Synthesis of 2-aryl-4-chloropyrroles via ring expansion of 2-aryl-1-chlorocyclopropanecarbaldehydes

Article abstract of DOI:10.1016/j.tet.2005.01.087

An efficient electrophile-induced ring opening of 2-aryl-1- chlorocyclopropanecarbaldehydes is described towards halogenated butanals, which were converted to the corresponding imines. These α,α,γ- trichloroimines proved to be good substrates for a nucleophile-induced ring closure towards 2-pyrrolines as versatile synthons for the synthesis of pyrroles bearing physiologically interesting substitution patterns.

Full text of DOI:10.1016/j.tet.2005.01.087

Tetrahedron 61 (2005) 2879–2887
Synthesis of 2-aryl-4-chloropyrroles via ring expansion of
2-aryl-1-chlorocyclopropanecarbaldehydes
*
Guido Verniest, Sven Claessens, Filip Bombeke, Tinneke Van Thienen and Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Received 23 September 2004; revised 14 January 2005; accepted 19 January 2005
Abstract—An efficient electrophile-induced ring opening of 2-aryl-1-chlorocyclopropanecarbaldehydes is described towards halogenated
butanals, which were converted to the corresponding imines. These a,a,g-trichloroimines proved to be good substrates for a nucleophile-
induced ring closure towards 2-pyrrolines as versatile synthons for the synthesis of pyrroles bearing physiologically interesting substitution
patterns.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
pyrrole (3) also inhibits various enzyme systems and the
cholesterol biosynthesis.3 Manzacidins A (4a) and B (4b)
are alkaloids isolated from the Okinawan sponge Hymeni-
acidon species.4 Roseophilin 5 is a 3-chloropyrrole found in
Streptomyces griseoviridis and displays antibiotic and anti-
leukemic properties.5 More than 20 compounds of the
‘oroidin’ (6) family of b-brominated pyrroles (i.e., 4-bromo-
and 4,5-dibromopyrrole-2-carboxamides) have been iso-
lated from Nature and tested for physiological activities.6
For instance, clathramides, isolated from Agelas clathrodes,
possess antifungal properties,7 while other oroidins show
antiserotoninergic (keramadine), cytotoxic (agelastatin),
antiviral (sceptrin), antihistaminergic (dispacamide) or
antifouling (mauritiamine) activities.6,8,9 With respect to
this diversity of activities related to halogenated pyrroles,
various synthetic methods to access these compounds
have been developed, where each method displays its
own advantages to access pyrroles with specific substitution
patterns.10 Of current interest for agrochemistry is the
synthesis of 3-halogenated pyrroles bearing electron with-
drawing groups (e.g., COOR, CN or CF3) (Fig. 2).11
In the unabated search for new physiologically active
compounds, the study of substituted pyrroles still remains
a subject of considerable importance. Halogenated
pyrroles isolated from Nature, associated with diverse
physiological activities, have served as lead structures to
synthesize pyrroles with current use in agrochemistry
(e.g., the antifungal pyrrolnitrin (1a) derivatives 1b,c)1
and medicine (e.g., 3-chloropyrrole 2, a fibrosis inhibitor)
(Fig. 1).2
Pentabromopseudilin 3 was first isolated from the marine
bacterium Alteromonas luteoviolaceus and shows antitumor,
antibacterial and antifungal activities. This polybrominated
Structure–activity relationship studies revealed that the
presence of an aryl moiety at one pyrrole a-carbon is
often responsible for specific biological activities, for
example, 2-arylpyrrole 7 and derivatives are insecticidal
compounds (100% mortality for Spodoptera eridania
treated with 7 at 10 mg/L).12 Related pyrroles 8 were
recently patented for the protection of wood from
termites.13 In addition, substituted pyrroles with cyano-
or carboxylic acid moieties at the a-carbon are important
intermediates in the synthesis of porphyrins and other
‘pigments of life’.14
Figure 1.
Keywords: Ring expansion; Pyrroles; Cyclopropanes.
* Corresponding author. Tel.: C32 9 264 59 51; fax: C32 9 264 62 43;
e-mail: norbert.dekimpe@UGent.be
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.087

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G. Verniest et al. / Tetrahedron 61 (2005) 2879–2887
reaction conditions did not result in the corresponding
imines 11. When an inverse imination procedure was
applied, a mixture of cyclopropanecarbaldehyde 9a and the
corresponding imine was obtained due to a-deprotonation
of 10 by isopropylamine. In order to eliminate the latter
reaction, g-bromo-a-chlorobutanal 10 was treated with
chlorine gas to synthesize the a,a-dichlorinated analogue,
which could be used as imine precursor. After chlorination,
an inseparable mixture of reaction products was obtained.
To overcome this problem an efficient synthesis of 4-aryl-
2,2,4-trichlorobutanals 12 was developed by a HCl-induced
ring opening and in situ chlorination of the obtained
intermediate a-chloroaldehydes.18 This procedure yielded
compounds 12 in almost quantitative yield, which could be
purified by distillation. Imination of compound 12 by the
use of various amines in the presence of titanium(IV)
chloride and subsequent treatment with potassium cyanide
in methanol yielded 5-aryl-3-chloro-2-cyano-2-pyrrolines
14 in good yield (Scheme 2). The obtained intermediate
imines 13 were not stable enough to purify by distillation or
chromatography and were used directly after isolation from
the reaction mixture. 2-Pyrrolines 14 proved to be stable at
low temperatures (K20 8C) for several days.
Figure 2.
In this article, an efficient synthesis of halogenated 2-
arylpyrroles from 3-aryl-2,2-dichlorocyclobutanones via the
intermediacy of 1-chlorocyclopropanecarbaldehydes is dis-
closed. Only a few publications report the use of
cyclopropanecarbaldehydes as building blocks for pyrrole
syntheses by thermal rearrangement of the corresponding
imines.15 In contrast, our approach deals with an initial ring
opening of appropriate 1-chlorocyclopropane-1-carbalde-
hydes. Subsequent imination of the resulting g-haloalde-
hydes followed by treatment with cyanide to induce a ring
closure provides a new entry towards synthetically useful
azaheterocyclic compounds.
2. Results and discussion
In continuation of the previously reported ring contraction
of 2,2-dihalocyclobutanones towards 1-chlorocyclopropane-
carbaldehydes 9, 16 attempts were made to validate the latter
compounds as useful synthons for the application in
azaheterocyclic synthesis.
Scheme 2.
Analogous to earlier reported electrophile-induced ring
opening reactions of cyclopropylketones under mild
conditions,17 a-chlorocyclopropanecarbaldehyde 9a was
treated with trimethylsilylchloride and sodium bromide to
yield a diastereomeric mixture of g-bromobutanals 10 (ratio
1:1) (Scheme 1). Compounds of this kind could be used to
construct five-membered azaheterocycles after imination.
Unfortunately, treatment of the aldehyde 10 with isopropyl-
amine in the presence of MgSO4 or TiCl4 under various
The treatment of 2-pyrrolines 14 with 4 equiv of 2 M
sodium methoxide in methanol at reflux temperature for 2 h
resulted in the formation of 3-chloropyrroles 16.
The mechanism can be rationalized by an initial base
induced isomerization towards 3-pyrrolines 15 and subse-
quent expulsion of cyanide. Further isomerization results in
2-aryl-4-chloropyrroles 16 in good yield (Scheme 2). With
this procedure b-chloropyrroles can be synthesized on a
multi-gram scale using cheap reagents and facile chemistry.
When handling pyrrolines 14 in wet solvents, often some
hydrolysis product was formed. These products (19) were
formed by electrophilic addition of a proton and subsequent
attack of water, as shown in Scheme 3. In a more controlled
manner, cis-substituted pyrrolidinones 19 could be obtained
quantitatively by treatment of pyrrolines 14 with aqueous
2 M HCl in acetic acid at room temperature. When higher
Scheme 1.

G. Verniest et al. / Tetrahedron 61 (2005) 2879–2887
2881
In a second approach, 2-pyrrolines 14 were oxidized
towards the corresponding pyrroles using DDQ in toluene.
This procedure yielded pyrroles in moderate yields. The
presence of the cyano functionality at the 2-position leaves
opportunities for functional group transformation to various
other physiologically interesting pyrroles, for example, 2-
acylpyrroles and derivatives. Attempts to hydrolyse the
cyano function with aqueous base or acid did not result in
pyrrole-2-carboxylate 23. Starting material accompanied
with decomposition products were recovered after treatment
of 21c with aq. 6 M HCl or 48% aq. HBr at reflux overnight.
Alkaline treatment with 50% aq. KOH at various tempera-
tures did not result in hydrolysis. Performing the reaction of
21c with KOH in boiling glycol, hydrolysis of the cyano
moiety and immediate decarboxylation occurred towards
pyrrole 16c.
Scheme 3.
To access 2-acylpyrroles 24a,b, pyrroles 21b,c were treated
with methyllithium resulting in the corresponding methyl-
imine, which was hydrolyzed by reaction with aq. 6 M HCl
at room temperature (Scheme 5, Table 1). Pyrrole-2-
carbaldehydes 24c–e could be synthesized by electrophilic
substitution of 2-unsubsituted pyrroles 16a–c. Vilsmeier
formylation of these pyrroles with DMF-POCl3 yielded
pyrrole-2-carbaldehydes 24c–e together with a minor
amount of the isomeric b-formylated pyrroles (10%–
35%), which could be easily separated by flash chromato-
graphy. Due to the fact that the electrophilic substitution of
pyrroles is kinetically driven to take place at the a-position,
the major compounds were the 2-formylated pyrroles 24c–e,
as expected. Analogous reactions were evaluated to
temperatures were applied (D, 15 h), a partial isomerization
of the cis-substituted pyrrolidinones 19 occurred towards
the more stable trans-3-chloro-5-phenyl-pyrrolidinones 20
resulting in a mixture of isomers (ratios, see Scheme 3),
which were separated by chromatography. The stereo-
chemical assignments of 19 and 20 were performed by
1
analysis of the coupling constants in H NMR.
In order to synthesize 2-cyanopyrroles which form a class
of compounds with specific physiological activities
(e.g., insecticide 712), the pyrrolines 14 were reacted with
NBS in tetrachloromethane to induce a radical bromination
yielding halogenated pyrrolines as good precursors for
pyrroles. Whereas the use of NBS only resulted in tarry
reaction mixtures, the reaction with NCS at reflux
temperatures in tetrachloromethane in the presence of a
catalytic amount of AIBN yielded 2-cyanopyrroles 21a,b in
good yield. In the reaction mixture, also minor amounts of
dichlorinated pyrroles 22 were detected (ratio 21/22 8:1),
which unfortunately could not be separated from the major
pyrroles 21 by flash chromatography. During optimalization
of the reaction by evaluation of various reaction conditions
and follow up of the formed reaction products by GC-MS, it
became clear that the formation of dichloropyrroles 22
started already at the early stage of the reaction, when still
starting material is present. No improvement of the ratio 21/
22 in favor of the monochloropyrrole 21 could be obtained
(Scheme 4).
Scheme 5.
Table 1. Synthesis of substituted 3-chloropyrroles 24 (Scheme 5)
Entry
Reaction conditions
Product
21b,c (R2ZCN)
(1) 1 equiv MeLi, THF, 0 8C, 30 min (2)
excess aq. 6 M HCl, rt, 1 h
(1) 1.2 equiv POCl3, DMF/CH2Cl2
(1:1), 0 8C, 5 h (2) excess aq. 1 M
NaOH, rt, 15 min
24a, 24b
16a–c (R2ZH)
24c–ea
16a (R2ZH)
1 equiv BuLi, 1 equiv ClCOOMe, THF,
0 8C, 2 h
24f
a Also the isomeric b-formylated pyrroles were formed (10–35%), which
could easily be separated by flash chromatography.
Scheme 4.

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G. Verniest et al. / Tetrahedron 61 (2005) 2879–2887
synthesize pyrrole-2-carboxylates. Friedel-Crafts acylation
using methyl chloroformate and aluminum(III) chloride in
carbon disulfide yielded a mixture of carboxylated pyrroles
25 and 24f with predominantly pyrrole 25 (ratio 1:4, resp.)
Substitution at b-position of pyrroles has previously been
observed when the nitrogen atom bears bulky groups.19
Indeed, the carboxylation of pyrrole 16c could be seen to be
a little more sterically demanding as compared with the
formylation, which shifts the ratio towards the 3-substituted
pyrrole 25. Also, under the used reaction conditions,
rearrangements of pyrrole substituents are known to result
in the thermodynamically most stable compounds (in casu
pyrrole 25).19 The HSAB-theory as a rationale for selective
acylations has only been demonstrated for pyrroles bearing
electron withdrawing groups at nitrogen, where the use of a
hard Lewis acid such as AlCl3 promotes C-3 acylation.20
However, N-alkyl- or N-unsubstituted pyrroles are generally
acylated at C-2. To accomplish a carboxylation at C-2,
deprotonation of the most acidic hydrogen of pyrrole 16c,
that is, the hydrogen at a-position, with BuLi and
subsequent reaction with methyl chloroformate yielded
exclusively methyl pyrrole-2-carboxylate 24f in good yield.
chlorination, the temperature was allowed to reach 65–
70 8C. After 15–20 min, when no temperature increase was
observed by addition of chlorine, the reaction was stopped
and cooled down to room temperature. The reaction mixture
was poured in 25 mL of concentrated HCl and extracted
with chloroform (3!20 mL). The combined organic
extracts were washed with an aqueous solution of sodium
bisulfite and subsequently with concentrated HCl (20 mL).
After drying (MgSO4), filtration and evaporation of the
solvent in vacuo, 2,2,4-trichloro-4-phenylbutanal 12a was
obtained which was purified by distillation (5.45 g, 81%).
3.1.1. 2,2,4-Trichloro-4-phenylbutanal 12a. Bp 80–85 8C,
0.05 mm Hg; yield 81%. H NMR (270 MHz, CDCl3): d
1
3.11 (1H, d!d, JZ15.5, 5.6 Hz, CHaHb), 3.32 (1H, d!d,
JZ15.5, 7.9 Hz, CHaHb), 5.22 (1H, d!d, JZ7.9, 5.6 Hz,
CH), 7.29–7.45 (5H, m, C6H5), 9.14 (1H, s, CHO). 13C
NMR (68 MHz, CDCl3): d 51.3 (CH2), 58.0 (CH), 85.9
(CCl2), 2!127.0 (2!CHar), 2!128.8 (2!CHar), 129.0
(CHar), 139.3 (Cquat), 183.5 (C]O). IR (NaCl) nmax
1738 cmK1. MS (70 eV) m/z (%) 250/52/54/56 (MC, 10);
151/53 (31); 138/40 (97); 125/27 (100); 115 (70); 91 (46);
77 (10).
In conclusion it can be stated that various interesting
halogenated pyrroles can be synthesized in a straightforward
manner from readily available 1-chlorocyclopropane-
carbaldehydes.16 In addition to the presence of a halogen
at b-position of the synthesized pyrroles, other interesting
substituents in relation to physiological activities, such as
an aryl, cyano or carbonyl moiety at a-position were
introduced to end up with highly substituted pyrroles with
specific substitution patterns.
3.1.2. 2,2,4-Trichloro-4-(4-chlorophenyl)butanal 12b. Bp
105–109 8C, 0.05 mm Hg; yield 76%. H NMR (270 MHz,
1
CDCl3): d 3.07 (1H, d!d, JZ15.2, 5.7 Hz, CHaHb), 3.28
(1H, d!d, JZ15.2, 7.8 Hz, CHaHb), 5.20 (1H, d!d, JZ
7.8, 5.7 Hz, CH), 7.26–7.36 (4H, m, C6H4), 9.17 (1H, s,
CHO). 13C NMR (68 MHz, CDCl3): d 50.9 (CH2), 57.3
(CH), 85.6 (CCl2), 2!128.6 (2!CHar), 2!129.2 (2!
CHar), 135.0 (Cquat), 138.1 (Cquat), 183.6 (C]O). IR (NaCl)
nmax 1742 cmK1. MS (70 eV) m/z (%): no MC, 214/16/18
(MCK2Cl, 44); 173 (100); 150 (95); 126 (36).
3. Experimental
1H NMR spectra (270 MHz or 300 MHz) and 13C NMR
spectra (68 MHz or 75 MHz) were recorded with a Jeol
JNM-EX 270 NMR spectrometer or a Jeol Eclipse FT 300
NMR spectrometer, respectively. Peak assignments were
performed with the aid of the DEPT-technique, 2D-COSY
and HETCOR spectra. IR assignments were obtained from a
Perkin Elmer Spectrum One spectrophotometer. Mass
spectra were recorded on an Agilent 1100 Series VL mass
spectrometer (ES) or a HP 5973 MSD spectrometer (70 eV).
Elemental analysis was performed on a Perkin Elmer 2400
Elemental Analyser and via a Callisto CF-Isotope Ratio
Mass Spectrometer. Melting points were measured with a
Bu¨chi B-450 apparatus. Flash chromatography was carried
out on a glass column with ACROS silica gel (particle size
0.035–0.07 mm, pore diameter ca. 6 nm). HRMS data were
obtained with a VG Quattro II, ESI ionization (cone voltage
40 V).
3.2. Synthesis of 1-alkyl-5-aryl-3-chloro-2-cyano-2-
pyrrolines 14
As a representative example, the synthesis of 3-chloro-2-
cyano-1-isopropyl-5-phenyl-2-pyrroline 14c is given. To a
solution of 1.00 g (3.98 mmol) of 2,2,4-trichloro-4-phenyl-
butanal 12a in 10 mL of dry diethyl ether was added 0.45 g
(2.38 mmol, 0.6 equiv) of titanium(IV) chloride in 5 mL of
dry pentane at 0 8C. After addition, the mixture was stirred
for 15 min at 0 8C, followed by addition of 0.94 g
(15.92 mmol, 4 equiv) of isopropylamine in 10 mL of dry
diethyl ether. Cooling was stopped and the mixture was
stirred for 15 h. Subsequently, the mixture was poured in
25 mL of aq. 1 M NaOH and rapidly extracted with diethyl
ether (3!25 mL). The extract was dried (K2CO3/MgSO4)
and the solvent was removed in vacuo at 0–10 8C. The
resulting aldimine 13 (R1Z C6H5, R2Z i-Pr) was used
as such (without purification; purity O90%) to minimize
decomposition. To 1.16 g (3.98 mmol) of N-(2,2,4-tri-
chloro-4-phenyl-1-butylidene)isopropylamine in 20 mL of
methanol was added 0.28 g (4.37 mmol, 1.1 equiv) of
potassium cyanide and the mixture was heated under reflux
for 4 h. After reaction, the mixture was poured in 20 mL of
aq. 0.5 M NaOH and extracted with dichloromethane (3!
20 mL). After drying (MgSO4) and evaporation of the
solvents, pyrroline 14c was obtained and was purified by
flash chromatography (0.57 g, 58%).
3.1. Synthesis of 4-aryl-2,2,4-trichlorobutanals 12
As a representative example, the synthesis of 2,2,4-
trichloro-4-phenylbutanal 12a is described. A solution of
4.56 g (25.26 mmol) of 1-chloro-2-phenylcyclopropane-1-
carbaldehyde 9a16 and 5.53 g (50.52 mmol, 2 equiv) of
DMF-HCl in 5.00 g of DMF was heated to 40–60 8C. After
reaction for 20 min, 10 mL of dry chloroform was added
and chlorine gas was bubbled through the solution. During

G. Verniest et al. / Tetrahedron 61 (2005) 2879–2887
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3.2.1. 1-tert-Butyl-3-chloro-2-cyano-5-phenyl-2-pyrro-
line 14a. Recrystallization (Et2O/hexane, 1:3), yield 64%,
mp 84–85 8C. H NMR (270 MHz, CDCl3): d 1.25 (9H, s,
CH(CH3)2), 4.49 (1H, d!d, JZ11.1, 11.4 Hz, CH), 7.26–
7.38 (4H, m, C6H4). 13C NMR (75 MHz, CDCl3): d 19.3
(CH3), 19.6 (CH3), 45.2 (CH2), 51.1 (CH(CH3)2), 62.2
(NCH), 112.1 (CN), 121.6 (Cquat), 2!128.3 (2!CHar),
128.5 (Cquat), 2!129.0 (2!CHar), 133.5 (Cquat), 141.8
(Cquat). IR (NaCl) nmax 2213, 1453 cmK1. MS (70 eV) m/z
(%): 280/82/84 (MC, 68); 265/67/69 (100); 238 (34); 203
(34); 125 (57).
1
C(CH3)3), 2.49 (1H, d!d, JZ17.8, 6.6 Hz, CHaHb), 3.43
(1H, d!d, JZ17.8, 11.5 Hz, CHaHb), 4.67 (1H, d!d, JZ
11.5, 6.6 Hz, CH), 7.25–7.39 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): d 3!28.3 (C(CH3)3), 45.2 (CH2), 57.7
(C(CH3)3), 61.5 (NCH), 113.9 (CN), 119.8 (Cquat), 2!
125.7 (2!CHar), 126.1 (Cquat), 127.2 (CHar), 2!128.8 (2!
CHar), 145.7 (Cquat). IR (KBr) nmax 2226 cmK1. MS (70 eV)
m/z (%): 260/62 (MC, 12); 204/206 (100); 169 (41); 168
(12); 115 (11); 57 (85).
3.3. Synthesis of 1-alkyl-2-aryl-4-chloropyrroles 16
As a representative example, the synthesis of 4-chloro-1-
isopropyl-2-phenylpyrrole 16c is described. To 5.00 g
(20.28 mmol) of 3-chloro-2-cyano-1-isopropyl-5-phenyl-2-
pyrroline 14c was added 41 mL (81.13 mmol, 4 equiv) of
2 M NaOMe in MeOH at room temperature. The mixture
was refluxed for 2 h, cooled and poured in 100 mL of water.
After extraction with dichloromethane (3!50 mL), the
extract was dried (MgSO4) and the solvents evaporated
in vacuo. The resulting pyrrole was purified by flash
chromatography (3.96 g, 83%).
3.2.2. 3-Chloro-1-cyclohexyl-2-cyano-5-phenyl-2-pyrro-
line 14b. Flash chromatography (hexane/EtOAc 9:1, RfZ
0.54), yield 54%. 1H NMR (270 MHz, CDCl3): d 1.01–1.83
(10H, m, 5!CH2), 2.61 (1H, d!d, JZ17.3, 10.9 Hz,
CHaHb), 2.85–3.07 (1H, m, NCH), 3.23 (1H, d!d, JZ17.3,
11.5 Hz, CHaHb), 4.57 (1H, d!d, JZ11.5, 10.9 Hz, NCH),
7.28–7.36 (5H, m, C6H5). 13C NMR (68 MHz, CDCl3): d
25.4 (CH2), 25.6 (CH2), 25.9 (CH2), 29.6 (CH2), 30.4 (CH2),
45.1 (CH2CCl), 59.4 (NCH), 63.0 (NCH), 112.0 (CN),
120.7 (Cquat), 120.9 (Cquat), 2!126.5 (2!CHar), 127.6
(CHar), 2!128.6 (2!CHar), 143.1 (Cquat). IR (NaCl) nmax
2228 cmK1. MS (70 eV) m/z (%): 286/288 (MC, 35); 243/
245 (23); 204/206 (100); 169 (38); 83 (24); 55 (62).
3.3.1. 1-tert-Butyl-4-chloro-2-phenylpyrrole 16a. Flash
chromatography (hexane/EtOAc 95:5, RfZ0.58), yield
52%, mp 77 8C. H NMR (270 MHz, CDCl3): d 1.39 (9H,
1
s, C(CH3)3), 5.95 (1H, d, JZ2.3 Hz, NC]CH), 6.82 (1H, d,
JZ2.3 Hz, NCHZC), 7.32–7.36 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): d 3!31.8 (C(CH3)3), 58.0 (C(CH3)3),
109.5 (Cquat), 111.5 (NC]CH), 116.0 (NCHZC), 2!127.5
(2!CHar), 127.9 (CHar), 2!131.7 (2!CHar), 133.8
(Cquat), 136.1 (Cquat). IR (KBr): nmax 1368 cmK1. MS
(70 eV) m/z (%): 233/235 (MC, 16); 178/180 (12); 177/179
(100); 57 (27). Anal. Calcd for C14H16NCl: C, 71.94; H,
6.90; N, 5.99. Found: C, 72.12; H, 7.09; N, 5.86.
3.2.3. 3-Chloro-2-cyano-1-isopropyl-5-phenyl-2-pyrro-
line 14c. Flash chromatography (hexane/EtOAc 4:1, RfZ
0.60), yield 58%. 1H NMR (300 MHz, CDCl3): d 0.98 (3H,
d, JZ6.9 Hz, CH3), 1.23 (3H, d, JZ6.9 Hz, CH3), 2.63 (1H,
dd, JZ17.3, 11.5 Hz, CHaHb), 3.21 (1H, d!d, JZ17.3,
11.2 Hz, CHaHb), 3.33 (1H, sept, JZ6.9 Hz, CH(CH3)2),
4.48 (1H, d!d, JZ11.2, 11.5 Hz, CH), 7.25–7.50 (5H, m,
C6H5). 13C NMR (75 MHz, CDCl3): d 2!19.3 (2!CH3),
45.1 (CH2), 50.8 (CH(CH3)2), 63.0 (CH), 112.1 (CN), 120.8
(Cquat), 121.4 (Cquat), 2!126.7 (2!CHar), 127.7 (CHar),
2!128.7 (2!CHar), 142.9 (Cquat). IR (NaCl) nmax
2227 cmK1. MS (70 eV) m/z (%): 246/48 (MC, 55); 231/
33 (98); 169 (46); 142 (25); 91 (100); 77 (17).
3.3.2. 4-Chloro-1-cyclohexyl-2-phenylpyrrole 16b. Flash
chromatography (hexane/EtOAc 95:5, RfZ0.56), yield
67%. H NMR (270 MHz, CDCl3): d 1.14–1.98 (10H, m,
1
5!CH2), 3.88–3.40 (1H, m, NCH), 6.05 (1H, d, JZ1.9 Hz,
NC]CH), 6.77 (1H, d, JZ1.9 Hz, NCHZC), 7.29–7.44
(5H, m, C6H5). 13C NMR (68 MHz, CDCl3): d 25.3 (CH2),
2!25.8 (2!CH2), 2!34.8 (2!CH2), 55.6 (NCH), 108.1
(NC]CH), 111.6 (Cquat), 115.2 (NCHZC), 127.4 (CHar),
2!128.5 (2!CHar), 2!129.2 (2!CHar), 132.7 (Cquat),
133.7 (Cquat). IR (NaCl): nmax 1495, 1448, 1395 cmK1. MS
(70 eV) m/z (%): 259/61 (MC, 38); 178/180 (22); 177/179
(100); 115 (10); 55 (29); 41 (22). Anal. Calcd for
C16H18NCl: C, 73.98; H, 6.98; N, 5.39. Found: C, 73.75;
H, 7.11; N, 5.28.
3.2.4. 3-Chloro-2-cyano-5-phenyl-1-propyl-2-pyrroline
14d. This compound was unstable and could not be
completely purified by flash chromatography. The spectra
1
still contained impurities (ca. 10%); crude yield 79%. H
NMR (300 MHz, CDCl3): d 0.80 (3H, t, JZ7.3 Hz, CH3),
1.30–7.54 (2H, m, CH2CH3), 2.72 (1H, d!d, JZ12.7,
17.1 Hz, NCHCHaHb), 2.83 (1H, t, JZ6.6 Hz, NCHaHb),
2.85 (1H, t, JZ6.6 Hz, NCHaHb), 3.15 (1H, d!d, JZ11.0,
17.1 Hz, NCHCHaHb), 4.39 (1H, d!d, JZ12.7, 11.0 Hz,
NCHCH2), 7.31–7.65 (5H, m, C6H5). 13C NMR (75 MHz,
CDCl3): d 11.5 (CH3), 20.3 (CH2), 45.2 (CH2), 52.7
(NCH2), 67.8 (NCH), 111.8 (CN), 120.0 (Cquat), 2!127.3
(2!CHar), 127.8 (Cquat), 128.3 (CHar), 2!128.9 (2!
CHar), 141.1 (Cquat). IR (NaCl) nmax 2229 cmK1. MS (ESC)
m/z (%): 238/40 (MCKCNCH2O, 100).
3.3.3. 4-Chloro-1-isopropyl-2-phenylpyrrole 16c. Flash
chromatography (hexane/EtOAc 95:5, RfZ0.50), yield
83%, mp 42–43 8C. H NMR (270 MHz, CDCl3): d 1.35
1
(6H, d, JZ6.6 Hz, CH(CH3)2), 4.40 (1H, sept, JZ6.6 Hz,
CH(CH3)2), 6.05 (1H, d, JZ1.9 Hz, NC]CH), 6.78 (1H, d,
JZ1.9 Hz, NCHZC), 7.30–7.43 (5H, m, C6H5). 13C NMR
(68 MHz, CDCl3): d 2!23.9 (2!CH3), 47.7 (CH), 108.2
(NC]CH), 111.8 (Cquat), 114.3 (NCHZC), 127.6 (CHar),
2!128.5 (2!CHar), 2!129.3 (2!CHar), 132.7 (Cquat),
133.8 (Cquat). IR (KBr) nmax 1497, 1463, 1394 cmK1. MS
(70 eV) m/z (%): 219/21 (MC, 53); 178/80 (12); 177/79
(100); 115 (21). Anal. Calcd for C13H14NCl: C, 71.07; H,
3.2.5. 3-Chloro-5-(4-chlorophenyl)-2-cyano-1-isopropyl-
2-pyrroline 14e. Flash chromatography (hexane/EtOAc
1
4:1, RfZ0.60), yield 52%. H NMR (300 MHz, CDCl3): d
0.98 (3H, d, JZ6.9 Hz, CH3), 1.22 (3H, d, JZ6.9 Hz, CH3),
2.59 (1H, d!d, JZ17.5, 11.1 Hz, CHaHb), 3.23 (1H, d!d,
JZ17.5, 11.4 Hz, CHaHb), 3.35 (1H, sept, JZ6.9 Hz,

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G. Verniest et al. / Tetrahedron 61 (2005) 2879–2887
6.42; N, 6.38. Found: C, 71.06; H, 6.48; N, 6.34. HRMS:
Calcd for C13H14NCl, 220.0888; Found 220.0901.
(Cquat), 171.1 (C]O). IR (KBr) nmax 1677, 1495,
1457 cmK1. MS (ESC) m/z (%) 252/54 (MCHC, 60),
196/98 (100). Anal. Calcd for C14H18NOCl: C, 66.79; H,
7.21; N, 5.56. Found: C, 66.62; H, 7.38; N, 5.42.
3.3.4. 4-Chloro-2-phenyl-1-propylpyrrole 16d. Flash
chromatography (hexane/EtOAc 98:2, RfZ0.35), yield
59%. 1H NMR (300 MHz, CDCl3): d 0.79 (3H, t, JZ
7.4 Hz, CH3), 1.64 (2H, sext, JZ7.4 Hz, CH2CH3), 3.80
(3H, t, JZ7.4 Hz, NCH2), 6.10 (1H, d, JZ1.9 Hz,
NC]CH), 6.69 (1H, d, JZ1.9 Hz, NCHZC), 7.30–7.42
(5H, m, C6H5). 13C NMR (75 MHz, CDCl3): d 11.3 (CH3),
24.9 (CH2), 49.2 (NCH2), 108.8 (NC]CH), 111.7 (Cquat),
118.9 (NCH), 127.7 (CHar), 2!128.8 (2!CHar), 2!129.3
(2!CHar), 132.8 (Cquat), 134.5 (Cquat). IR (NaCl) nmax
1603, 1500, 1475, 1324 cmK1. MS (70 eV) m/z (%): 219/21
(MC, 100); 190/92 (84); 177/79 (39); 155 (37); 142 (15);
115 (20). Anal. Calcd for C13H14NCl: C, 71.07; H, 6.42; N,
6.38. Found: C, 71.18; H, 6.60; N, 6.21. HRMS: Calcd for
C13H14NCl, 220.0888; Found 220.0887.
3.4.2. cis-3-Chloro-1-isopropyl-5-phenyl-2-pyrrolidi-
none 19b. Flash chromatography (hexane/EtOAc 4:1,
1
RfZ0.31), yield 57%, mp 110–112 8C. H NMR (CDCl3):
d 0.99 (3H, d, JZ6.9 Hz, CH3), 1.25 (3H, d, JZ6.9 Hz,
CH3), 2.20 (1H, d!t, JZ14.3, 6.3 Hz, CHaHb), 3.06 (1H,
d!d!d, JZ14.3, 9.1, 7.8 Hz, CHaHb), 3.85 (1H, sept, JZ
6.9 Hz, CH(CH3)2), 4.45 (1H, d!d, JZ9.1, 6.3 Hz, CH),
4.62 (1H, d!d, JZ7.8, 6.3 Hz, CH), 7.32–7.42 (5H, m,
C6H5). 13C NMR (CDCl3): d 19.6 (CH3), 20.3 (CH3), 39.5
(CH2), 46.8 (CH(CH3)2), 54.3 (NCH), 60.3 (CHCl), 2!
127.5 (2!CHar), 128.6 (CHar), 2!129.0 (2!CHar), 141.2
(Cquat), 170.6 (C]O). IR (KBr) nmax 1677, 1419 cmK1. MS
(70 eV) m/z (%) 237/39 (MC, 9), 222/24 (30), 202 (100),
117(84). Calcd for C13H16NOCl: C, 65.68; H, 6.78; N, 5.89.
Found: C, 65.84; H, 6.95; N, 5.70.
3.3.5. 4-Chloro-2-(4-chlorophenyl)-1-isopropylpyrrole
16e. Flash chromatography (hexane/EtOAc 97:3, RfZ
0.42), yield 77%, mp 61 8C. H NMR (300 MHz, CDCl3):
1
3.4.3. trans-1-tert-Butyl-3-chloro-5-phenyl-2-pyrrolidi-
none 20a. Flash chromatography (hexane/EtOAc 9:1,
d 1.34 (6H, d, JZ6.7 Hz, CH(CH3)2), 4.34 (1H, sept, JZ
6.7 Hz, CH(CH3)2), 6.04 (1H, d, JZ1.9 Hz, NC]CH), 6.78
(1H, d, JZ1.9 Hz, NCHZC), 7.21–7.26 (2H, m, 2!CHar),
7.34–7.39 (2H, m, 2!CHar). 13C NMR (75 MHz, CDCl3): d
2!24.0 (2!CH3), 47.9 (CH), 108.6 (NC]CH), 112.1
(Cquat), 114.8 (NCHZC), 2!128.9 (2!CHar), 2!130.6
(2!CHar), 131.1 (Cquat), 132.6 (Cquat), 133.7 (Cquat). IR
(KBr) nmax 1495, 1415, 1288 cmK1. MS (70 eV) m/z (%)
253/55/57 (MC, 76), 211/13/15 (100), 176 (27), 149 (19).
Anal. Calcd for C13H13NCl2: C, 61.43; H, 5.16; N, 5.51.
Found: C, 61.59; H, 5.30; N, 5.37.
1
RfZ0.31), yield 70%, mp 81–82 8C. H NMR (CDCl3): d
1.37 (9H, s, C(CH3)3), 2.41 (1H, d!d!d, JZ12.7, 7.9,
1.4 Hz, CHaHb), 2.58 (1H, d!d!d, JZ12.7, 10.2, 8.5 Hz,
CHaHb), 4.67 (1H, d!d, JZ10.2, 7.9 Hz, CH), 4.92 (1H,
d!d, JZ8.5, 1.4 Hz, CHCl), 7.17–7.40 (5H, m, C6H5). 13
C
NMR (CDCl3): d 3!27.8 (3!CH3), 41.0 (CH2), 55.0 (CH),
56.0 (C(CH3)3), 59.8 (CHCl), 2!125.26 (2!CHar), 127.9
(CHar), 2!129.2 (2!CHar), 142.7 (Cquat), 170.6 (C]O).
IR (KBr) nmax 1690, 1455, 1398 cmK1. MS (ESC) m/z (%)
252/54 (MCHC, 75), 196/98 (100). Calcd for
C14H18NOCl: C, 66.79; H, 7.21; N, 5.56. Found: C, 66.67;
H, 7.43; N, 5.39.
3.4. Hydrolysis of 1-alkyl-5-aryl-3-chloro-2-cyano-2-
pyrrolines 14
3.4.4. trans-3-Chloro-1-isopropyl-5-phenyl-2-pyrrolidi-
none 20b. Flash chromatography (hexane/EtOAc 4:1,
RfZ0.06), yield 32%. H NMR (CDCl3): d 0.99 (3H, d,
As a representative example, the hydrolysis of 3-chloro-2-
cyano-1-isopropyl-5-phenyl-2-pyrroline 14c is described.
3-Chloro-2-cyano-1-isopropyl-5-phenyl-2-pyrroline 14c
(0.50 g, 2.03 mmol) was dissolved in 10 mL of a 1:1
mixture of acetic acid and aq. 2 M HCl. The solution was
stirred at room temperature in a well vented fume hood
(CAUTION: formation of HCN!) for 2 h and subsequently
poured in 25 mL of water and extracted with dichloro-
methane (3!25 mL). After drying (MgSO4) and evapora-
tion of the solvent in vacuo, cis-substituted pyrrolidinone
19b was obtained after flash chromatography (0.27 g, 57%).
When the reaction temperature was raised to reflux
temperatures (15 h) a mixture of cis- (19b) and trans-
substituted pyrrolidinones (20b) was obtained in a ratio 1:3,
respectively. The two isomers were easily separated by flash
chromatography.
1
JZ6.8 Hz, CH3), 1.27 (3H, d, JZ6.8 Hz, CH3), 2.44 (1H,
d!d!d, JZ14.0, 7.4, 5.3 Hz, CHaHb), 2.60 (1H, d!d!d,
JZ14.0, 7.4, 5.3 Hz, CHaHb), 3.89 (1H, sept, JZ6.8 Hz,
CH(CH3)2), 4.60 (1H, d!d, JZ7.4, 5.3 Hz, CH), 4.79 (1H,
d!d, JZ7.4, 5.3 Hz, CH), 7.33–7.42 (5H, m, C6H5). 13C
NMR (CDCl3): d 19.7 (CH3), 20.0 (CH3), 40.7 (CH2), 46.4
(CH(CH3)2), 55.1 (NCH), 59.7 (CHCl), 2!126.8 (2!
CHar), 128.5 (CHar), 2!129.1 (2!CHar), 140.8 (Cquat),
170.6 (C]O). IR (NaCl) nmax 1699, 1495, 1456, 1222 cmK1
.
MS (70 eV) m/z (%) 237/39 (MC, 13), 222/24 (30), 202
(100), 117(88). Anal. Calcd for C13H16NOCl: C, 65.68; H,
6.78; N, 5.89. Found: C, 65.90; H, 6.95; N, 6.03.
3.5. Synthesis of 1-alkyl-5-aryl-3-chloro-2-cyanopyrroles
21
3.4.1. cis-1-tert-Butyl-3-chloro-5-phenyl-2-pyrrolidinone
19a. Recrystallization (Et2O/hexane 1:1), yield 75%, mp
130 8C. H NMR (CDCl3): d 1.35 (9H, s, C(CH3)3), 2.09
(1H, d!t, JZ14.8, 2.5 Hz, CHaHb), 2.99 (1H, d!t, JZ
14.8, 9.0 Hz, CHaHb), 4.37 (1H, d!d, JZ9.0, 2.5 Hz, CH),
4.90 (d!d, JZ9.0, 2.5 Hz, CHCl), 7.27–7.36 (5H, m,
C6H5). 13C NMR (CDCl3): d 3!27.9 (3!CH3), 38.4
(CH2), 54.6 (CH), 56.3 (C(CH3)3), 61.2 (CHCl), 2!126.2
(2!CHar), 127.8 (CHar), 2!128.8 (2!CHar), 143.9
To a solution of 0.54 g (2.19 mmol) of 3-chloro-2-cyano-1-
isopropyl-5-phenyl-2-pyrroline 14c in 20 mL of dry toluene
was added 0.55 g (2.41 mmol, 1.1 equiv) of DDQ. The
resulting mixture was refluxed for 6 h. After reaction, the
mixture was diluted with 20 mL of pentane and the formed
heterogeneous mixture was filtered over Celitew. The
filtrate was diluted with 50 mL of water and extracted
with pentane (3!50 mL). The combined extracts were
1

G. Verniest et al. / Tetrahedron 61 (2005) 2879–2887
2885
dried (MgSO4), filtered and the solvent was removed in
vacuo. Purification of the synthesized pyrrole was per-
formed by a fast flash chromatography over a short (5 cm)
column of silica gel (0.23 g, 43%).
CH(CH3)2), 6.11 (1H, s, NC]CH), 7.22–7.28 (2H, m, 2!
CHar), 7.40–7.48 (2H, m, 2!CHar). 13C NMR (CDCl3): d
2!22.5 (2!CH3), 50.5 (CH), 100.4 (CN), 109.8
(NC]CH), 113.0 (Cquat), 124.9 (Cquat), 129.0 (Cquat), 2!
129.3 (2!CHar), 2!130.8 (2!CHar), 135.5 (Cquat), 138.1
(Cquat). IR (KBr) nmax 2215, 1449, 1337 cmK1. MS (70 eV)
m/z (%) 278/80/82 (MC, 54), 236/38/40 (100), 201/3 (16),
174 (21). Calcd for C14H12N2Cl2: C, 60.23; H, 4.33; N,
10.03. Found: C, 60.12; H, 4.50; N, 9.89.
3.5.1. 1-tert-Butyl-3-chloro-2-cyano-5-phenylpyrrole
21a. Flash chromatography (hexane/EtOAc 9:1, RfZ
0.43), yield 42%, mp 119–120 8C. H NMR (CDCl3): d
1
1.56 (9H, s, C(CH3)3), 5.96 (1H, s, CH), 7.26–7.46 (5H, m,
C6H5). 13C NMR (CDCl3): d 3!32.3 (3!CH3), 62.2
(C(CH3)3), 102.1 (CN), 112.4 (CH), 114.4 (Cquat), 125.4
(Cquat), 2!127.9 (2!CHar), 128.8 (CHar), 2!130.3 (2!
CHar), 134.7 (Cquat), 139.8 (Cquat). IR (KBr) nmax 2211,
1325 cmK1. MS (70 eV) m/z (%) 258/60 (MC, 5), 202/04
(100), 57 (20). Calcd for C15H15N2Cl: C, 69.63; H, 5.84; N,
10.83. Found: C, 69.75; H, 5.96; N, 10.68.
3.6. Synthesis of 2-acetylpyrroles 24a,b
A solution of 1.6 M MeLi in diethyl ether (2.60 mL,
4.09 mmol, 1 equiv) was added to a solution of 1.00 g
(4.09 mmol) of 3-chloro-2-cyano-1-isopropyl-5-phenylpyr-
role 21c in 50 mL of dry THF under N2-atmosphere. After
stirring for 2 h at room temperature, the reaction mixture was
diluted with 50 mL of water and subsequently extracted with
diethyl ether (3!25 mL). Drying of the solvents (MgSO4/
K2CO3), filtration and evaporation of the solvents in vacuo
yielded a mixture of 2-acetylpyrrole 21c and the correspond-
ing imine. Separation of these two products was not possible,
because the imine hydrolyzed towards 21c during flash
chromatography. The mixture was dissolved in 25 mL of
dichloromethane and 10 mL of aq. 6 M HCl was added. The
resulting biphasic solution was stirred at room temperature for
2 h and subsequently extracted with dichloromethane (3!
25 mL). Standard work up yielded 2-acetylpyrrole 24b, which
was purified by flash chromatography (0.62 g, 58%).
3.5.2. 3-Chloro-1-cyclohexyl-2-cyano-5-phenylpyrrole
21b. Flash chromatography (hexane/EtOAc 4:1, RfZ
0.26), yield 54%, mp 125 8C. H NMR (CDCl3): d 1.12–
1
2.32 (10H, m, 5!CH2), 4.05 (1H, t!t, JZ12.4, 3.7 Hz,
CHN), 6.12 (1H, s, CH), 7.26–7.32 and 7.41–7.51 (5H, m,
C6H5). 13C NMR (CDCl3): d 24.7 (CH2), 2!25.9 (2!
CH2), 2!32.6 (2!CH2), 58.2 (CHN), 100.6 (CN), 109.5
(CH), 113.3 (Cquat), 124.7 (Cquat), 2!128.9 (2!CHar),
129.0 (CHar), 2!129.3 (2!CHar), 130.7 (Cquat), 139.4
(Cquat). IR (NaCl) nmax 2212, 1333 cmK1. MS (ESC) m/z
(%) 285/87 (MCHC, 100), 203/04 (15). Anal. Calcd for
C17H17N2Cl: C, 71.70; H, 6.02; N, 9.84. Found: C, 71.51; H,
6.14; N, 9.88.
3.6.1. 2-Acetyl-3-chloro-1-cyclohexyl-5-phenylpyrrole
24a. Flash chromatography (hexane/EtOAc 4:1, RfZ
0.70), yield 47%. H NMR (CDCl3): d 1.07–2.06 (10H, m,
3.5.3. 3-Chloro-2-cyano-1-isopropyl-5-phenylpyrrole
21c. Flash chromatography (hexane/EtOAc 95:5, RfZ
0.25), yield 43%, mp 68–71 8C. H NMR (CDCl3): d 1.58
1
1
5!CH2), 2.66 (3H, s, CH3), 4.32–4.34 (1H, m, NCH), 6.11
(1H, s, CH), 7.32–7.45 (5H, m, C6H5). 13C NMR (CDCl3): d
25.0 (CH2), 2!26.3 (2!CH2), 31.7 (CH3), 2!32.4 (2!
CH2), 60.5 (CHN), 112.0 (CH), 121.2 (Cquat), 2!128.3
(2!CHar), 128.7 (CHar), 129.0 (Cquat), 2!129.8 (2!
CHar), 132.9 (Cquat), 141.5 (Cquat), 189.2 (C]O). IR (NaCl)
nmax 1654 cmK1. MS (ESC) m/z (%) 302/04 (MCHC, 65),
220/22 (100). Anal. Calcd for C18H20NOCl: C, 71.63; H,
6.68; N, 4.64. Found: C, 71.86; H, 6.52; N, 4.60.
(6H, d, JZ6.9 Hz, CH(CH3)2), 4.52 (1H, sept, JZ6.9 Hz,
CH(CH3)2), 6.11 (1H, s, NC]CH), 7.28–7.34 (2H, m, 2!
CHar), 7.43–7.49 (3H, m, 3!CHar). 13C NMR (CDCl3): d
2!22.5 (2!CH3), 50.3 (NCH), 100.0 (CN), 109.6
(NC]CH), 113.2 (Cquat), 124.9 (Cquat), 2!128.8 (2!
CHar), 129.2 (CHar), 2!129.6 (2!CHar), 130.7 (Cquat),
139.4 (Cquat). IR (KBr) nmax 2211, 1454 cmK1. MS (70 eV)
m/z (%) 244/46 (MC, 38), 202/4 (100), 166 (9), 140 (16).
Calcd for C14H13N2Cl: C, 68.71; H, 5.35; N, 11.45. Found:
C, 68.88; H, 5.49; N, 11.30.
3.6.2. 2-Acetyl-3-chloro-1-isopropyl-5-phenylpyrrole
24b. Flash chromatography (hexane/EtOAc 97:3, RfZ
0.20), yield 58%, mp 42 8C. 1H NMR (CDCl3): d 1.42
(6H, d, JZ7.0 Hz, CH(CH3)2), 2.67 (3H, s, CH3CO), 4.73
(1H, sept, JZ7.0 Hz, CH(CH3)2), 6.12 (1H, s, NC]CH),
7.34–7.38 (2H, m, 2!CHar), 7.41–7.47 (3H, m, 3!CHar).
13C NMR (CDCl3): d 2!22.4 (2!CH3), 31.7 (CH3), 51.8
(CH), 111.9 (NC]CH), 121.5 (Cquat), 2!128.5 (2!CHar),
128.9 (CHar), 2!129.9 (2!CHar), 132.7 (Cquat), 141.4
(Cquat), 189.0 (C]O). IR (KBr) nmax 1651, 1445 cmK1. MS
(70 eV) m/z (%) 261/63 (MC, 58), 219/21 (50), 204/6 (100),
149 (25). Anal. Calcd for C15H16NOCl: C, 68.83; H, 6.16;
N, 5.35. Found: C, 69.01; H, 6.31; N, 5.54.
3.5.4. 3-Chloro-2-cyano-5-phenyl-1-propylpyrrole 21d.
Flash chromatography (hexane/EtOAc 9:1, RfZ0.35), yield
1
43%. H NMR (CDCl3): d 0.79 (3H, t, JZ7.5 Hz, CH3),
1.70 (2H, sext, JZ7.5 Hz, CH3CH2), 3.98 (2H, t, JZ7.5 Hz,
NCH2), 6.18 (1H, s, NC]CH), 7.32–7.49 (5H, m, C6H5).
13C NMR (CDCl3): d 10.9 (CH3), 24.5 (CH2), 48.7 (NCH2),
103.5 (CN), 110.1 (NC]CH), 112.4 (Cquat), 123.1 (Cquat),
2!129.0 (2!CHar), 3!129.2 (2!CHar and Cquat), 130.6
(CHar), 139.7 (Cquat). IR (NaCl) nmax 2217, 1460, 1337 cmK1
.
MS (70 eV) m/z (%) 244/46 (MC, 83), 202/4 (100), 190
(23), 180 (24), 166 (13), 140 (20). Anal. Calcd for
C14H13N2Cl: C, 68.71; H, 5.35; N, 11.45. Found: C,
68.59; H, 5.47; N, 11.37.
3.7. Synthesis of 2-formylpyrroles 24c,d,e
3.5.5. 3-Chloro-5-(4-chlorophenyl)-2-cyano-1-isopropyl-
pyrrole 21e. Flash chromatography (hexane/EtOAc 97:3,
RfZ0.19), yield 50%, mp 102 8C. 1H NMR (CDCl3): d 1.59
(6H, d, JZ6.9 Hz, CH(CH3)2), 4.46 (1H, sept, JZ6.9 Hz,
To a solution of 1.00 g (4.56 mmol) of 3-chloro-1-
isopropyl-5-phenylpyrrole 16c in 20 mL of DMF and
20 mL of dry dichloromethane was added a solution of
0.84 g (5.47 mmol, 1.2 equiv) of POCl3 in 5 mL of dry

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G. Verniest et al. / Tetrahedron 61 (2005) 2879–2887
dichloromethane at 0 8C under N2-atmosphere. After
stirring for 5 h, the reaction mixture was diluted with
25 mL of aq. 1 M NaOH at 0 8C and stirred for 15 min at the
same temperature. The mixture was poured in 25 mL of
water and extracted with dichloromethane (3!30 mL). The
extracts were dried over MgSO4 and after filtration, the
solvent was removed in vacuo. To remove residual DMF,
additional evaporation at high vacuum (0.01 mm Hg) was
applied. This procedure yielded a mixture of 2- and 4-
(2.28 mmol, 1 equiv) of methyl chloroformate in 5 mL of
dry THF was added via a syringe and the mixture was stirred
for 2 h at 0 8C. After reaction, 25 mL of water was added,
the organic phase was separated and the aqueous phase was
extracted with diethyl ether (3!25 mL). After drying
(MgSO4) and evaporation of the solvents, compound 24f
was recrystallized yielding 0.49 g (77%) of pure compound.
3.8.1. Methyl (3-chloro-1-isopropyl-5-phenylpyrrol-2-
yl)carboxylate 24f. Recrystallization (pentane), yield
1
formylated pyrroles (ratio 65:35, calculated from H NMR
spectra, which were easily separated by flash
chromatography.
1
77%, mp 66 8C. H NMR (CDCl3): d 1.47 (6H, d, JZ
7.0 Hz, CH(CH3)2), 3.90 (3H, s, OCH3), 4.71 (1H, sept, JZ
7.0 Hz, CH(CH3)2), 6.11 (1H, s, NC]CH), 7.33–7.38 (2H,
m, 2!CHar), 7.40–7.47 (3H, m, 3!CHar). 13C NMR
(CDCl3): d 2!22.4 (2!CH3), 51.4 and 51.5 (NCH and
OCH3), 111.5 (NC]CH), 119.3 (Cquat), 120.9 (Cquat), 2!
128.5 (2!CHar), 128.8 (CHar), 2!129.9 (2!CHar), 132.7
(Cquat), 140.1 (Cquat), 161.5 (C]O). IR (KBr) nmax 1697,
1454, 1223 cmK1. MS (70 eV) m/z (%) 277/79 (MC, 100),
246/48 (36), 235/37 (47), 204/6 (96). Calcd for
C15H16NO2Cl: C, 64.87; H, 5.81; N, 5.04. Found: C,
64.99; H, 6.03; N, 4.91.
3.7.1. 1-tert-Butyl-3-chloro-2-formyl-5-phenylpyrrole
24c. Flash chromatography (hexane/EtOAc 9:1, RfZ0.36),
yield 71%, mp 103 8C. H NMR (CDCl3): d 1.52 (9H, s,
1
C(CH3)3), 6.04 (1H, s, CH), 7.25–7.42 (5H, m, C6H5), 9.80
(1H, s, CHO). 13C NMR (CDCl3): d 32.2 (C(CH3)3), 62.5
(C(CH3)3), 113.9 (CH), 2!128.1 (2!CHar), 128.3 (Cquat),
128.7 (CHar), 2!129.5 (2!CHar), 131.0 (Cquat), 135.6
(Cquat), 144.7 (Cquat), 177.3 (C]O). IR (KBr) nmax
1655 cmK1. MS (ESC) m/z (%) 262/64 (MCHC, 5),
206/08 (100). Calcd for C15H16NOCl: C, 68.83; H, 6.16; N,
5.35. Found: C, 68.71; H, 6.32; N, 5.24.
3.9. Synthesis of methyl (4-chloro-2-phenylpyrrol-3-yl)-
carboxylate 25
3.7.2. 3-Chloro-1-cyclohexyl-2-formyl-5-phenylpyrrole
24d. Flash chromatography (hexane/EtOAc 9:1, RfZ
0.35), yield 76%, mp 142-143 8C. H NMR (CDCl3): d
1
3-Chloro-1-isopropyl-5-phenylpyrrole 16c (0.10 g, 0.45 mmol)
was dissolved in 10 mL of carbon disulfide and cooled to
0 8C. To the cold solution, 45 mg (0.48 mmol, 1.05 equiv)
of methyl chloroformate and 64 mg (0.48 mmol,
1.05 equiv) of aluminum(III) chloride were added under
N2-atmosphere and the mixture was allowed to reach room
temperature. After stirring for 4 h, the mixture was diluted
with 20 mL of water and extracted with dichloromethane
(3!25 mL). After drying (MgSO4), the solvents were
removed in vacuo, in a fume hood (CS2!) yielding a mixture
of methoxycarbonylated pyrroles 25 and 24f (ratio 1:4,
resp.), which were separated by flash chromatography.
0.81–2.42 (10H, m, 5!CH2), 4.16–4.28 (1H, m, CHN),
6.19 (1H, s, CH), 7.29–7.36 (2H, m, 2!CHar), 7.44–7.48
(3H, m, 3!CHar), 9.79 (1H, s, CHO). 13C NMR (CDCl3): d
24.5 (CH2), 2!26.0 (2!CH2), 2!31.0 (2!CH2), 59.1
(CHN), 111.2 (CH), 126.1 (Cquat), 2!128.6 (2!CHar),
129.1 (CHar), 2!129.4 (2!CHar), 130.9 (Cquat), 131.7
(Cquat), 143.0 (Cquat), 176.9 (C]O). IR (KBr) nmax
1667 cmK1. MS (ESC) m/z (%) 288/90 (MCHC, 100).
Calcd for C17H18NOCl: C, 70.95; H, 6.30; N, 4.87. Found:
C, 71.11; H, 6.48; N, 4.76.
3.7.3. 3-Chloro-2-formyl-1-isopropyl-5-phenylpyrrole
24e. Flash chromatography (hexane/EtOAc 9:1, RfZ0.54),
yield 50%, mp 59 8C. 1H NMR (CDCl3): d 1.49 (6H, d, JZ
6.9 Hz, CH(CH3)2), 4.64 (1H, sept, JZ6.9 Hz, CH(CH3)2),
6.18 (1H, s, NC]CH), 7.33–7.37 (2H, m, 2!CHar), 7.43–
7.50 (3H, m, 3!CHar), 9.80 (1H, s, CHO). 13C NMR
(CDCl3): d 2!21.4 (2!CH3), 50.9 (CH), 111.1 (NC]CH),
126.1 (Cquat), 2!128.8 (2!CHar), 129.2 (Cquat), 129.3
(CHar), 2!129.5 (2!CHar), 131.6 (Cquat), 142.8 (Cquat),
176.7 (C]O). IR (KBr) nmax 2845, 2806, 1655, 1450,
1207 cmK1. MS (70 eV) m/z (%) 247/49 (MC, 83), 205
(100), 149 (31), 140 (18), 115 (16). Anal. Calcd for
C14H14NOCl: C, 67.88; H, 5.70; N, 5.65. Found: C, 68.01;
H, 5.82; N, 5.67. HRMS: Calcd for C14H14NOCl, 248.0837;
Found 248.0831.
3.9.1. Synthesis of methyl 4-chloro-2-phenylpyrrol-3-yl
carboxylate 25. Flash chromatography (hexane/EtOAc 9:1,
RfZ0.23), yield 63%, mp 109 8C. 1H NMR (CDCl3): d 1.30
(6H, d, JZ6.7 Hz, CH(CH3)2), 3.60 (3H, s, OCH3), 4.10
(1H, sept, JZ6.7 Hz, CH(CH3)2), 6.79 (1H, s, NCHZC),
7.26–7.30 (2H, m, 2!CHar), 7.42–7.46 (3H, m, 3!CHar).
13C NMR (CDCl3): d 2!23.7 (2!CH3), 48.2 (OCH3), 50.9
(CH), 110.4 (Cquat), 113.2 (Cquat), 115.3 (NCHZC), 2!
128.2 (2!CHar), 128.7 (CHar), 2!130.5 (2!CHar), 131.7
(Cquat), 138.1 (Cquat), 164.1 (C]O). IR (KBr): nmax 1695,
1543, 1478, 1256 cmK1. MS (70 eV) m/z (%) 277/79 (MC,
68), 246/48 (13), 235/37 (45), 203/5 (100), 140 (64). Calcd
for C15H16NO2Cl: C, 64.87; H, 5.81; N, 5.04. Found: C,
64.71; H, 5.95; N, 4.88.
3.8. Synthesis of methyl (3-chloro-1-isopropyl-5-phenyl-
pyrrol-2-yl)carboxylate 24f
Acknowledgements
3-Chloro-1-isopropyl-5-phenylpyrrole 16c (0.50 g,
2.28 mmol) was dissolved in 25 mL of dry THF and cooled
to K78 8C. Under N2-atmosphere, 0.92 mL (2.28 mmol,
1 equiv) of a 2.5 M BuLi solution in hexane was added and
the mixture was stirred at 0 8C. After 30 min, 0.21 g
The authors are indebted to the IWT (Flemish Institute for
the Promotion of Scientific-Technological Research in
Industry), the FWO-Flanders and Ghent University (GOA)
for financial support.

G. Verniest et al. / Tetrahedron 61 (2005) 2879–2887
2887
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