Regioselective synthesis of highly aryl-substituted pyrrole carboxylates as useful medicinal chemistry leads

Article abstract of DOI:10.1080/00397910701481237

The regioselective syntheses of two pharmaceutically relevant pyrrole scaffolds are described. A synthetic route for the preparation of differentially substituted pyrrole-3,4-dicarboxylates is presented and exemplified. This route circumvents some of the

Full text of DOI:10.1080/00397910701481237

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Regioselective Synthesis of Highly
Aryl‐Substituted Pyrrole Carboxylates as
Useful Medicinal Chemistry Leads
Ulhas Bhatt a , Bryan C. Duffy a , Peter R. Guzzo a , Leifeng Cheng b &
Thomas Elebring b
a Albany Molecular Research, Inc. , Albany, New York, USA
b AstraZeneca R&D Mölndal , Mölndal, Sweden
Published online: 14 Aug 2007.
To cite this article: Ulhas Bhatt , Bryan C. Duffy , Peter R. Guzzo , Leifeng Cheng & Thomas Elebring (2007)
Regioselective Synthesis of Highly Aryl‐Substituted Pyrrole Carboxylates as Useful Medicinal Chemistry Leads,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
37:16, 2793-2806, DOI: 10.1080/00397910701481237
To link to this article: http://dx.doi.org/10.1080/00397910701481237
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Synthetic Communicationsw, 37: 2793–2806, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701481237
Regioselective Synthesis of Highly Aryl-
Substituted Pyrrole Carboxylates as Useful
Medicinal Chemistry Leads
Ulhas Bhatt, Bryan C. Duffy, and Peter R. Guzzo
Albany Molecular Research, Inc., Albany, New York, USA
Leifeng Cheng and Thomas Elebring
¨ ¨
AstraZeneca R&D Molndal, Molndal, Sweden
Abstract: The regioselective syntheses of two pharmaceutically relevant pyrrole
scaffolds are described. A synthetic route for the preparation of differentially substi-
tuted pyrrole-3,4-dicarboxylates is presented and exemplified. This route circumvents
some of the problems and limitations associated with previous butynedioic diester con-
densations and 1,3-dipolar cycloaddition reactions. A route to the related 4,5-diarylpyr-
role-2-carboxylic acid scaffold is also presented. Both routes allow for the
regiocontrolled preparation of highly substituted pyrrole pharmacophore cores.
Keywords: condensation, heterocycles, hydrazides, ketones, pyrroles
INTRODUCTION
Pharmaceutically relevant molecules tend to fall into classes based on privi-
leged core structures. The bis-aryl substituted five-membered heterocycle
template is observed in many recently approved pharmaceuticals. One
subset of this template is the biologically active bis-aryl pyrrole series. The
most well-known example is atorvastatin calcium (Fig. 1).
Received in the USA January 10, 2007
Address correspondence to Bryan C. Duffy, Albany Molecular Research, Inc.,
30 Corporate Circle, P. O. Box 15098, Albany, NY 12212-5098, USA. E-mail:
bryan.duffy@amriglobal.com
2793

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U. Bhatt et al.
Figure 1. Bis-aryl pyrroles.
Although many examples of scaffold I have been prepared by
Paal–Knorr[1] synthesis in the literature, scaffolds II and III are much less
common. Most literature syntheses of pyrrole-3,4-dicarboxylates (II) are
based on the condensation of a 2-phenylsulfonylaziridine with a butynedioic
diester[2] or other 1,3-dipolar cycloadditions to a substituted alkyne.[3]
These earlier routes possess the inherent disadvantage of poor regiocontrol
in preparing unsymmetrical diester products. The only literature preparation
of scaffold III is based on aryl couplings with bromopyrroles.[4] As part of
a drug discovery program, a regioselective route to unsymmetrical dicarbox-
ylate scaffold II and also a novel route to 4,5-diarylpyrrole-2-carboxylic acid
scaffold III were developed. These routes provide regiocontrolled method-
ology to pharmaceutically interesting cores with multiple points of
derivatization.
RESULTS AND DISCUSSION
The preparation of scaffold of type II was initiated with the intention of
preparing regiocontrolled, pentasubstituted pyrrole products. Ethyl and
tert-butyl esters were chosen based on their complementary hydrolysis pro-
cedures. This selective deprotection approach allowed further regiocontrolled
carboxylate derivatization at each site. Commercially available acid chlorides
1a and 1b were used to prepare the respective Weinreb[5] amides 2a[6] and
2b[7] in ꢀ95% yield (Scheme 1).

Aryl-Substituted Pyrrole Carboxylates
2795
Scheme 1. (i) HCl † NH(OMe)Me, pyridine, CH2Cl2; (ii) t-BuOAc, LDA, THF,
–788C; (iii) NaOEt, EtOH, then ethyl 2-bromoacetoacetate; (iv) EtOH, AcOH.
2a: 1H NMR (300 MHz, CDCl3) d 7.66 (d, J ¼ 8.7 Hz, 2H), 7.38
(d, J ¼ 8.7 Hz, 2H), 3.54 (s, 3H), 3.36 (s, 3H); ESI MS m/z 200
[C9H10ClNO2 þ H]þ. Our data were in good agreement with those provided
in Ref. 6.
2b: 1H NMR (300 MHz, CDCl3) d 7.66 (d, J ¼ 8.7 Hz, 2H), 7.38
(d, J ¼ 8.7 Hz, 2H), 3.54 (s, 3H), 3.36 (s, 3H); ESI MS m/z 234
[C9H9Cl2NO2 þ H]þ. Our data were in good agreement with those provided
in Ref. 7.
Condensation of the N,O-dimethylhydroxyamides with the enolate of
tert-butyl acetate gave esters 3a and 3b in 100% and 89% yields, respectively.
The key step in the synthesis was the condensation of the b-ketoesters with an
a-haloketone.[8] Deprotonation of 3a and 3b with sodium ethoxide in ethanol
followed by treatment of each with ethyl 2-bromoacetoacetate gave highly
functionalized, key intermediates 4a and 4b in 19% and 25% yields, respect-
ively. Paal–Knorr cyclizations of 4a or 4b with anilines 5a–c in refluxing
acetic acid and ethanol gave pyrroles 6a–d in yields ranging from 20–77%.
To demonstrate their selective deprotection potential, compounds 6a–c
were first hydrolyzed to their corresponding acids (7a–c) in good yields
(75–98%) using sodium hydroxide in aqueous ethanol (Scheme 2).
Four traditional amide couplings were performed on this system using
benzotriazo-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
(BOP reagent)[9] to give hydrazides 8a–d in yields ranging from 45 to
69%. Alternatively, ester 6d was treated with trifluoroacetic acid to selectively
deprotect the t-butyl ester in the presence of the ethyl ester to give carboxylic
acid 9 quantitatively (Scheme 3). Coupling of acid 9 with 1-aminopiperidine

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U. Bhatt et al.
Scheme 2. (i) NaOH, H2O/EtOH, reflux; (ii) BOP reagent, Et3N, 1-aminopiperidine,
CH2Cl2; (iii) BOP reagent, Et3N, 4-trifluoromethylphenyl hydrazine, CH2Cl2.
gave the alternatively substituted derivative 10 in 56% yield. The utility of this
route was further demonstrated through the preparation of pyrrolosuccinimide
12. Ester 10 was hydrolyzed under basic conditions to give acid 11 in 87%
yield. The cyclization of 11 to form ring-fused 12 in 65% yield was used to
Scheme 3. (i) CF3COOH, CH2Cl2; (ii) BOP reagent, Et3N, 1-aminopiperidine,
CH2Cl2; (iii) NaOH, H2O/EtOH, reflux; (iv) BOP reagent, Et3N, CH2Cl2.

Aryl-Substituted Pyrrole Carboxylates
2797
confirm the structure of intermediate 11. The formation of acid 11 also fully
exemplified the ability to selectively deprotect and derivatize the differen-
tiated esters in either order.
The preparation of scaffold III began with the preparation of ketones 14a
and 14b in 57% and 59% yield respectively.
1
Data for 14a: H NMR (300 MHz, CDCl3) d 7.92 (dd, J ¼ 6.9 Hz,
1.5 Hz, 2H), 7.43 (dd, J ¼ 7.2 Hz, 1.8 Hz, 2H), 7.31 (d, J ¼ 8.4 Hz, 2H),
7.18 (d, J ¼ 8.4 Hz, 2H), 4.23 (s, 2H).
1
Data for 14b: H NMR (300 MHz, CDCl3) d 7.97 (dd, J ¼ 6.6 Hz,
1.8 Hz, 2H), 7.40–7.50 (m, 3H), 7.15–7.25 (m, 2H), 4.37 (s, 2H). Our data
were in good agreement with those provided in Ref. 10.
This was achieved through the addition of Grignard reagents 13a and 13b
to previously prepared Weinreb amide 2a (Scheme 4). The ketones were
deprotonated and condensed with methyl glycidate ester to give alcohols
15a and 15b in 34% and 47% yield, respectively. Dess–Martin periodinane
oxidation[11] of the alcohols provided the key precursors 1,4-diketoesters
16a and 16b for the pyrrole-forming cyclization.
Esters 16a and 16b were condensed with n-propylamine and methylamine
respectively (Scheme 5). Condensation of 16a with n-propylamine in
refluxing acetic acid and ethanol gave 17a in 61% yield from 15a. Hydrolysis
of 17a with sodium hydroxide in aqueous ethanol gave the acid intermediate
in 73% yield. The acid was immediately coupled with BOP reagent and
1-aminopiperidine to give amide 18a in 59% yield. The volatility of methyl-
amine solutions required the condensation of diketone 16b be performed in a
Scheme 4. (i) 2a, ether; (ii) (a) NaH, THF, 08C, (b) methyl-(R)-glycidate; (iii) Dess–
Martin periodinane, CH2Cl2.

2798
U. Bhatt et al.
Scheme 5. (i) n-propylamine, CH3CO2H, EtOH, reflux; (ii) methylamine, CH3CO2H,
EtOH, sealed tube; (iii) NaOH, EtOH, H2O, reflux; (iv) BOP, 1-aminopiperidine, Et3N,
CH2Cl2; (v) KOH, 18-crown-6, ethylene glycol, reflux.
sealed tube. In addition to forming the pyrrole, the excess of highly nucleophi-
lic methylamine displaced the methyl ester simultaneously under the conden-
sation conditions to give methyl amide 17b in 75% yield. The methyl amide of
17b proved difficult to hydrolyze; however, treatment of 17b with potassium
hydroxide and 18-crown-6 at high temperature in ethylene glycol afforded the
acid intermediate in 95% yield. Coupling of the crude acid and 1-aminopiper-
idine with BOP reagent furnished pyrrole 18b in 26% yield.
In summary, we have exemplified the preparation of two highly functio-
nalized, medicinally interesting pyrrole scaffolds. The scaffolds can be
quickly prepared from commercially available starting materials. The
products from these pyrrole syntheses provide sites for further derivatization
via the differentially protected esters of scaffold II or the single methyl ester of
scaffold III. These synthetic routes complement the currently available litera-
ture methods for the preparation of highly substituted pyrrole scaffolds.
EXPERIMENTAL
Unless otherwise noted, reagents and solvents were used as received from
commercial suppliers. All reactions were performed using oven-dried
glassware under an atmosphere of nitrogen unless otherwise indicated.
Proton and carbon nuclear magnetic resonance spectra were obtained on a
Bruker AV 300 spectrometer at 300 MHz for proton or on a Bruker AV 500

Aryl-Substituted Pyrrole Carboxylates
2799
spectrometer at 500 MHz for proton. Spectra are given in parts per million (d),
and coupling constants, J, are reported in Hertz. Tetramethylsilane was used
as an internal standard for proton spectra, and the solvent peak was used as
the reference peak for carbon spectra. Melting points were obtained in open
capillary tubes and are uncorrected. Mass spectra were obtained on a
Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) mass
spectrometer. HPLC analyses were obtained using a Symmetry C18 column
(250 ꢁ 4.6 mm, Waters) with UV detection at 254 nm using gradient
elution (10% to 100% acetonitrile in water containing 0.1% TFA over
30 min, then hold for 5 min).
General Procedure for the Preparation of Compounds 3a and b
A solution of lithium diisopropylamide (LDA) was prepared at 2108C by the
addition of 1.6 M n-BuLi in hexanes (1.0 eq) to diisopropylamine (1.0 eq) in
THF followed by warming to room temperature. The solution of LDA was
cooled to 2788C, and tert-butyl acetate (1.0 eq) was added to it dropwise.
After 15 min, a solution of compound 2 (0.8 eq) in THF was slowly added
to it. The solution was stirred for an hour at 2788C and then allowed to
warm to room temperature over 3 h. The solution was acidified with
aqueous 1 N HCl solution and extracted into ether. The organic layer was
dried (MgSO4) and concentrated to afford the crude product, which was
used directly in the next step.
Data
3-(4-Chlorophenyl)-3-oxo-propionic acid tert-butyl ester (3a). (6.8 g,
ꢀ100%); 1H NMR (300 MHz, CDCl3) (keto form only)
d 7.88
(d, J ¼ 8.7 Hz, 2H), 7.45 (d, J ¼ 8.7 Hz, 2H), 3.87 (s, 2H), 1.43 (s, 9H);
ESI MS m/z 198 [C13H15ClO32C4H9 þ H]þ.
3-(2,4-Dichlorophenyl)-3-oxo-propionic acid tert-butyl ester (3b). (5.5 g,
1
89%); H NMR (300 MHz, CDCl3) (keto form only) d 7.88 (d, J ¼ 8.7 Hz,
2H), 7.45 (d, J ¼ 8.7 Hz, 2H), 3.87 (s, 2H), 1.43 (s, 9H); ESI MS m/z 233
[C13H14Cl2O32C4H9 þ H]þ.
General Procedure for the Preparation of Compounds 4a and b
(General Method A)
A solution of b-keto ester 3a and b (1.0 eq) in ethanol was treated with a
solution of sodium ethoxide in ethanol (1.2 eq). After 10 min, this solution
was added to a solution of ethyl 2-bromoacetoacetate (1.1 eq) in 1:1

2800
U. Bhatt et al.
ethanol/toluene. The resulting solution was stirred at room temperature for
7 h. The solution was quenched by adding 0.5 N HCl solution and extracted
into EtOAc. The organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by flash column chromatography
to afford product 4a and b.
Data
2-Acetyl-3-(4-chlorobenzoyl)-succinic acid 4-tert-butyl ester 1-ethyl ester
1
(4a): (1.4 g, 19%); H NMR (300 MHz, CDCl3) d 8.02–8.06 (m, 2H), 7.26–
7.48 (m, 2H), 5.21 (d, J ¼ 6.8 Hz, 0.5 H), 5.11 (d, J ¼ 6.6 Hz, 0.5H), 4.70
(d, J ¼ 5.7 Hz, 0.5H), 4.68 (d, J ¼ 5.7 Hz, 0.5H), 4.25 (q, J ¼ 2.7 Hz, 1H),
4.07 (q, J ¼ 3.6 Hz, 1H), 2.50 (s, 1.5H), 2.38 (s, 1.5H), 1.32 (s, 4.5H), 1.26
(s, 4.5H), 1.13(t, J ¼ 4.5 Hz, 3H);ESIMSm/z327[C19H23ClO6 2 C4H9 þ H]þ.
2-Acetyl-3-(2,4-dichlorobenzoyl)-succinic acid 4-tert-butyl ester 1-ethyl
ester (4b): (2.62 g, 25%); 1H NMR (300 MHz, CDCl3) d 8.02–8.07
(m, 2H), 7.45–7.49 (m, 2H), 5.22 (d, J ¼ 11.1 Hz, 0.5H), 5.12
(d, J ¼ 11.1 Hz, 0.5 H), 4.70 (d, J ¼ 6.0 Hz, 0.5H), 4.67 (d, J ¼ 6.0 Hz,
0.5H), 4.25 (q, J ¼ 7.2 Hz, 1H), 4.07 (q, J ¼ 7.2 Hz, 1H), 2.50 (s, 1.5H),
2.38 (s, 1.5H), 1.32 (s, 4.5H), 1.30 (s, 4.5H), 1.10 (t, J ¼ 7.2 Hz, 3H); ESI
MS m/z 327 [C19H23ClO6 2 C4H9 þ H]þ.
General Procedure for the Preparation of Compounds 6a–d
(General Method B)
A solution of compound 4a and b (1.0 eq), substituted aniline 5a–c (1.6 eq),
and acetic acid (1.0 eq) in ethanol was heated at reflux for 24 h. After cooling,
the reaction was quenched by the addition of a saturated aqueous NaHCO3
solution and extracted into EtOAc. The organic layer was dried (MgSO4)
and concentrated under reduced pressure. The residue was purified by flash
column chromatography to afford the product 6a–d.
Data
1-(2-Chlorophenyl)-2-(4-chlorophenyl)-5-methyl-1H-pyrrole-3,4-dicarbo
xylic acid 3-tert-butyl ester 4-ethyl ester (6a): (0.5 g, 36%); 1H NMR
(300 MHz, CDCl3) d 7.10–7.50 (m, 8H), 4.34 (d, J ¼ 7.2 Hz, 2H), 2.22
(s, 3H), 1.37 (s, 9H); ESI MS m/z 418 [C25H25Cl2NO4 – C4H9 þ H]þ.
2-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-5-methyl-1H-pyrrole-3,4-di
carboxylic acid 3-tert-butyl ester 4-ethyl ester (6b): (0.12 g, 20%); 1H NMR
(300 MHz, CDCl3) d 6.70–7.40 (m, 7H), 4.34 (d, J ¼ 7.2 Hz, 2H), 3.78

Aryl-Substituted Pyrrole Carboxylates
2801
(s, 3H), 2.04 (s, 3H), 1.36 (t, J ¼ 7.2 Hz, 3H), 1.28 (s, 9H); ESI MS m/z 504
[C26H27Cl2NO5 þ H]þ.
1,2-Bis-(4-chlorophenyl)-5-methyl-1H-pyrrole-3,4-dicarboxylic acid
3-tert-butyl ester 4-ethyl ester (6c): (0.53 g, 77%); 1H NMR
(300 MHz, CDCl3) d 7.31 (d, J ¼ 8.7 Hz, 2H), 7.18 (d, J ¼ 8.5 Hz, 2H),
7.05 (d, J ¼ 8.5 Hz, 2H), 6.96 (d, J ¼ 8.4 Hz, 2H), 4.33 (q, J ¼ 7.2 Hz,
2H), 2.28 (s, 3H), 1.38 (s, 9H), 1.36 (t, J ¼ 6.9 Hz, 3H); ESI MS m/z
418 [(C25H25Cl2NO4 2 C4H9) þ H]þ.
2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-5-methyl-1H-pyrrole-3,4-dicar-
1
boxylic acid 3-tert-butyl ester 4-ethyl ester (6d): (1.55 g, 48%); H NMR
(300 MHz, CDCl3) d 7.14 (d, J ¼ 8.5 Hz, 2H), 7.06 (d, J ¼ 8.5 Hz, 2H),
6.93 (d, J ¼ 8.9 Hz, 2H), 6.84 (d, J ¼ 8.9 Hz, 2H), 4.33 (q, J ¼ 7.2 Hz,
2H), 3.80 (s, 3H), 2.27 (s, 3H), 1.38 (s, 9H), 1.33 (t, J ¼ 7.2 Hz, 3H); ESI
MS m/z 414 [C26H28ClNO5 2 C4H9 þ H]þ.
General Procedure for the Preparation of Compounds 7a–c
(General Method C)
A solution of compound 6a–c (1.0 eq) in ethanol was combined with a 1.0 M
solution of NaOH (3 eq). The resulting solution was heated at reflux for 6 h,
poured into ice-cold aqueous 0.5 N HCl solution, and extracted into EtOAc.
The organic layer was separated, dried (MgSO4), and concentrated under
reduced pressure to afford product 7a–c.
Data
1-(2-Chlorophenyl)-2-(4-chlorophenyl)-5-methyl-1H-pyrrole-3,4-dicar-
1
boxylic acid 3-tert-butyl ester (7a): (0.40 g, 75%); H NMR (300 MHz,
CD3OD) d 7.20–7.52 (m, 8H), 2.29 (s, 3H), 1.24 (s, 9H); ESI MS m/z
446 [C23H21Cl2NO4 þ H]þ.
2-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-5-methyl-1H-pyrrole-3,4-
dicarboxylic acid 3-tert-butyl ester (7b): (0.13 g, 98%); 1H NMR (300 MHz,
CD3OD) d 7.20–7.52 (m, 8H), 2.29 (s, 3H), 1.24 (s, 9H); ESI MS m/z 446
[C24H23Cl2NO5 þ H]þ.
1,2-Bis-(4-chlorophenyl)-5-methyl-1H-pyrrole-3,4-dicarboxylic acid 3-
1
tert-butyl ester (7c): (0.44 g, 88%); H NMR (300 MHz, CD3OD) d 7.39
(d, J ¼ 7.2 Hz, 2H), 7.26 (d, J ¼ 8.4 Hz, 2H), 7.10–7.20 (m, 4H), 2.35
(s, 3H), 1.25 (s, 9H); ESI MS m/z 387 [C23H17Cl2NO4 2 C4H9 þ H]þ.

2802
U. Bhatt et al.
General Procedure for the Preparation of Hydrazides 8a–d
(General Method D)
This procedure illustrates the general methods for the preparation of hydra-
zides 8a–d, 10, 12, 18a, and 18b. A solution of acid 7a–c (1.0 eq) in
CH2Cl2 at 08C under N2 was treated with triethylamine (2.5 eq), BOP
reagent (1.2 eq), and 1-aminopiperidine (1.2 eq for targets 8a–c) or
4-trifluoromethylphenyl hydrazine (1.2 eq for target 8d). The resulting
solution was stirred at room temperature for 18 h and then diluted with
water. The organic layer was separated, washed with water, dried (MgSO4),
and concentrated under reduced pressure. The residue was purified by flash
column chromatography to afford product 8a–d.
Data
1-(2-Chlorophenyl)-2-(4-chlorophenyl)-5-methyl-4-(piperidin-1-ylcar-
bamoyl)-1H-pyrrole-3-carboxylic acid tert-butyl ester (8a): (0.15 g,
69%); mp 225–2268C; 1H NMR (300 MHz, CDCl3) d 7.10–7.50
(m, 8H), 2.84–2.87 (m, 4H), 2.10 (s, 3H), 1.70–1.76 (m, 4H), 1.45–1.50
(m, 2H), 1.22 (s, 9H); ESI MS m/z 528 [C28H31Cl2N3O3 þ H]þ; HPLC
96.0% (AUC), tR ¼ 19.3 min.
2-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-5-methyl-4-(piperidin-
1-ylcarbamoyl)-1H-pyrrole-3-carboxylic acid tert-butyl ester (8b):
(0.11 g, 45%); mp 188–1898C; 1H NMR (300 MHz, CDCl3) d 7.39
(d, J ¼ 1.7 Hz, 1H), 7.18–7.20 (m, 2H), 7.08 (d, J ¼ 8.0 Hz, 2H), 6.86
(d, J ¼ 8.5 Hz, 2H), 3.75 (s, 3H), 2.84–2.88 (m, 4H), 2.16 (s, 3H), 1.72–
1.76 (m, 4H), 1.40–1.60 (m, 2H), 1.18 (s, 9H); ESI MS m/z 558
[C29H33Cl2N3O4 þ H]þ; HPLC .99% (AUC), tR ¼ 19.4 min.
1,2-Bis-(4-chlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-1H-pyrrole-
1
3-carboxylic acid tert-butyl ester (8c): (0.29 g, 55%); mp 271–2728C; H
NMR (300 MHz, CD3OD) d 7.36 (d, J ¼ 8.6 Hz, 2H), 7.23 (d, J ¼ 8.4 Hz,
2H), 7.09–7.15 (m, 4H), 2.83–2.85 (m, 4H), 2.15 (s, 3H), 1.70–1.76
(m, 4H), 1.45–1.50 (m, 2H), 1.23 (s, 9H); ESI MS m/z 528
[C28H31Cl2N3O3 þ H]þ; HPLC 97.5% (AUC), tR ¼ 19.9 min.
1-(2-Chlorophenyl)-2-(4-chlorophenyl)-5-methyl-4-[N0-(4-trifluoromethyl-
phenyl)-hydrazinocarbonyl]-1-H-pyrrole-3-carboxylic acid tert-butyl
1
ester (8d): (0.14 g, 65%); mp 169–1708C; H NMR (300 MHz, CDCl3) d
7.20–7.50 (m, 10H), 7.03 (d, J ¼ 8.4 Hz, 2H), 2.18 (s, 3H), 1.23 (s, 9H);
ESI MS m/z 604 [C30H26Cl2F3N3O3 þ H]þ; HPLC . 99% (AUC),
tR ¼ 31.5 min.

Aryl-Substituted Pyrrole Carboxylates
2803
5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-5-methyl-1H-pyrrole-3,4-dicar-
boxylic acid 4-ethyl ester (9). A solution of compound 8d (0.40 g,
0.85 mmol) in CH2Cl2 (1.0 mL) was treated with trifluoroacetic acid
(0.6 mL) and stirred at room temperature for 3 h. The solution was concen-
trated under reduced pressure, and the resulting residue was co-evaporated
from ether to afford acid 9 (0.35 g, 100%) as a brown solid; 1H NMR
(300 MHz, DMSO-d6) d 7.29 (d, J ¼ 6.6 Hz, 2H), 7.15–7.20 (m, 4H), 6.93
(d, J ¼ 6.6 Hz, 2H), 4.20 (q, J ¼ 7.0 Hz, 2H), 3.75 (s, 3H), 2.17 (s, 3H),
1.25 (t, J ¼ 7.2 Hz, 3H); ESI MS m/z 414 [C22H20ClNO5 þ H]þ.
5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-2-methyl-4-(piperidn-1-ylcar-
bamoyl)-1H-pyrrole-3-carboxylic acid ethyl ester (10). Compound 9
(0.25 g, 0.60 mmol) was treated with 1-aminopiperidine using general
method D to afford 10: (0.17 g, 56%); 1H NMR (300 MHz, CDCl3) d
7.08–7.12 (m, 4H), 6.85–6.91 (m, 4H), 4.33 (q, J ¼ 7.2 Hz, 2H), 3.80
(s, 3H), 2.60–2.70 (m, 4H), 2.05 (s, 3H), 1.60–1.65 (m, 4H), 1.30–1.40
(m, 2H), 1.26 (t, J ¼ 7.2 Hz, 3H); ESI MS m/z 496 [C27H30ClN3O4 þ H]þ.
5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-2-methyl-4-(piperidin-1-ylcarba-
moyl)-1H-pyrrole-3-carboxylic acid (11). A solution of compound 10 (0.17 g,
0.33 mmol) in ethanol (2 mL) was combined with a 1.0 M solution of NaOH
(2 mL, 2.0 mmol). The resulting solution was heated at reflux for 18 h,
poured into ice-cold, aqueous 1 N HCl, and extracted into EtOAc. The
organic layer was separated, dried (MgSO4), and concentrated to afford acid
1
11 (0.14 g, 87%) as a yellow powder; H NMR (300 MHz, CD3OD) d 7.22
(d, J ¼ 8.5 Hz, 2H), 7.13 (d, J ¼ 8.5 Hz, 2H), 7.08 (d, J ¼ 8.9, 2H), 6.93
(d, J ¼ 8.9 Hz, 2H), 3.80 (s, 3H), 3.30–3.40 (m, 4H), 2.36 (s, 3H), 1.80–
1.90 (m, 4H), 1.50–1.70 (m, 2H); ESI MS m/z 468 [C25H26ClN3O4 þ H]þ.
4-(4-Chlorophenyl)-5-(4-methoxyphenyl)-6-methyl-2-piperidin-1-yl-5H-
pyrrole[3,4-c]pyrrole-1,3-dione (12). Acid 11 (0.11 g, 0.24 mmol) was
treated according to general method D without the additional of a hydrazine
to afford compound 12 (0.07 g, 65%) as a white powder. Mp 237–2398C;
1H NMR (300 MHz, CDCl3)
d
7.29 (d, J ¼ 8.6 Hz, 2H), 7.18
(d, J ¼ 8.5 Hz, 2H), 7.08 (d, J ¼ 8.7 Hz, 2H), 6.95 (d, J ¼ 8.7 Hz, 2H),
3.86 (s, 3H), 3.32–3.36 (m, 4H), 2.25 (s, 3H), 1.70–1.74 (m, 4H), 1.45–
1.50 (m, 2H); ESI MS m/z 450 [C25H24ClN3O3 þ H]þ; HPLC . 99%
(AUC), tR ¼ 27.2 min.
General Procedure for the Preparation of Compounds 15a and b
(General Method E)
A solution of ketone 14a and b (1.0 eq) in THF was treated with washed 60%
NaH dispersion in oil (1.0 eq). After 15 min a solution of methyl (2R)-

2804
U. Bhatt et al.
glycidate (1.0 eq) was added, and the resulting solution was stirred at room
temperature for 18 h. The reaction was quenched through the addition of
saturated aqueous NH4Cl solution and extracted into diethyl ether. The
organic layer was separated, dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by flash column chromatography
to afford ester 15a and b.
Data
4,5-Bis-(4-chlorophenyl)-2-hydroxy-5-oxo-pentanoic acid methyl ester
(15a): (1.41 g, 34%); 1H NMR (mixture of diasteroisomers) (300 MHz,
CDCl3) d 7.10–7.90 (m, 8H), 4.80–5.00 (m, 2H), 4.20–4.30 (m, 1H),
3.80–3.90 (m, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 2.80–3.00 (m, 2H), 2.10–
2.40 (m, 2H); ESI MS m/z 349 [C18H15Cl3O4 – OH þ H]þ.
5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-2-hydroxy-5-oxo-pentanoic
1
acid methyl ester (15b): (3.61 g, 47%); H NMR (mixture of diasteroi-
somers) (300 MHz, CDCl3) d 7.90 (d, J ¼ 1.7 Hz, 1H), 7.87 (d, J ¼ 1.7 Hz,
1H), 7.35–7.45 (m, 3H), 7.10–7.20 (m, 2H), 5.30–5.40 (m, 1H), 4.20–4.30
(m, 0.5H), 4.00–4.10 (m, 0.5H), 3.78 (s, 1.5H), 3.71 (s, 1.5H), 2.82 (dd,
J ¼ 24 Hz, 5.5 Hz, 1H), 2.70–2.80 (m, 0.5H), 2.40–2.50 (m, 0.5H), 2.20-
2.30 (m, 0.5H), 1.85–1.95 (m, 0.5H); ESI MS m/z 383 [C18H15Cl3O4 2
OH þ H]þ.
General Procedure for the Preparation of Compounds 16a and b
(General Method F)
A solution of alcohol 15a and b (1.0 eq) was taken up in CH2Cl2 containing
Dess–Martin periodinane (1.0 eq), and the resulting solution was stirred at
room temperature for 3 h. The solution was diluted with CH2Cl2 and
washed successively with aqueous Na2S2O3 solution and aqueous NaHCO3
solution. The organic layer was separated, dried (MgSO4), and concentrated
under reduced pressure to give diketones 16a and b, which were used
without further purification.
Data
1
4,5-Bis-(4-chlorophenyl)-2,5-dioxo-pentanoic acid methyl ester (16a): H
NMR (300 MHz, CDCl3) d 7.10–7.40 (m, 8H), 5.00 (m, 1H), 3.80–4.00
(m, 4H), 3.00–3.20 (m, 1H).
5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-2,5-dioxo-pentanoic acid methyl
1
ester (16b): H NMR (300 MHz, CDCl3) d 7.00–8.20 (m, 7H), 4.47 (dd,

Aryl-Substituted Pyrrole Carboxylates
2805
J ¼ 10.5 Hz, 3.3 Hz, 1H), 3.90 (s, 3H), 3.80–3.90 (m, 1H), 3.02 (dd,
J ¼ 18.6 Hz, 3.3 Hz, 1H).
4,5-Bis-(4-chlorophenyl)-1-propyl-1H-pyrrole-2-carboxylic acid methyl
ester (17a). A solution of ketone 16a (1.4 g, 3.8 mmol) and n-propyl amine
(0.50 mL, 6.1 mmol) in ethanol (10 mL) and acetic acid (5 mL) was heated at
508C for 20 h. The solution was cooled to room temperature and concentrated
to half its volume under reduced pressure. The concentrate was diluted with
EtOAc and washed with water followed by saturated aqueous NaHCO3. The
organic layer was separated, dried (MgSO4), and concentrated under reduced
pressure. The residue was then purified by flash column chromatography
(silica gel, 9:1 hexanes/EtOAc) to afford 17a (0.91 g, 61% over two steps);
1H NMR (300 MHz, CDCl3) d 7.40 (d, J ¼ 6.6 Hz, 2H), 7.10–7.30 (m, 5H),
7.00 (dd, J ¼ 6.3 Hz, 2.0 Hz, 2H), 4.15 (t, J ¼ 7.5 Hz, 2H), 3.87(s, 3H), 1.55–
1.65 (m, 2H), 0.74 (t, J ¼ 7.5 Hz, 3H), ESI MS m/z 388 [C21H19Cl2NO2 þ H]þ.
5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-1-methyl-1H-pyrrole-2-car-
boxylic acid methylamide (17b). Solutions of diketone 16b (2.20 g,
5.7 mmol) in EtOH (5 mL), methylamine in EtOH (20 mL, 33 wt.%), and
neat acetic acid (10 mL) were charged into a sealed tube. The reaction
mixture was heated at 1008C for 14 h and then cooled to room temperature.
The solution was concentrated under reduced pressure, and the residue was
diluted with EtOAc. The organic layer was separated, washed with
saturated aqueous NaHCO3, dried (MgSO4), and concentrated under
reduced pressure. The crude residue was purified by flash column chromato-
graphy (silica gel, 4:1 hexanes/ethyl acetate) to give 17b (1.67 g, 75%); mp
1
166–1678C; H NMR (300 MHz, CDCl3) d 7.36 (d, J ¼ 2.1 Hz, 1H), 7.30
(d, J ¼ 8.4 Hz, 2H), 7.08 (d, J ¼ 8.4 Hz, 2H), 7.03 (dd, J ¼ 8.3 Hz, 2.1 Hz,
1H), 6.86 (d, J ¼ 8.4 Hz, 1H), 6.68 (s, 1H), 6.02 (d, J ¼ 3.1 Hz, 1H), 3.84
(s, 3H), 2.97 (d, J ¼ 4.5 Hz, 3H); ESI MS m/z 393 [C19H15Cl3N2O þ H]þ;
HPLC 97.0% (AUC), tR ¼ 25.8 min.
4,5-Bis-(4-chlorophenyl)-1-propyl-1H-pyrrole-2-carboxylic acid piperidin-
1-ylamide (18a). A solution of compound 17a (0.90 g, 2.3 mmol) in EtOH
(15 mL) was combined with aqueous 1.0 N NaOH (8 mL, 8 mmol). The
resulting mixture was heated at reflux for 28 h, poured into ice-cold aqueous
1 N HCl, and extracted into EtOAc. The organic extract was dried (MgSO4)
and concentrated under reduced pressure to afford the corresponding acid
(0.79 g, 73%) as a light brown solid. The crude acid was treated by general
method D to afford hydrazide 18a (0.56 g, 59%) as a white powder; mp
1
195–1968C; H NMR (300 MHz, CDCl3) d 7.29 (d, J ¼ 1.9 Hz, 1H), 7.00–
7.10 (m, 2H), 6.90–6.95 (m, 2H), 6.70–6.80 (m, 3H), 5.53 (s, 1H), 4.16
(t, J ¼ 7.5 Hz, 2H), 2.80–3.00 (m, 4H), 1.74–1.80 (m, 4H), 1.50–1.60
(m, 2H), 0.71 (t, J ¼ 7.5 Hz, 3H); ESI MS m/z 456 [C25H27Cl2N3O þ H]þ;
HPLC 99.0% (AUC), tR ¼ 24.7 min.

2806
U. Bhatt et al.
5-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-1-methyl-1H-pyrrole-2-car-
boxylic acid piperidin-1-ylamide (18b). Amide 17b (0.040 g, 0.10 mmol)
in ethylene glycol (1.0 mL) was treated with KOH (0.030 g, 0.53 mmol)
and 18-crown-6 (0.10 g, 0.38 mmol). The resulting mixture was heated at
reflux for 6 h, cooled to room temperature, and diluted with EtOAc. The
organic layer was separated, washed with aqueous 1 N HCl, dried
(MgSO4), and concentrated under reduced pressure to afford the correspond-
ing acid (0.050 g, 95%). The crude acid was treated by general method D to
afford hydrazide 18b (0.040 g, 26%) as a white powder; mp 208–2108C; 1H
NMR (300 MHz, CD3OD) d 7.40 (d, J ¼ 2.1 Hz, 1H), 7.35 (d, J ¼ 8.6 Hz,
2H), 7.16 (d, J ¼ 8.6 Hz, 3H), 7.07 (d, J ¼ 8.3 Hz, 1H), 6.87 (s, 1H), 3.77
(s, 3H), 2.80–2.90 (m, 4H), 1.70–1.80 (m, 4H), 1. 40–1.50 (m, 2H); ESI
MS m/z 462 [C23H22Cl3N3O þ H]þ; HPLC 96.2% (AUC), tR ¼ 19.9 min.
REFERENCES
1. Bean, G. P. The synthesis of 1H-pyrroles. Chem. Heterocycl. Compd. 1990, 48,
105–294.
2. Reutrakul, V.; Prapansiri, V.; Panyachotipun, C. A new method for the synthesis of
2-phenylsulfonyl carbanion with imines. Tetrahedron Lett. 1984, 25, 1949–1952.
3. Hamaguchi, M.; Ibata, T. Intermediatory formation of mesoionic imidazolium-
4-oxides in the reaction of a-haloacyl chlorides with amidines. Chem. Lett.
1975, 169–170.
4. Handy, S. T.; Bregman, H.; Lewis, J.; Zhang, X.; Zhang, Y. An unusual dehalo-
genation in the Suzuki coupling of 4-bromopyrrole-2-carboxylates. Tetrahedron
Lett. 2003, 44, 427–430.
5. Nahm, S.; Weinreb, S. M. N-Methoxy-N-methamides as effective acylating agents.
Tetrahedron Lett. 1981, 22, 3815–3818.
6. Mani, N. S.; Jablonowski, J. A.; Jones, T. K. A scalable synthesis of a histamine H3
receptor antagonist. J. Org. Chem. 2004, 69, 8115–8117.
7. Persson, T.; Nielsen, J. Synthesis of N-methoxy-N-methyl-b-enaminoketoesters:
New synthetic precursors for the regioselective synthesis of heterocyclic
compounds. Org. Lett. 2006, 8, 3219–3222.
8. Roomi, M. W.; Macdonald, S. F. Hantzsch pyrrole synthesis. Can. J. Chem. 1970,
48, 1689–1697.
9. Castro, B.; Doromy, J. R.; Evin, G.; Selve, C. Reactifs de couplage peptidique IV
(1)—L’hexafluorophosphate de benzotriazolyl-N-oxytrisdimethylamino-phos-
phonium (B.O.P). Tetrahedron Lett. 1975, 1219–1222.
10. Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.;
McCreary, A. C.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; de
Loof, W.; Verveer, P. C.; Kruse, C. G. Bioisosteric replacements of the pyrazole
moiety of rimonabant. J. Med. Chem. 2005, 48, 1823–1838.
11. Dess, D. B.; Martin, J. C. Readily accessible 12-I-5 oxidant for the conversion of
primary and secondary alcohols to aldehydes and ketones. J. Org. Chem. 1983, 48,
4155–4156.