles. However, most methodologies focus on using the unsubstituted pyrrole unit,
and do not embrace the necessity to work with pyrroles already bearing substituents on the 3ꢀ, 4ꢀ and 5ꢀ
positions. Furthermore, these methodologies typically involve Nꢀalkyl and Nꢀaryl pyrroles,3ꢀ7,11ꢀ16
thereby incorporating protecting groups that, courtesy of inherent challenges encountered in
deprotection, are largely impractical for use in a synthetic sequence.17 An exception to these
generalities resulted in the first total synthesis of lamellarin L, and involved decarboxylative arylation
of a pyrrole that is Nꢀprotected by an ethyl benzene derivative and that is highly substituted about the
carbon atoms of the pyrrole.18 The complex natural product bears Nꢀsubstitution with features based on
ethyl benzene, and thus deprotection was not required in this case.
Bilodeau, Forgione and coꢀworkers reported a comprehensive investigation of the reactivity of
Nꢀprotected 2ꢀpyrrole carboxylic acid in palladiumꢀcatalyzed decarboxylative arylation with ArꢀX (X =
iodides, chlorides, bromides and triflates) affording the targeted biaryls (Scheme 1, top).19 The role of
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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both solvent and base was studied, as was the use of palladiumꢀbased catalysts either preꢀmade or
formed in situ. The crossꢀcoupling reaction was evaluated using conventional and microwaveꢀpromoted
heating. The pyrrolic nitrogen atom was protected with methyl or aryl groups to demonstrate that Nꢀ
methyl 2ꢀpyrrole carboxylic acid undergoes decarboxylative arylation with higher efficiency than the
corresponding Nꢀaryl analogue.19 However, despite significant success, this work was applied only to
the unsubstituted and commercially available 2ꢀpyrrole carboxylic acid (no further substituents about
the pyrrolic core), and removal of these Nꢀprotecting groups is known to be challenging with
pyrroles.17
Scheme 1 Decarboxylative arylation and the work reported herein.
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We herein report palladiumꢀcatalyzed decarboxylative arylation involving stoichiometric
amounts of Nꢀ2ꢀ(trimethylsilyl)ethoxymethyl 2ꢀpyrrole carboxylic acids and phenyl bromide. The 2ꢀ
(trimethylsilyl)ethoxymethyl (SEM) group is conducive to deprotection subsequent to coupling
(Scheme 1, bottom). Pyrroles substituted in the 3ꢀ, 4ꢀ and 5ꢀpositions, in addition to the requisite 2ꢀ
carboxylic acid, were used. These pyrroles stem from Knorrꢀtype reactions,20 are widely used in the
generation of diꢀ and triꢀ species20ꢀ24 and bear benzyl esters in the 2ꢀposition functionality to provide
ready access to the required carboxylic acid.25ꢀ27 The efficiency of other aryl halides was also
evaluated.
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Results and discussion
We began by evaluating the effectiveness of decarboxylative arylation with pyrroles bearing 3ꢀ, 4ꢀ and
5ꢀsubstituents. As Nꢀmethyl pyrroles feature prominently in the work involving the core (unsubstituted)
pyrrole unit,19 we Nꢀmethylated the substituted pyrroles 1a-c (Scheme 2).17 Adapting a literature
procedure,21 pyrroles 1a-c were reacted with MeI in the presence of NaOH and TBAB. Although the
protection of electronꢀdeficient pyrroles (1a and 1c) occurred smoothly and in quantitative yields,
methylation of electronꢀrich 1b resulted in a lower yield.
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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Scheme 2 N-Methylation of pyrroles 1a-c.
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Given the benzyl ester functionality at the αꢀposition, Nꢀmethyl pyrroles 2a-c were submitted to
hydrogenolysis to form the targeted carboxylic acids 3a-c.28 The crude acids were carried directly into
the reported palladiumꢀcatalyzed decarboxylative arylation (Scheme 3, method a).19 Decarboxylative
crossꢀcoupling using electronꢀrich 3b was unsuccessful as polymerization dominated. However, 2ꢀ
phenyl pyrroles 4a (50% yield, based on stoichiometry of pyrrole starting material) and 4c (43%) were
isolated alongside the corresponding αꢀfree derivatives 5a and 5c in 3:1 and 10:1 ratios, respectively
(the 2ꢀPh and 2ꢀH analogs were inseparable in each case). As the literature conditions use 2 eq. of 2ꢀ
pyrrole carboxylic acids and 1 eq. of PhBr,19 the isolation of the αꢀfree pyrrole is not unexpected and
presumably arises due to nonꢀcatalyzed decarboxylation of pyrroles at temperatures below 170 ºC.7
Furthermore, the literature yields are based on the limiting reagent, which is the aryl halide, and so
necessarily result in conversion of <50% of the desired pyrrole.
Scheme 3 Decarboxylative arylation of substituted N-Me pyrroles.
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Focusing on the electronꢀpoor pyrrole, the reaction was repeated using 1 eq. of 3a and 1.1 eq. of
PhBr to produce pure 4a in 96% yield. These results demonstrate the electronic effect of substituents
on the reactivity of Nꢀmethyl pyrroles: electronꢀrich pyrroles undergo polymerization under these
conditions (2b), yet pyrroles bearing carbonyl functional group at either the distal βꢀ or αꢀpositions (2a,
2c) can be coupled in moderate to excellent yield.
The success of this decarboxylative coupling with pyrroles substituted in the 3ꢀ, 4ꢀ and 5ꢀ
positions is significant, as such pyrroles are routinely used in the preparation of diꢀ and triꢀpyrrolic
compounds such as BODIPYs and prodigiosenes. Furthermore, placement of a benzyl ester at the 2ꢀ
position is facile courtesy of Knorrꢀtype reactions.20 However, given that the deprotection of Nꢀmethyl
pyrroles is challenging,17 we sought a route towards pyrroles amenable to decarboxylative arylation at
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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the 2ꢀposition yet acquiescent to deprotection at the nitrogen atom. As palladiumꢀcatalyzed direct CꢀH
arylation with Nꢀunprotected pyrroles is known,29 we submitted the Nꢀunprotected pyrrole 1a to the
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decarboxylative arylation conditions (method b, Scheme 3). However, H NMR spectroscopic analysis
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of the crude mixture showed only the two starting materials (PhBr and 1a), as well as a significant
amount of the corresponding αꢀfree pyrrole. This result suggested that protection of the pyrrolic
nitrogen atom is indeed required for decarboxylative arylation to proceed.
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Cognizant that NꢀBoc pyrroles are facile to deprotect under mild conditions17 and that direct Cꢀ
H arylation involving NꢀBoc pyrroles has been reported,30,31 Bocꢀprotected 6a was submitted to
hydrogenolysis followed by the conditions for palladiumꢀcatalyzed decarboxylative arylation (Scheme
4). Unfortunately, the desired phenyl pyrrole 7a was not isolated and the majority of the material was
recollected as the corresponding N-deprotected αꢀfree derivative.32 NꢀTosylation of pyrrole 1a proved
wholly unsatisfactory,33,34 again demonstrating the fickle nature of Nꢀprotection of pyrroles.17
Scheme 4 Attempted decarboxylative arylation using N-Boc pyrrole 6a.
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We turned our attention to protecting groups that would mimic the methyl group of Nꢀmethyl
pyrrole yet enable removal after the crossꢀcoupling step. The 2ꢀ(trimethylsilyl)ethoxy methyl (SEM)
protecting group has been used to protect functionalities such as alcohols, imines, imidazoles and
pyrroles. It is easily introduced, more selective than other protecting groups (e.g. methyl group), and,
most importantly is removed under reaction conditions compatible with other functional groups.35,36
Furthermore, the SEM group has been shown to be effective as a protecting group for pyrazoles
undergoing C−H arylation.37 Pleasingly, reaction of the pyrrolide of 1a with SEMꢀCl gave the NꢀSEM
pyrrole 8a. Hydrogenolysis of the benzyl ester gave the acid 9a, which was used in the subsequent
palladiumꢀcatalyzed decarboxylative arylation step without isolation (Scheme 5). The desired 2ꢀphenyl
pyrrole 10a was obtained in an inseparable mixture with the corresponding αꢀfree pyrrole 11a. Based
on 1H NMR spectroscopic analysis of the isolated mixture, the conversion to 10a and 11a proceeded in
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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3:2 ratio (Scheme 5). With this encouraging result in hand, the conditions for the decarboxylative
arylation between 2ꢀpyrrole carboxylic acid 9a and PhBr were optimized (Table 1).
Scheme 5 Decarboxylative arylation using SEM-protected pyrrole 8a.
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Table 1 Optimization using 2-pyrrole carboxylic acid 9
O
O
O
conditionsa
Ph
CO2H
N
N
N
SEM
SEM
SEM
9a
10a
11a
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Conversionb,c
(10a:11a:9a)
55:45:0
t (min)
Entry
Base
PhBr
T
(eq.)
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.3
1.5
2
(º C)
150
190
170
150
170
190
190
170
150
190
150
150
150
150
Cs2CO3 (1.5 eq.)
Cs2CO3 (1.5 eq.)
KOAc (1.5 eq.)
KOAc (1.5 eq.)
KOAc (1.5 eq.)
KOAc (1.5 eq.)
KOAc (1.5 eq.)
KOtBu (1.5 eq.)
KOtBu (1.5 eq.)
KOtBu (1.5 eq.)
KOtBu (3 eq.)
10
10
10
10
20
10
20
10
10
10
10
10
10
10
1
2
3
4
5
6
7
8
9
10
11
12
13
14
77:23:0
83:17:0
78:22 :0
81:19:0
82:18:0
82:18:0
85:0:15
89:0:11
85:0:15
67:0:33
92:traces:traces
96:traces:traces
93:traces:traces
KOtBu (1.5 eq.)
KOtBu (1.5 eq.)
KOtBu (1.5 eq.)
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Note: aReactions were performed in 2ꢀ5 mL microwave vials, using 0.05 equivalents of Pd(PtBu3)2, as catalyst, and DMF, as solvent.
bAccording to 1H NMR spectroscopic analysis of the crude mixture; cPercentages are based on the integrals relative to the proton peaks of
the SEMꢀprotecting group.
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The temperature was both decreased to 150 ºC (entry 1) and increased to 190 ºC (entry 2).
Formation of the αꢀfree pyrrole 11a decreased when the reaction was carried out at 190 ºC. Cs2CO3 was
replaced by KOAc, and variation of temperature and time explored (entries 3ꢀ7). However, no
improvements were obtained. Surprisingly, the use of KtOBu (entries 8ꢀ14) afforded 10a in 85%
conversion (entry 8), without formation of 11a, yet with 15% of unreacted starting material. Cognizant
that KtOBu has a pka of 17, higher than that of Cs2CO3 (10) and KOAc (4.8), deprotonation of 9a
might occur more readily than the palladiumꢀcatalyzed decarboxylation. Increasing the temperature to
7
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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190 ºC (compare entries 9 and 10) did not increase the conversion to product. The presence of the
unreacted 9a might be due to insufficient KtOBu or PhBr in the reaction mixture. However, when the
equivalents of the base were doubled (entry 11), the conversion of 9a to 10a decreased. Increasing the
equivalents of PhBr to 1.3 (entry 12), 1.5 (entry 13) and 2 (entry 14) gave almost full conversion to 2ꢀ
phenyl pyrrole 10a, with only traces of starting materials and αꢀfree pyrrole observed in the product
mixture. The optimized reaction conditions (entry 13) were repeated and 10a was isolated in 54%
yield, after purification using column chromatography on silica. The use of other phenyl halides met
with little success. Indeed, when the optimized conditions (entry 13, using PhꢀX) were applied with
phenyl chloride and phenyl triflate, instead of phenyl bromide, only the αꢀfree derivative 11a was
isolated. The use of phenyl iodide gave the desired pyrrole 10a in a yield of only 25%. Thus, aryl
bromides were established as the aryl halide coupling partner of choice.
With a successful route to 10a in hand, the removal of the SEMꢀprotecting group was
investigated (Scheme 6). Adapting a literature procedure,36 a solution of the NꢀSEM 2ꢀphenyl pyrrole
10a in THF was treated with 5 eq. of 1 M TBAF and heated at reflux temperature for 19 hours. The
desired deprotected 2ꢀphenyl pyrrole 12a was thus obtained.
Scheme 6 SEM-deprotection of pyrrole 10a.
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In order to evaluate the feasibility of palladiumꢀcatalyzed decarboxylative arylation and Nꢀ
deprotection involving substituted NꢀSEM pyrroles, the substrate scope was explored using pyrroles
1b-h, featuring various functionalities about the pyrrolic core (Scheme 7). Despite the different
electronic nature of pyrroles 1b-h, SEMꢀprotection was consistent and highꢀyielding across all the
substrates reported herein, although we note, from other examples in our lab, that this is not always the
case for SEMꢀprotection of pyrroles. The SEMꢀprotected pyrroles 8b-h were submitted to
hydrogenolysis and the resulting carboxylic acids reacted with PhBr under the optimized
decarboxylative arylation reaction conditions (Table 1, entry 13). Electronꢀrich pyrroles 10b and 10e
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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were obtained successfully and in comparable isolated yields to that of 10a. However, attempts to
achieve Nꢀdeprotection resulted only in decomposition of the starting materials. SEMꢀdeprotection was
also attempted on pyrrole 8b and again decomposition of the starting material was observed. This
suggests that removal of the SEM protecting group is challenging when working with electronꢀrich
pyrroles. Hydrogenolysis of the benzyl ester of pyrrole 8c was unsuccessful and a mixture of
deformylated products was instead obtained. 2ꢀPhenyl pyrroles 10d and 10h were successfully
produced as the major components of inseparable mixtures containing the corresponding αꢀfree
derivatives (see Supporting Information). The yields are calculated based on the conversion of 9d and
9h into 10d and 10h, respectively, and the mass of the product mixture. Upon deprotection, the targeted
compounds 12d and 12h were separated from the unwanted αꢀfree derivatives, and isolated in 52% and
65% yields, respectively. Hydrogenolysis of unsubstituted SEMꢀprotected pyrrole 8f, followed by
decarboxylative arylation provided 10f in 60% yield. In contrast, submitting the carboxylic acid 9f to
Bilodeau and Forgione’s reaction conditions19 afforded 10f in only 28% yield. Removal of the SEMꢀ
protecting group proceeded smoothly to provide the Nꢀunprotected 2ꢀphenyl pyrrole 12f in good yield.
The electronꢀpoor pyrrole 9g underwent successful decarboxylative arylation, but could not be purified
from the multiple other SEMꢀproducts that were unexpectedly generated.
Scheme 7 Palladium-catalyzed decarboxylative arylation and SEM-deprotection of pyrroles 8b-h.
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The feasibility of the decarboxylative arylation and SEMꢀdeprotection involving pyrrole 8a and
various coupling partners was explored (Scheme 8). 2ꢀAryl pyrroles 10iꢀ10k were successfully
produced, giving 10i and 10j as the major components of inseparable mixtures containing the
corresponding αꢀfree derivative. Upon deprotection in each case, the unwanted αꢀfree derivative was
separated from the targeted 12i and 12j and the desired 2ꢀaryl pyrroles thus isolated. The 2ꢀthienyl
pyrrole 10k was produced in 37% and separated from the αꢀfree derivative prior to the successful
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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deprotection step. However, 2ꢀpyridyl bromide was an unsuccessful coupling partner, with the reaction
producing only the unwanted αꢀfree derivative.
Scheme 8 Palladium-catalyzed decarboxylative arylation and SEM-deprotection with aryl bromides.
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In summary, we report palladiumꢀcatalyzed decarboxylative arylation for heteroarylꢀaryl CꢀC
bond formation using substituted NꢀSEM pyrroles in stoichiometric amounts. Aryl bromide was found
to be a superior coupling partner compared to the corresponding chloride, triflate and iodide. Several
aryl bromides were successfully coupled to the 2ꢀposition of pyrroles. The influence of substituents
about the pyrrole core, both electronꢀdonating and electronꢀwithdrawing, was investigated. Compared
to Nꢀmethyl pyrroles, the use of SEM as an Nꢀprotecting group enables both decarboxylative arylation
and Nꢀdeprotection with select systems. Furthermore, the yields reported herein are based on the
amount of pyrrole used (rather than following literature precedent that bases yields on the amount of
aryl halide used).19 Although SEMꢀdeprotection of some electronꢀrich pyrroles was unsuccessful, the
deprotection of pyrroles bearing a mixture of alkylꢀ and Hꢀsubstitution, as well as acyl or pendant
carbonyl functionality, proceeded well. Certainly, the fickle nature of pyrroles as regards to
(de)protection means that protection strategies must be chosen with care. Nevertheless, for certain
systems, the use of NꢀSEM pyrroles provides a useful alternative when deprotection is required
following decarboxylative arylation.
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Experimental section
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General
All chemicals were purchased and used as received unless otherwise indicated. Moisture sensitive
reactions were performed in ovenꢀdried glassware and under a positive pressure of nitrogen via use of a
Schlenk line or glove box, both producing comparable yields. Airꢀ and moistureꢀsensitive compounds
were introduced via syringe or cannula through a rubber septum. Flash chromatography was performed
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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using ultraꢀpure silica (230ꢀ400 mm), unless indicated otherwise. The NMR spectra were recorded
using a 500 MHz spectrometer instrument using CDCl3, which was referenced at 7.26 ppm for 1H and
at 77.16 ppm for 13C. Coupling constants (J) are given in Hertz (Hz). Mass spectra were obtained using
TOF and LCQ Duo ion trap instruments operating in ESI+/− mode or APCI, as indicated. Compounds
1aꢀh25,27,38ꢀ42 were prepared according to literature procedures.
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Benzyl 4-acetyl-1,3,5-trimethyl-pyrrole-2-carboxylate (2a)
Adapting a literature procedure21 pyrrole 1a (0.50 g, 1.84 mmol) was dissolved in CH2Cl2 (20 mL) and
NBu4Br (59 mg, 0.184 mmol) and MeI (126 µL, 2.02 mmol) were added. The mixture was stirred
vigorously at 0 °C as 5 M NaOH (10 mL) was added dropꢀwise. The mixture darkened, and was
allowed to warm to room temperature and then stirred for 18 h. The organic fraction was separated and
washed with brine (100 mL), dried over Na2SO4, and filtered over a pad of neutral silica using
methanol:CH2Cl2 (5:95). After removal of the solvent in vacuo, pyrrole 2a was isolated as an offꢀwhite
1
solid (0.61 g, 99%). H NMR (500 MHz; CDCl3) 2.45 (s, 3H), 2.46 (s, 3H), 2.52 (s, 3H), 3.77 (s, 3H),
5.32 (s, 2H), 7.43ꢀ7.33 (m, 5H) ppm. 13C NMR (125 MHz; CDCl3) 12.4, 13.7, 32.0, 66.1, 123.5, 128.3,
128.8, 129.5, 136.2, 140.5, 162.1, 196.6 (1 carbon unaccounted for) ppm. HRMSꢀESI (m/z): [M+Na]+
calcd for C17H19NO3, 308.1263; found, 308.1257.
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Benzyl 4-ethyl-1,3,5-trimethyl-pyrrole-2-carboxylate (2b)
Adapting a literature procedure,28 pyrrole 1b (2.12 g, 8.2 mmol) was dissolved in CH2Cl2 (20 mL), and
NBu4Br (0.26 g, 0.82 mmol) and MeI (0.56 mL, 9.06 mmol) were added. The mixture was stirred
vigorously at 0 °C as 5 M NaOH (20 mL) was added dropꢀwise. The reaction vessel and condenser
tube were sealed, and the mixture was heated at 50 °C for 3 days. Although a considerable amount of
starting material was still present, the organic fraction was separated and washed with brine (100 mL),
and dried over Na2SO4. Purification using chromatography (SiO2, hexane/EtOAc 90/10 then 80/20)
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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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gave pyrrole 2b as a colourless oil (0.48 g, 22%). 1H NMR (500 MHz; CDCl3) 1.02 (t, J = 7.5 Hz, 3H),
2.16 (s, 3H), 2.26 (s, 3H), 2.39 (q, J = 7.5 Hz, 2H), 3.77 (s, 3H), 5.29 (s, 2H), 7.30 (t, J = 7.2 Hz, 1H),
13
7.36 (t, J = 7.4 Hz, 2H), 7.42 (d, J = 7.3 Hz, 2H) ppm. C NMR (125 MHz; CDCl3) 10.4, 11.8, 15.8,
17.6, 33.0, 65.26, 122.8, 127.6, 128.0, 128.1, 128.6, 137.1, 162.1 (1 carbon unaccounted for) ppm.
HRMSꢀESI (m/z): [M+Na]+ calcd for C17H21NO, 294.1470; found, 294.1465.
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Benzyl 4-ethyl-5-formyl-1,3-dimethyl-pyrrole-2-carboxylate (2c)
Adapting a literature procedure,19 pyrrole 1c (1.70 g, 6.27 mmol) was dissolved in CH2Cl2 (20 mL) and
NBu4Br (0.20 g, 0.627 mmol) and MeI (0.43 mL, 6.89 mmol) were added. The mixture was stirred
vigorously at 0 °C as 5 M NaOH (15 mL) was added dropꢀwise. The mixture darkened, and was
allowed to warm to room temperature as the reaction stirred for 18 h. The organic fraction was
separated and washed with brine (100 mL), dried over Na2SO4, and filtered over a pad of neutral silica
using methanol:CH2Cl2 (5:95). After removal of the solvent in vacuo, pyrrole 2c was isolated as a
brown solid (1.78g, 99%). 1H NMR (500 MHz; CDCl3) 1.13 (t, J = 7.6 Hz, 3H), 2.20 (s, 3H), 2.71 (q, J
13
= 7.6 Hz, 2H), 4.16 (s, 3H), 5.34 (s, 2H), 7.44ꢀ7.34 (m, 5H), 9.90 (s, 1H) ppm. C NMR (125 MHz;
CDCl3) 10.8, 16.6, 16.8, 34.8, 66.7, 126.0, 127.0, 128.5, 128.8, 130.0, 135.8, 138.0, 161.7, 180.3 (1
carbon unaccounted for) ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C17H19NO3, 308.1263; found,
308.1257.
244
245
246
247
248
249
General procedure for the decarboxylative Pd-coupling of pyrrole 2 (GP1):
Adapting literature procedures,19,35 a solution of pyrrole 2 (1 equiv), 10 mol% Pd/C (10% of the mass
of 2) and NEt3 (few drops) were dissolved in EtOH (0.08 M). The reaction mixture was purged three
times with N2 before the introduction of H2 atmosphere. After stirring the reaction mixture for 19 h,
nitrogen atmosphere was introduced and the reaction was filtered through a plug of Celite® and rinsed
with MeOH. Removal of the solvent under reduced pressure gave pyrrole 3, which was used in the next
12

Page 13 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
250
251
252
253
254
255
256
257
step without further purification. Pyrrole 3 (1 equiv), PhBr (1.1 equiv), NBu4Cl (1 equiv), Cs2CO3 (1.5
equiv), and Pd(P(tBu)3)2 (0.05 equiv) were combined in an open microwave vial. The vessel was
crimped through the use of a septum cap, a nitrogen atmosphere introduced and anhydrous DMF was
added (0.1 M). The mixture was stirred for 30 s, and then submitted to microwaveꢀpromoted heating
conditions (150 °C, 10 min, high absorption). The mixture was diluted with ethyl acetate (50 mL) and
washed with a saturated solution of NaHCO3 (× 3) and water (× 2). The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The crude mixtures were purified using column
chromatography on SiO2 (EtOAc/hexane, 10% ꢀ 30%) to give the desired products.
258
259
260
261
262
263
4-Acetyl 3,5-dimethyl-2-phenyl-1-methyl-pyrrole (4a)
1
Pyrrole 4a was obtained according to GP1 as a colorless solid (28 mg, 96%). H NMR (500 MHz;
CDCl3) 2.17 (s, 3H), 2.48 (s, 3H), 2.56 (s, 3H), 3.34 (s, 3H), 7.25 (d, J = 6.9 Hz, 2H), 7.38 (t, J = 7.4
Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H) ppm. 13C NMR (125 MHz; CDCl3) 12.7, 13.0, 31.6, 31.7, 116.4,
121.6, 127.8, 128.5 (2C), 131.2 (2C), 131.6, 132.1, 135.7, 196.1 ppm. HRMSꢀESI (m/z): [M+Na]+
calcd for C15H17NO, 250.1208; found, 250.1202.
264
265
266
267
268
269
270
271
272
3-Ethyl-1,4-dimethyl-5-phenyl-pyrrole-2-carbaldehyde (4c)
Pyrrole 4c was obtained according to GP1 as a beige solid containing both the product 4c (43%, based
on the amount of 4c in the isolated mixture) and the decarboxylated derivative 5c in a 10:1 ratio, which
was not easily separated using chromatography. 1H NMR (500 MHz; CDCl3) 1.16 (t, J = 7.6 Hz, 0.1 ×
3H, CH2CH3 of 5c), 1.22 (t, J = 7.6 Hz, 0.9 × 3H, CH2CH3 of 4c), 1.93 (s, 0.9 × 3H, CH3 of 4c), 2.03
(s, 0.1 × 3H, CH3 of 5c), 2.69 (q, J = 7.6 Hz, 0.1 × 2H, CH2CH3 of 5c), 2.76 (q, J = 7.6 Hz, 0.9 × 2H,
CH2CH3 of 4c), 3.75 (s, 0.9 × 3H, CH3 of 4c), 3.85 (s, 0.1 × 3H, CH3 of 5c), 6.59 (s, 0.1 × 1H, ArꢀH of
5c), 7.29 (d, J = 6.9 Hz, 0.9 × 2H, ArꢀH of 4c), 7.41 (t, J = 7.4 Hz, 0.9 × 1H, ArꢀH of 4c), 7.47 (t, J =
7.3 Hz, 0.9 × 2H, ArꢀH of 4c), 9.66 (s, 0.1 × 1H, CHO of 5c), (9.75 (s, 0.9 × 1H, CHO of 4c) ppm. 13C
13

Page 14 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
273
274
NMR (125 MHz; CDCl3) 9.2, 16.7, 17.3, 34.2, 117.3, 127.2, 128.5, 128.6, 130.3, 130.8, 139.7, 141.3,
177.7 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C15H17NO, 250.1208; found, 250.1202.
275
276
277
278
279
280
281
282
283
284
285
286
Benzyl 4-acetyl-3,5-dimethyl-1-tert-butylcarboxylate-pyrrole-2-carboxylate (6a)
Pyrrole 1a (0.50 g, 1.84 mmol) and DMAP (25 mg, 0.22 mmol) were dissolved in anhydrous MeCN
(20 mL) and the solution was degassed with nitrogen for 10 minutes with stirring. (Boc)2O (1.08 g,
4.97 mmol) was added dropwise as a solution in anhydrous MeCN (5 mL). The mixture was stirred for
20 minutes, after which no starting material was detectable using TLC analysis. Removal of the solvent
and excess (Boc)2O in vacuo yielded the crude product, which was subjected to column
chromatography on Brockman III basic alumina using EtOAc:hexanes (5:95) as eluent. The product
1
was obtained as a light yellow oil (0.66 g, 97%). H NMR (500 MHz; CDCl3) 1.51 (s, 9H), 2.43 (s,
3H), 2.44 (s, 3H), 2.53 (s, 3H), 5.32 (s, 2H), 7.31ꢀ7.41 (m, 5H) ppm. 13C NMR (125 MHz; CDCl3)
12.7, 13.2, 27.6 (3C), 31.9, 66.7, 86.1, 120.9, 124.6, 128.4, 128.4, 128.7, 128.7, 129.1, 135.9, 139.3,
149.3, 161.1, 196.3 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C21H25NO5, 394.1630; found,
394.1608.
287
288
289
290
291
292
293
294
295
General procedure for SEM-protection of pyrrole 1 (GP2)
Adapting a literature procedure,36 pyrrole 1 (1.0 equiv) was added in one portion to a stirred solution of
NaH (60% dispersion in mineral oil, 1.1 equiv) in DMF (0.4 M) at room temperature and under
nitrogen atmosphere. When the evolution of H2 ceased, 2ꢀ(trimethylsilyl)ethoxymethyl chloride (1.1
equiv) was added dropwise at 0 ºC. The reaction mixture was allowed to warm up to room temperature,
stirred until complete consumption of the starting material (according to TLC analysis) and poured into
a saturated solution of NaHCO3 at 0 ºC. The crude mixture was extracted with EtOAc (× 3) and the
combined organic fractions washed with water (× 2) and brine, dried over Na2SO4 and concentrated
under reduced pressure.
14

Page 15 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
296
297
298
299
300
301
302
303
Benzyl 4-acetyl-3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole-2-carboxylate (8a)
Pyrrole 8a was obtained according to GP2. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 80/20) to give 8a as a colorless oil (73%). H NMR (500
MHz; CDCl3) ꢀ0.04 (s, 9H), 0.83ꢀ0.87 (m, 2H), 2.45 (s, 3H), 2.51 (s, 3H), 2.53 (s, 3H), 3.47ꢀ3.50 (m,
13
2H), 5.32 (s, 2H), 5.70 (s, 2H), 7.32ꢀ7.43 (m, 5H) ppm. C NMR (125 MHz; CDCl3) ꢀ1.3, 12.3, 13.7,
18.1, 32.0, 65.8, 66.3, 73.2, 120.2, 124.5, 128.4, 128.8, 130.0, 136.1, 141.3, 161.9, 196.8 (1 carbon
unaccounted for) ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C22H31NNaO4Si, 424.1915; found,
424.1930.
304
305
306
307
308
309
310
311
Benzyl 4-ethyl-3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole-2-carboxylate (8b)
Pyrrole 8b was obtained according to GP2. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 100/0, 98/2, 96/4) to give 8b as a colorless oil (73%). H
NMR (500 MHz; CDCl3) ꢀ0.05 (s, 9H), 0.84ꢀ0.87 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H), 2.24 (s, 3H), 2.26
(s, 3H), 2.39 (q, J = 7.5 Hz, 2H), 3.48ꢀ3.51 (m, 2H), 5.30 (s, 2H), 5.69 (s, 2H), 7.29ꢀ7.43 (m, 5H) ppm.
13C NMR (125 MHz; CDCl3) ꢀ1.3, 10.1, 11.9, 15.5, 17.4, 18.1, 65.2, 65.5, 73.1, 118.3, 124.0, 128.0,
128.2, 128.6, 129.4, 134.1, 136.9, 162.0 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C22H33NNaO3Si,
410.2122; found, 410.2124.
312
313
314
315
316
317
Benzyl 4-ethyl-5-formyl-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole-2-carboxylate (8c)
Pyrrole 8c was obtained according to GP2. The crude mixture was purified using column
chromatography on SiO2 (hexanes/EtOAc, 90/10 to 80/20) to give 8c as a colorless oil (81%). 1H NMR
(500 MHz; CDCl3) ꢀ0.07 (s, 9H), 0.81ꢀ0.86 (m, 2H), 1.14 (t, J = 7.5 Hz, 3H), 2.21 (s, 3H), 2.73 (q, J =
13
7.5 Hz, 2H), 3.42ꢀ3.48 (m, 2H), 5.35 (s, 2H), 6.08 (s, 2H), 7.36ꢀ7.45 (m, 5H), 9.95 (s, 1H) ppm. C
NMR (125 MHz; CDCl3) ꢀ1.3, 10.7, 16.2, 17.1, 18.0, 65.8, 66.9, 73.8, 126.6, 127.6, 128.5, 128.6,
15

Page 16 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
318
319
128.8, 130.2, 135.7, 139.2, 161.6, 180.5 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C22H31NNaO4Si,
424.1915; found, 424.1912.
320
321
322
323
324
325
326
Benzyl 3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole-2-carboxylate (8d)
Pyrrole 8d was obtained according to GP2. The crude mixture was purified using column
chromatography on SiO2 (hexanes/EtOAc, 100/0 to 95/5) to give 8d as a colorless oil (78%). 1H NMR
(500 MHz; CDCl3) ꢀ0.04 (s, 9H), 0.85ꢀ0.88 (m, 2H), 2.29 (s, 6H), 3.50ꢀ3.53 (m, 2H), 5.30 (s, 2H), 5.69
(s, 2H), 5.82 (s, 1H), 7.31ꢀ7.43 (m, 5H) ppm. 13C NMR (125 MHz; CDCl3) ꢀ1.3, 12.4, 14.7, 18.1, 65.3,
65.5, 73.2, 112.3, 119.0, 128.0, 128.2, 128.6, 131.3, 136.8, 137.2, 161.9 ppm. HRMSꢀESI (m/z):
[M+Na]+ calcd for C20H29NNaO3Si, 382.1809; found, 382.1821.
327
328
329
330
331
332
333
334
335
Benzyl
4-(2-methoxy-2-oxoethyl)-3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole-2-
carboxylate (8e)
Pyrrole 8e was obtained according to GP2. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 100/0, 90/10, 85/15) to give 8e as a colorless oil (91%). H
NMR (500 MHz; CDCl3) ꢀ0.04 (s, 9H), 0.84ꢀ0.88 (m, 2H), 2.26 (s, 3H), 2.27 (s, 3H), 3.40 (s, 2H),
3.49ꢀ3.52 (m, 2H), 3.65 (s, 3H), 5.29 (s, 2H), 5.70 (s, 2H), 7.30ꢀ7.42 (m, 5H) ppm. 13C NMR (125
MHz; CDCl3) ꢀ1.3, 10.5, 12.1, 18.1, 30.3, 52.0, 65.3, 65.6, 73.2, 114.7, 118.7, 128.1, 128.2, 128.6,
129.9, 135.7, 136.7, 161.9, 172.2 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C23H33NNaO5Si,
454.2020; found, 454.2028.
336
337
338
339
340
Benzyl 1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole-2-carboxylate (8f)
Pyrrole 8f was obtained according to GP2. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 95/5) to give 8f as a colorless oil (85%). H NMR (500
MHz; CDCl3) ꢀ0.04 (s, 9H), 0.87ꢀ0.92 (m, 2H), 3.50ꢀ3.55 (m, 2H), 5.29 (s, 2H), 5.71 (s, 2H), 6.19 (dd,
J = 3.7, 2.8 Hz, 1H), 7.03ꢀ7.04 (m, 1H), 7.06 (dd, J = 3.8, 1.7 Hz, 1H), 7.31ꢀ7.36 (m, 1H), 7.37ꢀ7.39
16

Page 17 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
(m, 2H), 7.42ꢀ7.43 (m, 2H) ppm. 13C NMR (125 MHz; CDCl3) ꢀ1.3, 18.0, 65.7, 66.1, 77.0, 109.0,
119.5, 123.3,128.1, 128.2, 128.7, 129.0, 136.6, 160.9 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for
C18H25NNaO3Si, 354.1496; found, 354.1487.
Benzyl 3,5-dimethyl-4-(2,2,2-trifluoroacetyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole-2-
carboxylate (8g)
Pyrrole 8g was obtained according to GP2. The crude mixture was purified using column
chromatography on SiO2 (hexanes/EtOAc, 90/10) to give 8g as a pale yellow oil (53%). 1H NMR (500
MHz; CDCl3): ꢀ0.04 (s, 9H), 0.86 (t, J = 8.1 Hz, 2H), 2.44 (s, 3H), 2.51 (s, 3H), 3.51 (t, J = 8.1 Hz,
13
2H), 5.33 (s, 2H), 5.72 (s, 2H), 7.43ꢀ7.34 (m, 5H) ppm. 19F NMR (471 MHz; CDCl3) ꢀ74 ppm. C
NMR (126 MHz; CDCl3): ꢀ1.3, 12.2, 12.7, 18.1, 66.2, 66.6, 73.6, 116.4 (q, J = 290 Hz), 117.7, 121.5,
128.5, 128.6, 128.8, 131.3, 135.8, 144.2, 161.6, 179.3 (q, J = 37 Hz) ppm. HRMSꢀESI (m/z): [M+Na]+
calcd for C22H28F3NNaO4Si, 478.1632; found, 478.1631.
Benzyl 4-ethyl 3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole-2,4-dicarboxylate (8h)
Pyrrole 8h was obtained according to GP2. The crude mixture was purified using column
chromatography on SiO2 (hexanes/EtOAc, 90/10) to give 8h as a pale yellow oil (79%). 1H NMR (500
MHz; CDCl3): ꢀ0.04 (s, 9H), 0.85 (t, J = 8.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H), 2.53 (s, 3H), 2.58 (s,
3H), 3.49 (t, J = 8.1 Hz, 2H), 4.29(q, J = 7.1 Hz, 2H), 5.32 (s, 2H), 5.72 (s, 2H), 7.39ꢀ7.31 (m, 3H),
7.42 (d, J = 7.1 Hz) ppm. 13C NMR (126 MHz; CDCl3): ꢀ1.3, 12.0, 13.1, 14.5, 18.1, 59.8, 65.7, 66.1,
73.2, 76.9, 77.2, 77.4, 114.1, 120.1, 128.29, 128.33, 128.7, 132.2, 136.3, 142.8, 161.9, 165.6 ppm.
HRMSꢀESI (m/z): [M+Na]+ calcd for C23H33NNaO5Si, 454.2020; found, 454.2001.
361
362
363
364
General procedure for the decarboxylative Pd-coupling of pyrrole 8 (GP3):
Adapting GP1, a solution of pyrrole 8 (1 equiv), 10 mol% Pd/C (10% of the mass of 8) and NEt3 (few
drops) were dissolved in EtOH (0.08 M). The reaction mixture was purged three times with nitrogen
before the introduction of a H2 atmosphere. After stirring the reaction for 19 h, N2 atmosphere was
17

Page 18 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
365
366
367
368
369
370
371
372
373
374
375
introduced and the reaction was filtered through a plug of Celite® and rinsed with MeOH. Removal of
the solvent under reduced pressure gave pyrrole 9, which was used in the next step without further
purification. Pyrrole 9 (1 equiv), PhBr (1.5 equiv), NBu4Cl (1 equiv), KOtBu (1.5 equiv), and
Pd(P(tBu)3)2 (0.05 equiv) were combined in an open microwave vial. The vessel was crimped through
the use of a septum cap, a nitrogen atmosphere introduced and anhydrous DMF was added (0.1 M).
Alternatively, pyrrole 9 was added to a microwave vial which was subsequently sealed with a rubber
septum and a nitrogen atmosphere introduced. The vial was then brought into a glovebox, where the
remaining reagents and solvent were added and the vessel sealed. The mixture was stirred for 30 s, and
then submitted to microwaveꢀpromoted heating conditions (150 °C, 10 min, high absorption). The
mixture was diluted with ethyl acetate (50 mL) and washed with a saturated solution of NaHCO3 (× 3)
and water (× 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure.
376
377
378
379
380
381
382
383
4-Acetyl 3,5-dimethyl-2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl) pyrrole (10a)
Pyrrole 10a was obtained according to GP3. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 80/20) to give 10a as a colorless oil (54%). H NMR (500
MHz; CDCl3) ꢀ0.05 (s, 9H), 0.76ꢀ0.80 (m, 2H), 2.16 (s, 3H), 2.49 (s, 3H), 2.61 (s, 3H), 3.26ꢀ3.29 (m,
13
2H), 5.04 (s, 2H), 7.28ꢀ7.30 (m, 2H), 7.36ꢀ7.45 (m, 3H) ppm. C NMR (125 MHz; CDCl3) ꢀ1.3, 12.4,
12.8, 18.0, 31.7, 65.6, 72.8, 116.7, 122.8, 128.0, 128.5, 131.5, 131.9, 136.0, 196.5 (1 carbon
unaccounted for) ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C20H29NNaO2Si, 366.1860; found,
366.1859.
384
385
386
387
3-Ethyl-2,4-dimethyl-5-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole (10b)
Pyrrole 10b was obtained according to GP3. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 90/10) to give 10b (43%) as a colorless oil. H NMR (500
MHz; CDCl3) ꢀ0.01 (s, 9H), 0.82ꢀ0.86 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H), 2.03 (s, 3H), 2.31 (s, 3H), 2.49
18

Page 19 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
388
389
390
(q, J = 7.5 Hz, 2H), 3.31ꢀ3.34 (m, 2H), 5.06 (s, 2H), 7.30ꢀ7.44 (m, 5H) ppm. 13C NMR (125 MHz;
CDCl3) ꢀ1.3, 9.8, 10.0, 15.8, 18.0 (2C), 64.9, 73.1, 115.7, 122.3, 125.0, 126.6, 128.2, 130.1, 130.8,
133.3 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C20H31NNaOSi, 352.2067; found, 352.2064.
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
3,5-Dimethyl-2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole (10d)
Pyrrole 10d was obtained according to GP3. The crude mixture was purified using column
chromatography on SiO2 (hexanes/EtOAc, 98/2) to give a colorless oil containing both the product 10d
(35%, based on the amount of 10d in the isolated mixture) and the decarboxylated derivative 11d in a
1
4:1 ratio. H NMR (500 MHz; CDCl3) ꢀ0.04 (s, 0.8 × 9H, TMS of 10d), 0.00 (s, 0.2 × 9H, TMS of
11d), 0.78ꢀ0.82 (m, 0.8 × 2H, CH2ꢀTMS of 10d), 0.87ꢀ0.93 (m, 0.2 × 2H, CH2ꢀTMS of 11d), 2.03 (s,
0.8 × 3H, CH3 of 10d), 2.05 (s, 0.2 × 3H, CH3 of 11d), 2.24 (s, 0.2 × 3H, CH3 of 11d), 2.34 (s, 0.8 ×
3H, CH3 of 10d), 3.27ꢀ3.32 (m, 0.8 × 2H, CH2CH2ꢀTMS of 10d), 3.45ꢀ3.50 (m, 0.2 × 2H, CH2CH2ꢀ
TMS of 11d), 5.05 (s, 0.8 × 2H, CH2O of 10d), 5.07 (s, 0.2 × 2H, CH2O of 11d), 5.76 (s, 0.2 × 1H, Arꢀ
H of 11d) 5.88 (s, 0.8 × 1H, ArꢀH of 10d), 6.42 (s, 0.2 × 1H, ArꢀH of 11d), 7.30ꢀ7.43 (m, 5H) ppm. 13C
NMR (125 MHz; CDCl3) ꢀ1.3, ꢀ1.2, 11.8, 11.9, 12.2, 14.4, 17.9, 18.0, 65.0, 65.3, 73.0, 75.7, 109.8,
116.4, 118.0, 118.9, 126.8, 128.3, 129.4, 130.8, 130.9, 133.2 (significant overlap between 13CꢀNMR
signals of 10d and 11d in spectrum) ppm. HRMSꢀESI (m/z) for 10d: [M+Na]+ calcd for
C18H27NNaOSi, 324.1754; found, 324.1745. HRMSꢀESI (m/z) for 11d: [M+Na]+ calcd for
C12H23NNaOSi, 248.1441; found, 248.1435.
406
407
408
409
410
3,5-Dimethyl-4-(2-methoxy-2-oxoethyl)-2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole
(10e)
Pyrrole 10e was obtained according to GP3. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 90/10) to give 10e (52%) as a colorless oil. H NMR (500
MHz; CDCl3) ꢀ0.04 (s, 9H), 0.78ꢀ0.83 (m, 2H), 1.98 (s, 3H), 2.30 (s, 3H), 3.27ꢀ3.32 (m, 2H), 3.46 (s,
19

Page 20 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
13
411
412
413
2H), 3.69 (s, 3H), 5.02 (s, 2H), 7.28ꢀ7.42 (m, 5H) ppm. C NMR (125 MHz; CDCl3) ꢀ1.3, 10.0, 10.1,
18.0, 30.9, 51.9, 65.0, 73.1, 112.9, 116.2, 126.9, 127.1, 128.3, 130.4, 130.9, 132.9, 172.9 ppm. HRMSꢀ
ESI (m/z): [M+Na]+ calcd for C21H31NNaO3Si, 396.1965; found, 396.1963.
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
2-Phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrole (10f)
Pyrrole 10f was obtained according to GP3. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 95/5) to give 10f as a colorless oil (60%). H NMR (500
MHz; CDCl3) 0.00 (s, 9H), 0.90ꢀ0.93 (m, 2H), 3.51ꢀ3.54 (m, 2H), 5.23 (s, 2H), 6.25ꢀ6.26 (m, 1H), 6.31
(dd, J = 3.5, 1.7 Hz, 1H), 6.90 (dd, J = 2.7, 1.7 Hz, 1H), 7.30ꢀ7.33 (m, 1H), 7.40 (t, J = 7.8 Hz, 2H),
7.55 (d, J = 7.8 Hz, 2H) ppm. 13C NMR (125 MHz; CDCl3) ꢀ1.3, 18.0, 65.8, 76.2, 108.8, 109.7, 123.5,
127.1, 128.5, 129.0, 133.1, 135.3 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C16H23NNaOSi,
296.1441; found, 296.1436.
Ethyl 2,4-dimethyl-5-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl) -pyrrole-3-carboxylate (10h)
Pyrrole 10h was obtained according to GP3. The crude mixture was purified using column
chromatography on SiO2 (hexanes/EtOAc, 80/20) to give a colorless oil containing both the product
10h (35%) and the decarboxylated derivative 11h in a 3:1 ratio. 1H NMR (3 MHz; CDCl3) ꢀ0.06 (s, 9H,
TMS of 10h), ꢀ0.02 (s, 9H, TMS of 11h), 0.77 (t, J = 8.4 Hz, 2H, CH2ꢀTMS of 10h), 0.88 (t, J = 8.2
Hz, 2H, CH2ꢀTMS of 11h), 1.34ꢀ1.39 (m, 6H, CH3CH2O(CO) of 10h and 11h), 2.15 (s, 3H, CH3 of
10h), 2.21 (s, 3H, CH3 of 11h), 2.53 (s, 3H, CH3 of 11h), 2.63 (s, 3H, CH3 of 10h), 3.25 (t, J = 8.4 Hz,
2H, CH2CH2ꢀTMS of 10h), 3.46 (t, J = 8.4 Hz, 2H, CH2CH2ꢀTMS of 11h), 4.24ꢀ4.34 (m, 4H,
CH3CH2O(CO) of 10h and 11h), 5.04 (s, 2H, CH2O of 10h), 5.010 (s, 2H, CH2O of 11h), 6.38 (s, 1H,
ArꢀH of 11h), 7.27ꢀ7.28 (m, 2H, ArꢀH of 10h), 7.38ꢀ7.45 (m, 3H, ArꢀH of 10h) ppm (significant
1
13
overlap between HꢀNMR signals of 10h and 11h in spectrum). C NMR (125 MHz; CDCl3) ꢀ1.3, ꢀ
1.2, 11.8, 11.9, 12.2, 14.4, 17.9, 18.0, 65.0, 65.3, 73.0, 75.7, 109.8, 116.4, 118.0, 118.9, 126.8, 128.3,
129.4, 130.8, 130.9, 133.2 ppm (significant overlap between 13CꢀNMR signals of 10h and 11h in
20

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Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
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436
spectrum). HRMSꢀESI (m/z) for 10h: [M+Na]+ calcd for C21H31NNaO3Si, 396.1965; found, 396.1982.
HRMSꢀESI (m/z) for 11h: [M+Na]+ calcd for C15H27NNaOSi, 320.1652; found, 320.1640.
437
438
439
1-(5-(4-methoxyphenyl)-2,4-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrol-3-yl)ethanone
(10i)
Pyrrole 10i was obtained according to GP3. The crude mixture was purified using column
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
chromatography on SiO2 (hexanes/EtOAc, 90/10) to give a white solid containing both the product 10i
1
(20%) and the decarboxylated derivative 11a in a 6:1 ratio. H NMR (500 MHz; CDCl3) ꢀ0.04 (s, 9H,
TMS of 10i), ꢀ0.01 (s, 9H, TMS of 11a), 0.79 (t, J = 8.3 Hz, 2H, CH2ꢀTMS of 10i), 0.89 (t, J = 8.1 Hz,
2H, CH2ꢀTMS of 11a), 2.14 (s, 3H, CH3 of 10i), 2.25 (s, 3H, CH3 of 11a), 2.43 (s, 3H, CH3 of 11a),
2.48 (s, 3H, CH3 of 10i), 2.52 (s, 3H, CH3 of 11a), 2.60 (s, CH3 of 10i), 3.29 (t, J = 8.3 Hz, 2H,
CH2CH2ꢀTMS of 10i), 3.47 (t, J = 8.1 Hz, 2H, CH2CH2ꢀTMS of 11a), 3.86 (s, 3H, ArꢀOCH3 of 10i),
5.01 (s, 2H, CH2O of 10i), 5.11 (s, 2H, CH2O of 11a), 6.39 (s, 1H, PyrroleꢀH of 11a), 6.96 (d, J = 8.7
13
Hz, 2H, ArꢀH of 10i), 7.21 (d, J = 8.6 Hz, 2H, ArꢀH of 10i) ppm. C NMR (125 MHz; CDCl3) ꢀ1.3,
12.2, 12.4, 12.9, 13.7, 17.9, 18.0, 31.4, 31.6, 55.4, 65.6, 65.9, 72.8, 75.7, 113.9, 116.6, 119.2, 120.3,
122.7, 122.9, 124.0, 131.6, 132.7, 135.7, 136.3, 159.4, 196.1, 196.5 ppm. HRMSꢀESI (m/z) for 10i:
[M+Na]+ calcd for C21H31NNaO3Si, 396.1965; found, 396.1971. HRMSꢀESI (m/z) for 11a: [M+Na]+
calcd for C14H25NNaO2Si, 290.1547; found, 290.1545.
1-(2,4-dimethyl-5-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-
yl)ethanone (10j)
Pyrrole 10j was obtained according to GP3. The crude mixture was purified using column
chromatography on SiO2 (hexanes/EtOAc, 90/10) to give a white solid containing both the product 10j
1
(36%) and the decarboxylated derivative 11a in a 6:1 ratio. H NMR (300 MHz; CDCl3) ꢀ0.04 (s, 9H,
TMS of 10j), ꢀ0.02 (s, 9H, TMS of 11a), 0.1 (t, J = 8.3 Hz, 2H, CH2ꢀTMS of 10j), 0.89 (t, J = 8.2 Hz,
2H, CH2ꢀTMS of 11a), 2.17 (s, 3H, CH3 of 10j), 2.25 (s, 3H, CH3 of 11a), 2.43 (s, 3H, CH3 of 11a),
2.49 (s, 3H, CH3 of 10j), 2.52 (s, 3H, CH3 of 11a), 2.61 (s, CH3 of 10j), 3.33 (t, J = 8.3 Hz, 2H,
21

Page 22 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
CH2CH2ꢀTMS of 10j), 3.46 (t, J = 8.2 Hz, 2H, CH2CH2ꢀTMS of 11a), 5.01 (s, 2H, CH2O of 10j), 5.11
(s, 2H, CH2O of 11a), 6.39 (s, 1H, PyrroleꢀH of 11a), 7.44 (d, J = 7.9 Hz, 2H, ArꢀH of 10j), 7.69 (d, J
= 8.0 Hz, 2H, ArꢀH of 10j) ppm. 19F NMR (471 MHz; CDCl3) ꢀ63 ppm. 13C NMR (125 MHz; CDCl3) ꢀ
1.3, 12.2, 12.4, 12.8, 13.7, 17.9, 18.0, 31.4, 31.7, 65.8, 65.9, 72.9, 75.7, 110.1, 117.8, 119.2, 120.3,
123.1, 125.4, 129.8, 130.1, 130.4, 131.6, 135.7, 136.7, 196.1, 196.3 ppm. HRMSꢀESI (m/z) for 10j:
[M+Na]+ calcd for C21H28F3NNaO2Si, 434.1734; found, 434.1731. HRMSꢀESI (m/z) for 11a: [M+Na]+
calcd for C14H25NNaO2Si, 290.1547; found, 290.1551.
1-(2,4-dimethyl-5-(thiophen-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)ethanone
(10k)
Pyrrole 10k was obtained according to GP3. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 90/10) to give 10k (37%) as a colorless oil. H NMR (500
MHz; CDCl3) ꢀ0.03 (s, 9H), 0.81ꢀ0.84 (m, 2H), 2.20 (s, 3H), 2.47 (s, 3H), 2.60 (s, 3H), 3.34ꢀ3.37 (m,
2H), 5.10 (s, 2H), 7.00 (dd, J = 3.5 and 1.1 Hz, 1H) 7.12 (dd, J = 5.2 and 3.5 Hz, 1H), 7.44 (dd, J = 5.2
and 1.1 Hz, 1H) ppm. 13C NMR (125 MHz; CDCl3) ꢀ1.3, 12.5, 13.1, 18.0, 31.6, 65.8, 72.8, 120.0,
122.9, 123.6, 127.2, 127.7, 130.4, 132.2, 136.9, 196.2 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for
C18H27NNaO2SSi, 372.1424; found, 372.1414.
476
477
478
479
480
481
482
483
General procedure for the deprotection of pyrrole 10 (GP4):
Adapting literature procedures,36 TBAF (1 M solution in THF, 5 equiv.) was added dropwise to a
solution of pyrrole 10 (1 equiv.) in THF (0.1 M) at room temperature and under nitrogen atmosphere.
The reaction mixture was heated to reflux temperature for 19 h. If TLC analysis still showed starting
material, TBAF (1 M solution in THF, 5 equiv.) was added and the reaction mixture was heated at
reflux temperature for an additional 10 h. Water was added to the reaction mixture and the two layers
were separated. The aqueous layers was extracted with EtOAc (× 3). The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated under reduced pressure.
22

Page 23 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
484
485
486
487
488
489
4-Acetyl 3,5-dimethyl-5-phenyl-1H-pyrrole (12a)
Pyrrole 12a was obtained according to GP4. The crude mixture was purified using column
chromatography on SiO2 (hexanes/EtOAc, 50/50) to give 12a as a white solid (54%). Mp: 160ꢀ162 ºC.
1H NMR (500 MHz; CDCl3) 2.38 (s, 3H), 2.47 (s, 3H), 2.56 (s, 3H), 7.27ꢀ7.45 (m, 5H), 8.17 (br s, 1H)
13
ppm. C NMR (125 MHz; CDCl3) 12.8, 15.3, 31.2, 117.0, 122.9, 127.0, 127.8, 127.9, 128.9, 132.7,
134.9, 195.8 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for C14H15NNaO, 236.1046; found, 236.1044.
490
491
492
493
494
495
3,5-Dimethyl-2-phenyl-1H-pyrrole (12d)
Pyrrole 12d was obtained according to GP4. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 98/2) to give 12d as a colorless oil (52%). H NMR (500
MHz; CDCl3) 2.11 (s, 3H), 2.16 (s, 3H), 5.70 (s, 1H), 7.05ꢀ7.12 (m, 1H), 7.23ꢀ7.27 (m, 4H), 7.66 (br s,
1H) ppm. 13C NMR (125 MHz; CDCl3) 12.6, 13.1, 110.4, 116.6, 125.6, 126.0, 126.9, 127.6, 128.8,
134.0 ppm. HRMSꢀESI (m/z): [M]+ calcd for C12H14N, 172.1121; found, 172.1117.
496
497
498
499
500
501
502
503
504
505
506
2-Phenyl-1H-pyrrole (12f)
Pyrrole 12f was obtained according to GP3. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 90/10) to give 12f as a white solid (71%). H NMR (500
MHz; CDCl3) 6.29ꢀ6.32 (m, 1H), 6.52ꢀ6.54 (m, 1H), 6.86ꢀ6.88 (m, 1H), 7.18ꢀ7.24 (m, 1H), 7.34ꢀ7.39
13
(m, 2H), 7.46ꢀ7.50 (m, 2H), 8.43 (br s, 1H) ppm. C NMR (125 MHz; CDCl3) 106.1, 110.3, 118.9,
124.0, 126.4, 129.0, 132.3, 132.9 ppm. HRMSꢀAPCI (m/z): [M+H]+ calcd for C10H10N, 144.0808;
found, 144.0814. The reported data are in agreement with those in the literature.43
Ethyl 2,4-dimethyl-5-phenyl-1H-pyrrole-3-carboxylate (12h)
Pyrrole 12h was obtained according to GP4. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 90/10) to give 12a as a pale yellow solid (65%). H NMR
(500 MHz; CDCl3) 1.37 (t, J = 7.1 Hz, 3H), 2.38 (s, 3H), 2.55 (s, 3H), 4.30 (q, J = 7.1 Hz, 2H), 7.28ꢀ
23

Page 24 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
13
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
7.29 (m, 1H), 7.36ꢀ7.42 (m, 4H), 8.06 (br s, 1H) ppm. C NMR (125 MHz; CDCl3) 12.0, 14.3, 14.7,
59.3, 112.6, 118.1, 126.8, 127.4, 127.4, 128.9, 133.0 ppm. HRMSꢀESI (m/z): [M+Na]+ calcd for
C15H17NNaO2, 266.1151; found, 266.1148.
1-(5-(4-methoxyphenyl)-2,4-dimethyl-1H-pyrrol-3-yl)ethanone (12i)
Pyrrole 12i was obtained according to GP4. The crude mixture was purified using column
chromatography on SiO2 (hexanes/EtOAc, 80/20) to give 12i as a brown solid (24%). 1H NMR (500
MHz; CDCl3) 2.34 (s, 3H), 2.46 (s, 3H), 2.55 (s, 3H), 3.84 (s, 3H), 6.96 (d, J = 8.7 Hz, 2H), 7.29 (d, J
= 8.7 Hz, 2H), 8.04 (br s, 1H) ppm. 13C NMR (126 MHz; CDCl3) 12.78, 15.28, 31.20, 55.50, 110.14,
114.36, 116.16, 125.28, 127.72, 129.19, 134.41, 158.86, 195.80 ppm. HRMSꢀAPCI (m/z): [M+H]+
calcd for C15H18NO2, 244.1332; found, 244.1324.
1-(2,4-dimethyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrrol-3-yl)ethanone (12j)
Pyrrole 12j was obtained according to GP4. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 80/20) to give 12j as a pale beige solid (48%). H NMR
(500 MHz; CDCl3) 2.38 (s, 3H), 2.46 (s, 3H), 2.56 (s, 3H), 7.46 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.2
19
13
Hz, 2H), 8.33 (br s, 1H) ppm. F NMR (471 MHz; CDCl3) ꢀ63 ppm. C NMR (125 MHz; CDCl3)
12.8, 15.3, 31.3, 118.6, 123.2, 125.4, 125.9, 126.5, 127.6, 128.6, 135.8, 136.2, 195.8 ppm. HRMSꢀESI
(m/z): [M+Na]+ calcd for C15H14FNNaO, 304.0920; found, 304.0926.
1-(2,4-dimethyl-5-(thiophen-2-yl)-1H-pyrrol-3-yl)ethanone (12k)
Pyrrole 12k was obtained according to GP4. The crude mixture was purified using column
1
chromatography on SiO2 (hexanes/EtOAc, 85/15) to give 12k as a pale beige solid (58%). H NMR
(500 MHz; CDCl3) 2.41 (s, 3H), 2.46 (s, 3H), 2.55 (s, 3H), 7.02 (dd, J = 3.5 and 0.9 Hz, 2H), 7.08 (dd,
J = 5.1 and 3.6 Hz, 2H), 7.28 (dd, J = 5.1 and 1.0 Hz), 8.08 (br s, 1H) ppm. 13C NMR (125 MHz;
CDCl3) 12.7, 15.1, 31.1, 118.1, 122.8, 124.2, 124.3, 127.5, 133.3, 134.2, 134.9, 195.5ppm. HRMSꢀESI
(m/z): [M+Na]+ calcd for C12H13NNaOS, 242.0610; found, 242.0615.
24

Page 25 of 28
Decarboxylative arylation of substituted pyrroles N-protected with
2-(trimethylsilyl)ethoxymethyl (SEM)
531
532
Supplementary material
Supplementary material is available with the article through the journal Web site at XXX.
533
534
535
Acknowledgement
Financial support from the Natural Sciences and Engineering Council of Canada (NSERC) is gratefully
acknowledged.
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
References and Notes
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(2)
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(5)
(6)
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(8)
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TOC artwork
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