Synthesis of long-chain 3-alkylpyrroles bearing terminal carboxy or amino groups

Article abstract of DOI:10.1002/hlca.200590183

Two new ω-(1H-pyrrol-3-yl)alkanoic acids 8a,b and the corresponding amines 9a,b were prepared on large scale in 41-51 and 27-39% overall yield, respectively, starting from N-phenylsulfonyl-protected pyrrole. The target compounds contain the desired functional groups for attachment of biomolecules such as proteins. During synthesis, an unprecedented partial reduction of the pyrrole ring with NaBH₃CN in glacial AcOH was observed, for which a plausible mechanism is proposed (Scheme 3).

Full text of DOI:10.1002/hlca.200590183

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Synthesis of Long-Chain 3-Alkylpyrroles Bearing Terminal Carboxy or Amino
Groups
by Jose¬ M.Freitas a)b), LuÌsa M.Abrantes b), and Tamis Darbre*a)
a) Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, CH-3012 Berne
(phone: ‡ 41-31-6314370; fax: ‡ 41-31-6314499; e-mail:darbre@ioc.unibe.ch)
b
√
) Centro de QuÌmica e BioquÌmica, Faculdade de Ciencias, Universidade de Lisboa, Campo Grande,
PT-1749-016 Lisboa
Two new w-(1H-pyrrol-3-yl)alkanoic acids 8a,b and the corresponding amines 9a,b were prepared on large
scale in 41 51 and 27 39% overall yield, respectively, starting from N-phenylsulfonyl-protected pyrrole. The
target compounds contain the desired functional groups for attachment of biomolecules such as proteins. During
synthesis, an unprecedented partial reduction of the pyrrole ring with NaBH3CN in glacial AcOH was observed,
for which a plausible mechanism is proposed (Scheme 3).
Introduction. Tailoring of conducting polymers has been explored for several
applications, including the preparation of new electro-catalytic materials and the
construction of biosensors [1]. Derivatives of 3-alkylpyrroles bearing a long alkyl chain
(C8 C12) with a reactive end group constitute valuable monomers for the formation of
conducting polymers. When such polymers are used to immobilize biomolecules, the
alkyl chain can increase the stability and activity of, e.g., proteins [2]. Synthetic
methods for the construction of terminally functionalized 3-alkylpyrroles have been
developed only for compounds with short alkyl chains comprising three to five C-atoms.
Hence, in this paper, we report a facile and versatile synthesis of extended 3-
alkylpyrroles with terminal COOH and NH2 groups, respectively.
Results and Discussion. We were interested in developing a synthesis of pyrrole
derivatives in very high yields, avoiding lengthy purification procedures, and the
possibility to use it for large-scale preparations.
The introduction of long alkyl chains in the pyrrole required the preparation of
monoacyl chlorides from the corresponding diacids (Scheme 1). Thus, suberic acid
(ˆoctanedioic acid; n ˆ 6) and dodecanedioic acid (n ˆ 10) were transformed into their
respective dimethyl esters 1a,b in 90 99% yield. Partial hydrolysis in the presence of
Ba(OH)2 [3] or KOH gave the mono-acids 2a,b. Higher yields of mono-acid (ca. 40%)
were obtained by treatment with 0.7 0.8m KOH solution for 3 4 h. The mono- and
diacids were separated by repeated washing with hexanes, the diacids being virtually
insoluble in this solvent, in contrast to the mono-acids, which are partially soluble. Both
the diesters and the diacids could be recovered and used again, which makes the overall
process more efficient. Finally, reaction of 2a,b with 2 equiv. of thionyl chloride
afforded the corresponding acid chlorides 3a,b, which were not isolated, but used
immediately after workup in a Friedel Crafts reaction (see below). Attempts to obtain
2a directly from suberic acid by mono-esterification [4] were not successful.
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 88 (2005)
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Scheme 1
The desired alkyl chain was introduced at the 3-position of pyrrole by Friedel
Crafts acylation [5] of 1-(phenylsulfonyl)-1H-pyrrole (4). The latter was obtained in
74% yield (after recrystallization) by an extremely exothermic reaction accomplished
by overnight treatment of pyrrole with phenylsulfonyl chloride in a suspension of
NaOH (3 equiv.) in CH2Cl2 (Scheme 2). The reaction took place in the absence of a
phase-transfer catalyst [6], and could be used for the preparation of quantities of 200 g
of 4.
Scheme 2
Acylation of 4 with 3a (1.5 equiv.) and AlCl3 (3 equiv.) gave rise to quantitative
conversion to methyl 8-oxo-8-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]octanoate (5a;
Scheme 2). According to Kakushima et al. [7], the amount of AlCl3 is crucial to
achieve complete conversion, and a lower regioselectivity was obtained with other
Lewis acid catalysts. The regioselective 3-acylation of 4 was confirmed by 1D and 2D
1H-NMR spectroscopic analysis (Figure). In the case of 5a, a strong coupling between
the two vicinal pyrrole H-atoms at d(H) 7.15 (dd, J ˆ 2, 2, HÀC(5)) and 6.69 (dd, J ˆ
2.2, 1.7, HÀC(4)) was observed, together with weak couplings with the less-shielded H-
atom at d(H) 7.72 7.75 (m, HÀC(2)).

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Helvetica Chimica Acta Vol. 88 (2005)
Figure. Two-dimensional 1H-NMR spectrum of 5a (300 MHz, CDCl3)
The tosylhydrazone 6a was obtained in 92% yield by treatment of 5a with 1-[(4-
methylphenyl)sulfonyl]hydrazine (1.2 equiv.) in anhydrous EtOH. This transformation
was envisaged since tosylhydrazones can be selectively reduced under considerably
milder conditions than CˆO groups [8]. Reduction of 6a was then carried out in glacial
AcOH with NaBH3CN (3 equiv.) to afford the desired octanoate 7a in 68% yield after
column chromatography, together with 21% of the side product 7'a due to simulta-
neous, partial pyrrole-ring reduction. Similarly, in the reaction sequence with n ˆ 10,
the corresponding 2,5-dihydro-1H-pyrrole derivative 7'b was also observed (11% yield;
by 1H-NMR) upon reduction of 6b, which yielded 7b as the main product (Scheme 2).
Whereas migration of CˆC bonds to the site of the carbonyl C-atom has been
observed in the reduction of a,b-unsaturated tosylhydrazones [9], the simultaneous
reduction of pyrrole rings has not been reported, to our knowledge. A possible
mechanism for the formation of 7'a is depicted in Scheme 3. Interestingly, this side
reaction could not be suppressed by lowering the temperature or by shortening the
reaction time.

Helvetica Chimica Acta Vol. 88 (2005)
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Scheme 3. Proposed Mechanism for the Observed Reduction of 6a to 7'a by NaBH3CN
With compounds 7a,b at hand, the syntheses of the corresponding carboxylic acids
8a,b (by hydrolysis) and amines 9a,b (by reduction of the corresponding amides) were
straightforward (Scheme 4). The acids 9a,b were obtained nearly quantitatively upon
basic hydrolysis of 7a,b. The overall yield of 9a from pyrrole proper was 41%, and that
of 9b was 51%.
Scheme 4

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Amide formation was carried out by bubbling NH3 through a solution of 7a or 7b in
MeOH for 10 min at 08, and by further stirring at room temperature after sealing the
reaction flask [10]. Addition of NH3 was repeated every 2 d, until no ester could be
detected by TLC. After 10 d, the amide 10a was obtained in 69% yield. Reduction with
an excess (10 equiv.) of LiAlH4 in THF finally gave the desired 8-(pyrrol-3-yl)octan-
amine (9a) in 95% yield. Although BH3 ¥ HF and BH3 ¥ Me2S are the reagents of choice
for most reductions of amides [11], in the present case, the simultaneous removal of the
phenylsulfonyl protecting group could be effected with LiAlH4, avoiding an additional
deprotection step. The conversion of pyrrole proper to 9a was achieved in an overall
yield of 27%, and the chain-elongated congener 9b was prepared in 39% overall yield.
Conclusions. An efficient synthesis of 3-alkylpyrroles with C8 and C12 alkyl chains
and COOH or NH2 functions in w-position has been developed. The protocol is
suitable for large-scale preparations, yielding compounds of high purity and in high
yields, with only few steps requiring purification. In the NaBH3CN reduction of 6a,b to
7a,b, the unexpected, partially ring-hydrogenated side products 7'a,b, respectively, were
observed, a reaction that has not been reported so far.
√
J. M. F. gratefully acknowledges financial support of his Ph.D. work by FundaÁaƒo para a Ciencia e
Tecnologia.
Experimental Part
General. All reactions were carried out, unless mentioned, in open flasks. Technical solvents were distilled
and dried prior to use. All chemicals were purchased in puriss. or anal. quality from Fluka, Sigma, or Aldrich,
and used as received, unless stated otherwise. Column chromatography (CC):silica gel 60 (0.04 0.063 mm;
Fluka). Thin layer chromatography (TLC):silica-gel Alugram SIL G/UV254 sheets (Macherey-Nagel);
visualization under UV light (254 nm) and/or by spraying with ninhydrin soln. (10% in EtOH) or
phosphomolybdic acid soln. (10% in EtOH), or cerium(IV) sulfate/phosphomolybdic acid soln. (made from
10.5 g cerium(IV) sulfate hydrate, 21 g phosphomolybdic acid, 60 ml conc. H2SO4, and 900 ml H2O). IR: Biorad
FTS 25 apparatus; in cmÀ1. NMR spectra: Bruker AC-300, at 300 and 75 MHz for 1H and 13C, resp., in CDCl3;
chemical shifts d in ppm rel. to residual solvent peaks; 13C-NMR multiplicities determined by DEPT; coupling
constants J in Hz. Mass spectra were provided by the Service of Mass Spectrometry, Department of Chemistry
and Biochemistry, University of Berne.
Dimethyl Octanedioate (1a). To a soln. of suberic acid (10 g, 57.4 mmol) in MeOH (45 ml) was added H2SO4
(1 ml), and the mixture was refluxed overnight. The soln. was concentrated in vacuo. The resulting precipitate
was poured on ice, and extracted with Et2O (3 Â 40 ml). The combined org. extracts were washed with 10% aq.
NaHCO3 soln. and brine, and dried (MgSO4). Evaporation under reduced pressure gave 1a as an oil (10.4 g,
90%). 1H-NMR:3.67 ( s, 2 CO2Me); 2.31 (dd, J ˆ 7.4, 7.7, 2 CH2CO2Me); 1.69 1.56 (m, 2 CH2CH2CO2Me);
1.39 1.24 (m, 2 CH2).
Dimethyl Dodecanedioate (1b). Prepared in analogy to 1a, but starting from dodecanedioic acid. The title
compound was isolated as a colorless solid in 99% yield. 1H-NMR:3.67 ( s, 2 CO2Me); 2.30 (t, J ˆ 7.5,
2 CH2CO2Me); 1.68 1.53 (m, 2 CH2CH2CO2Me); 1.36 1.21 (m, 6 CH2).
Octanedioic Acid Monomethyl Ester (2a). To a soln. of KOH (2.07 g, 37 mmol) in MeOH (45 ml), 1a (7.5 g,
37 mmol) was added, and the mixture was stirred for 4 h at r.t. The solvent was then removed, and Et2O and H2O
were added. The org. layer was separated, washed with brine, dried (MgSO4), and concentrated under reduced
pressure to afford 1a as an oil (2.57 g, 34%). The aq. layer was acidified with conc. HCl to pH 3, and extracted
with Et2O (2 Â 100 ml). The combined org. extracts were washed with brine and dried (MgSO4). The solvent
was removed to give a mixture of a colorless solid and an oil. Extensive washing with hexane removed the
suberic acid monomethyl ester, the acid being virtually insolubility in hexane. Evaporation of the washings gave
the title compound 2a as an oil (2.73 g, 41%). 1H-NMR:3.67 ( s, CO2Me); 2.41 2.27 (m, 2 CH2CO2); 1.72 1.56
(m, 2 CH2CH2CO2R); 1.44 1.25 (m, 2 CH2).

Helvetica Chimica Acta Vol. 88 (2005)
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Dodecanedioic Acid Monomethyl Ester (2b). Prepared in analogy to 2a, but starting from 1b. The title
compound was isolated as a colorless solid in 44% yield. 1H-NMR:3.67 ( s, CO2Me); 2.41 2.26 (m, 2 CH2CO2);
1.70 1.55 (m, 2 CH2CH2CO2); 1.40 1.21 (m, 6 CH2).
Methyl 8-Chloro-8-oxooctanoate (3a). A soln. of 2a (1 g, 5.32 mmol) in SOCl2 (1 ml, 14 mmol) was stirred
at 558 for 3 h. The SOCl2 was removed under reduced pressure to afford an orange oil, which was used
immediately in the next step.
Methyl 12-Chloro-12-oxododecanoate (3b). Prepared in analogy to 3a, but starting from 2b.
1-(Phenylsulfonyl)-1H-pyrrole (4). Freshly distilled pyrrole (87.4 g, 1.30 mol) was added to a well-agitated
suspension of crushed NaOH (161 g, 4.03 mol) pellets in CH2Cl2 (900 ml). This mixture was cooled to 08 (ice
bath), and stirred for 25 min. Then, a soln. of phenylsulfonyl chloride (263 g, 1.49 mol) in CH2Cl2 (180 ml) was
added dropwise over a period of 90 min. The mixture was stirred for 4 h at 08, and then at r.t. overnight. The
reaction was quenched with distilled H2O (2.60 l). The org. phase was separated, and the aq. layer was extracted
with CH2Cl2 (3 Â 180 ml). The combined org. extracts were washed neutral with distilled H2O, dried (MgSO4),
and concentrated to a grey solid. Recrystallization from MeOH afforded 4 as a white crystalline solid (198 g,
1
74%). H-NMR:7.90 7.83 ( m, 2 H of Ph); 7.64 7.57 (m, H of Ph); 7.55 7.47 (m, 2 H of Ph); 7.22 7.14 (m,
HÀC(2,5)); 6.35 6.28 (m, HÀC(3,5)).
Methyl 8-Oxo-8-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]octanoate (5a). To a well-agitated suspension of AlCl3
(34 g, 0.25 mol) in CH2Cl2 (150 ml) cooled to 08 (ice bath), 3a was slowly added, followed by dropwise addition
of 4 (18 g, 87 mmol) in CH2Cl2 (100 ml). The mixture was allowed to warm to r.t., stirred for 2.5 h, and then
poured on ice-cold, distilled H2O (600 ml). The org. layer was separated, and the aq. layer was extracted with
CH2Cl2 (3 Â 40 ml). The combined org. extracts were washed with sat. aq. NaHCO3 soln. and H2O, dried
(MgSO4), and concentrated under reduced pressure to afford 5a (32.8 g, 100%) as a colorless, soapy solid. TLC
(hexanes/AcOEt 7:3): Rf 0.50. IR (KBr):3433 w, 3130m, 3065w, 2932m, 2890w, 2866w, 2851w, 2360w, 2341w,
1731s, 1684s, 1541m, 1473s, 1449m, 1379s, 1338w, 1300m, 1261w, 1221s, 1175s, 1118s, 1066s, 912m, 823w, 797m,
1
753m, 726s, 682m, 615s, 591s, 559m. H-NMR:7.95 7.90 ( m, 2 H of Ph); 7.75 7.72 (m, HÀC(2) of pyrrole);
7.70 7.64 (ttt, J ˆ 1.3, 2.2, 1.3, H of Ph); 7.60 7.53 (m, 2 H of Ph); 7.15 (dd, J ˆ 2.2, 2.2, HÀC(5) of pyrrole); 6.69
(dd, J ˆ 2.2, 1.7, HÀC(4) of pyrrole); 3.67 (s, CO2Me); 2.77 2.67 (m, CH2C(O)C); 2.31 (t, J ˆ 7.5, CH2CO2Me);
1.75 1.55 (m, 2 CH2CH2COR); 1.43 1.28 (m, 2 CH2). 13C-NMR:195.38 ( s, CˆO); 174.16 (s, CO2Me); 138.24
(s, arom. C); 134.54 (d, arom. CH); 129.71 (d, arom. CH); 129.23 (s, C(3) of pyrrole); 127.14 (d, arom. CH);
124.08 (d, C(2) of pyrrole); 121.59 (d, C(5) of pyrrole); 112.53 (d, C(4) of pyrrole); 51.44 (q, CO2Me); 39.61 (t,
CH2C(O)C); 33.97 (t, CH2CO2Me); 28.88 (t, CH2); 24.72 (t, CH2CH2C(O)C); 24.02 (t, CH2CH2CO2Me). MS:
‡
‡
‡
377 (3.6, M ), 249 (100), 234 (87), 141 (48), 94 (33), 77 (88). HR-MS:377.129760 ( M , C19H23NO5S ; calc.
377.129695).
Methyl 12-Oxo-12-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]dodecanoate (5b). Prepared in analogy to 5a, but
starting from 3b. The title compound was isolated as a colorless, soapy solid in 98% yield. TLC (hexanes/AcOEt
8:2): Rf 0.33. IR (KBr):3442 w, 3350w, 3132m, 3089w, 3063m, 2926s, 2850s, 1732s, 1685s, 1583w, 1541s, 1474s,
1450s, 1422m, 1376s, 1336m, 1317m, 1279m, 1260m, 1205s, 1174s, 1122s, 1103s, 1062s, 912m, 819m, 797m, 758m,
727s, 705m, 681s, 609s, 592s, 558s. 1H-NMR:7.95 7.89 ( m, 2 H of Ph); 7.75 7.72 (m, HÀC(2) of pyrrole); 7.71
7.64 (ttt, J ˆ 1.3, 2.3, 1.3, H of Ph); 7.60 7.53 (m, 2 H of Ph); 7.17 7.14 (dd, J ˆ 2.3, 2.3, HÀC(5) of pyrrole);
6.72 6.68 (m, HÀC(4) of pyrrole); 3.67 (s, CO2Me); 2.76 2.68 (m, CH2C(O)C); 2.31 (t, J ˆ 2.3, CH2CO2Me);
1.73 1.55 (m, 2 CH2CH2C(O)C); 1.39 1.21 (m, 6 CH2). 13C-NMR:195.61 ( s, CˆO); 174.31 (s, CO2Me); 138.22
(s, arom. C); 134.53 (d, arom. CH); 129.70 (d, arom. CH); 129.20 (s, C(3) of pyrrole); 127.13 (d, arom. CH);
124.06 (d, C(2) of pyrrole); 121.55 (d, C(5) of pyrrole); 112.56 (d, C(4) of pyrrole); 51.42 (q, CO2Me); 39.80 (t,
CH2C(O)Àpyrrole); 34.10 (t, CH2CO2Me); 29.37 (t, CH2); 29.37 (t, CH2); 29.35 (t, CH2); 29.29 (t, CH2); 29.20 (t,
‡
CH2); 29.11 (t, CH2); 24.93 (t, CH2CH2C(O)C); 24.30 (t, CH2CH2CO2Me). MS:433 (4.1, M ), 249 (100), 234
‡
‡
(48), 141 (23), 94 (49), 77 (62). HR-MS:433.191860 ( M , C23H31NO5S ; calc. 433.192295).
Methyl 8-{[(4-Methylphenyl)sulfonyl]hydrazono}-8-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]octanoate (6a). 1-
[(4-Methylphenyl)sulfonyl]hydrazine (10.6 g, 57 mmol) was added to a soln. of 5a (18 g, 48 mmol) in anh.
EtOH (60 ml). The mixture was heated at reflux for 30 min. The solvent was removed to afford a brown solid,
which was washed with cold Et2O, and dried in vacuo to give 6a as a colorless solid (23.5 g, 92%). IR (KBr):3434
(br.), 3221m, 3137w, 2936m, 2860w, 2361s, 2342s, 1739s, 1654w, 1592w, 1559w, 1496w, 1449m, 1375s, 1332s, 1274w,
1240w, 1183s, 1163s, 1120w, 1064s, 954w, 921w, 869w, 817w, 728m, 687m, 669m, 633m, 618m, 590s, 553m, 458w,
419w. 1H-NMR:7.91 7.82 ( m, 5 arom. H); 7.68 7.58 (m, arom. H); 7.57 7.47 (m, 2 arom. H); 7.34 7.28 (m, 2
arom. H, HÀC(2) of pyrrole); 7.08 (t, J ˆ 2.6, HÀC(5) of pyrrole); 6.61 6.57 (dd, J ˆ 1.3, 1.3, HÀC(4) of
pyrrole); 3.69 (s, CO2Me); 2.45 2.23 (m, CH2CO2Me, CH2CˆN, PhMe); 1.71 1.49 (m, CH2CH2CO2Me);
1.48 1.36 (m, CH2CH2CˆN); 1.19 1.35 (m, 2 CH2). 13C-NMR:174.18 ( s, CˆO); 151.15 (s, arom. C); 144.10 (s,

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Helvetica Chimica Acta Vol. 88 (2005)
arom. C); 138.60 (s, arom. C); 134.18 (d, arom. CH); 129.54 (d, arom. CH); 128.07 (d, arom. CH); 127.94 (s, C(3)
of pyrrole); 126.84 (d, arom. CH); 121.75 (d, C(2) of pyrrole); 119.54 (d, C(5) of pyrrole); 112.15 (d, C(4) of
pyrrole); 51.59 (q, CO2Me); 33.73 (t, CH2CO2Me); 29.07 (t, CH2CˆN); 28.45 (t, CH2); 27.55 (t, CH2); 25.40 (t,
‡
CH2CH2CˆN); 24.17 (t, CH2CH2CO2Me); 21.59 (q, PhMe). MS:545 (0.3, M ), 361 (32), 246 (42), 220 (31),
‡
‡
141 (33), 106 (30), 91 (71), 77 (100). HR-MS:545.165040 ( M , C26H31N3O6S2 ; calc. 545.165430).
Methyl 12-{[(4-Methylphenyl)sulfonyl]hydrazono}-12-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]dodecanoate
(6b). Prepared in analogy to 6a, but starting from 5b. The title compound was isolated as a colorless solid in
71% yield. IR (KBr):3443 (br.), 3256 m, 3208m, 3137m, 3067w, 2977s, 2853m, 2360w, 2341w, 1734s, 1599m,
1495m, 1449m, 1366s, 1334s, 1175s, 1097m, 1068s, 917m, 813m, 728s, 685m, 623s, 590s, 561m. 1H-NMR:7.88 7.82
(m, 4 arom. H); 7.67 7.60 (m, arom. H); 7.56 7.49 (m, 2 arom. H); 7.42 7.39 (m, H); 7.33 7.28 (m, 2 arom. H,
HÀC(2) of pyrrole); 7.11 7.08 (dd, J ˆ 2.2, 2.2, HÀC(5) of pyrrole); 6.60 (q, J ˆ 1.7, HÀC(4) of pyrrole); 3.68
(s, CO2Me); 2.41 (s, PhMe); 2.38 2.28 (m, CH2CO2Me, CH2CˆN); 1.69 1.59 (m, CH2CH2CˆN); 1.47 1.16
‡
(m, 7 CH2). MS:601 (2.1, M ), 417 (39), 276 (63), 246 (72), 221 (42), 141 (39), 106 (56), 91 (76), 80 (59), 77
‡
‡
(100). HR-MS:601.227910 ( M , C30H39N3O6S2 ; calc. 601.228030.
Methyl 8-[1-(Phenylsulfonyl)-1H-pyrrol-3-yl]octanoate (7a) and Methyl 8-[2,5-Dihydro-1-(phenylsulfon-
yl)-1H-pyrrol-3-yl]octanoate (7'a). NaBH3CN (1.15 g, 18 mmol) was added to a soln. of 6a (3.34 g, 6 mmol) in
glacial AcOH (60 ml), and the mixture was stirred at 408 for 80 min. The reaction was quenched with ice-cold,
distilled H2O (150 ml), and the mixture was extracted with Et2O (3 Â 120 ml). The combined org. extracts were
washed with sat. aq. NaHCO3 soln. (strong gas evolution!) and H2O, until neutral, dried (MgSO4), and
concentrated on a rotatory evaporator. The resulting oil was purified by CC (SiO2; AcOEt/hexanes 1:9) to
afford 7a (1.51 g, 68%) as a colorless, soapy solid, together with the side product 7'a (21%).
Data of 7a. TLC (hexanes/AcOEt 9:1): Rf 0.25. IR (KBr):3439 w, 3126m, 3076w, 3031w, 3006w, 2922s,
2847s, 2533w, 2358w, 1904w, 1732s, 1584w, 1477m, 1445m, 1366s, 1307m, 1253s, 1221m, 1183s, 1107s, 1060s, 952w,
1
885w, 848w, 799m, 756m, 731s, 690s, 639s, 623m, 588s, 558s, 485w, 411w. H-NMR:7.87 7.79 ( m, 2 arom. H);
7.63 7.55 (m, arom. H); 7.53 7.45 (m, 2 arom. H); 7.10 7.05 (dd, J ˆ 2.4, 2.4, HÀC(2) of pyrrole); 6.92 6.87
(m, HÀC(5) of pyrrole); 6.17 6.12 (m, HÀC(4) of pyrrole); 3.67 (s, CO2Me); 2.40 2.25 (m, CH2CO2Me,
CH2C(C)ˆC); 1.67 1.42 (m, CH2CH2CO2Me, CH2CH2C(C)ˆC); 1.35 1.20 (m, 3 CH2). 13C-NMR:174.26 ( s,
CˆO); 139.26 (s, arom. C); 133.56 (d, arom. CH); 130.09 (s, C(3) of pyrrole); 129.24 (d, arom. CH); 126.63 (d,
arom. CH); 120.92 (d, C(2) of pyrrole); 117.24 (d, C(5) of pyrrole); 114.88 (d, C(4) of pyrrole); 51.44 (q,
CO2Me); 34.04 (t, CH2CO2Me); 29.82 (t, CH2C(C)ˆC); 29.02 (t, CH2); 28.96 (t, CH2); 26.68 (t,
‡
CH2CH2C(C)ˆC); 24.87 (t, CH2CH2CO2Me). MS:363 (18, M ), 221 (100), 141 (34), 80 (72), 77 (82). HR-
‡
‡
MS:363.150420 ( M , C19H25NO4S ; calc. 363.150430).
Data of 7'a. TLC (hexanes/AcOEt 9 :1): Rf 0.16. 1H-NMR:7.88 7.80 ( m, 2 arom. H); 7.63 7.48 (m, 3
arom. H); 5.28 5.22 (m, CHˆC); 4.14 4.06 (m, NCH2CHˆC); 4.04 3.96 (m, NCH2C(C)ˆC); 3.67 (s,
CO2Me); 2.30 (t, J ˆ 7.5, CH2CO2Me); 2.01 1.91 (m, CH2C(C)ˆC); 1.66 1.50 (m, CH2CH2CO2Me); 1.43 1.14
(m, 4 CH2). 13C-NMR:174.24 ( s, CˆO); 139.66 (s, arom. C); 137.26 (s, CHˆC); 132.59 (d, arom. CH); 129.10
(d, arom. CH); 127.35 (d, arom. CH); 117.85 (d, CHˆC); 56.49 (t, NCH2C(C)ˆC); 55.05 (t, NCH2CHˆC);
51.48 (q, CO2Me); 34.01 (t, CH2CO2Me); 28.96 (t, CH2C(C)ˆC); 28.94 (t, CH2); 28.55 (t, CH2); 27.08 (t,
‡
CH2CH2C(C)ˆC); 24.84 (t, CH2CH2CO2Me). MS:365 (0.9, M ), 224 (95), 208 (51), 192 (45), 141 (51), 94
(33), 80 (92), 77 (100).
Methyl 12-[1-(Phenylsulfonyl)-1H-pyrrol-3-yl]dodecanoate (7b). Prepared as described for 7a, but starting
from 6b. The title compound 7b was isolated as a colorless, soapy solid in 73% yield. The side product 7'b (11%)
was detected by 1H-NMR, but not isolated. TLC (hexanes/AcOEt 8 :2): Rf 0.65. IR (KBr):3438 w, 3164w,
3127m, 3077w, 3032w, 3007w, 2914s, 2847s, 2532w, 2361w, 1905w, 1731s, 1630w, 1570w, 1537w, 1477m, 1444s,
1367s, 1316m, 1287m, 1262s, 1230s, 1207s, 1183s, 1167s, 1108s, 1061s, 953m, 887w, 799m, 756m, 731s, 691s, 639s,
623s, 588s, 559s. 1H-NMR:7.86 7.80 ( m, 2 arom. H); 7.63 7.56 (ttt, J ˆ 1.3, 2.4, 1.3, arom. H); 7.53 7.45 (m, 2
arom. H); 7.09 7.06 (dd, J ˆ 2.2, 2.2, HÀC(2) of pyrrole); 6.92 6.88 (m, HÀC(5) of pyrrole); 6.18 6.14 (dd,
J ˆ 1.7, 1.7, HÀC(4) of pyrrole); 3.67 (s, CO2Me); 2.41 2.28 (tt, J ˆ 7.5, 7.5, CH2CO2Me, CH2C(C)ˆC); 1.69
1.58 (m, CH2CH2CO2Me); 1.56 1.43 (m, CH2CH2C(C)ˆC); 1.37 1.18 (m, 7 CH2). 13C-NMR:174.35 ( s,
CˆO); 139.24 (s, arom. C); 133.55 (d, arom. CH); 130.22 (s, C(3) of pyrrole); 129.23 (d, arom. CH); 126.62 (d,
arom. CH); 120.88 (d, C(2) of pyrrole); 117.22 (d, C(5) of pyrrole); 114.93 (d, C(4) of pyrrole); 51.44 (q,
CO2Me); 34.09 (t, CH2CO2Me); 29.90 (t, CH2C(C)ˆC); 29.51 (t, CH2); 29.40 (t, CH2); 29.35 (t, CH2); 29.22 (t,
‡
CH2); 29.18 (t, CH2); 29.12 (t, CH2); 26.72 (t, CH2CH2C(C) ˆ C); 24.92 (t, CH2CH2CO2Me). MS:419 (22, M ),
‡
‡
278 (81), 221 (100), 141 (71), 80 (90), 77 (89). HR-MS:419.214020 ( M , C23H33NO4S ; calc. 419.213031).
8-(1H-Pyrrol-3-yl)octanoic Acid (8a). A soln. of 7a (1.74 g, 4.8 mmol) in a 2 :1 (v/v) mixture (60 ml) of
MeOH and 5m aq. NaOH was refluxed for 1.5 h, and then allowed to cool to r.t. The MeOH was removed under

Helvetica Chimica Acta Vol. 88 (2005)
2477
reduced pressure, and the aq. mixture was acidified with HCl to pH 3, and then extracted with Et2O (3 Â 20 ml).
The combined org. extracts were washed neutral with H2O, dried (MgSO4), and concentrated under reduced
pressure to afford 8a as a colorless solid (0.98 g, 98%). IR (KBr):3383 s, 3042 (br.), 2920s, 2849s, 2703w, 2651w,
2610w, 1697s, 1549w, 1493w, 1465m, 1441m, 1400m, 1342m, 1309m, 1275m, 1238s, 1211m, 1185m, 1160w, 1074m,
1007w, 961w, 912m, 776s, 737m, 716m, 681m, 624w, 582m. 1H-NMR:8.12 7.88 ( m, NH); 6.76 6.70 (dd, J ˆ 2.6,
2.6, HÀC(2) of pyrrole); 6.61 6.55 (m, HÀC(5) of pyrrole); 6.12 6.08 (dd, J ˆ 2.6, 2.6, HÀC(4) of pyrrole);
2.53 2.44 (m, CH2C(C)ˆC); 2.34 (t, J ˆ 7.5, CH2CO2H); 1.71 1.51 (m, CH2CH2CO2H, CH2CH2C(C)ˆC);
1.43 1.30 (m, 3 CH2). 13C-NMR:178.68 ( s, CˆO); 117.59 (d, C(2) of pyrrole); 114.81 (d, C(5) of pyrrole);
108.55 (d, C(4) of pyrrole); 33.80 (t, CH2CO2H); 31.10 (t, CH2C(C)ˆC); 29.24 (t, CH2); 29.11 (t, CH2); 29.03 (t,
‡
CH2); 26.88 (t, CH2CH2C(C)ˆC); 24.69 (t, CH2CH2CO2H). MS:209 (9, M ), 94 (25), 80 (100). HR-MS:
‡
‡
209.141590 (M , C12H19NO2 ; calc. 209.141579).
12-(1H-Pyrrol-3-yl)dodecanoic Acid (8b). Prepared in analogy to 8a, but starting from 7b. The title
compound was isolated as a colorless solid in quant. yield. IR (KBr):3390 s, 3041m, 2919s, 2848s, 1693s, 1543w,
1494w, 1467m, 1438m, 1405m, 1341m, 1317m, 1293m, 1265m, 1244m, 1222s, 1202m, 1183m, 1161w, 1074m,
1017w, 961m, 909m, 766s, 579m. 1H-NMR:8.10 7.91 ( m, NH); 6.75 6.71 (dd, J ˆ 2.6, 2.6, HÀC(2) of pyrrole);
6.60 6.56 (m, HÀC(5) of pyrrole); 6.12 6.08 (m, HÀC(4)); 2.53 2.44 (m, CH2C(C)ˆC); 2.36 (t, J ˆ 7.5,
CH2CO2H); 1.70 1.50 (m, CH2CH2CO2H, CH2CH2C(C) ˆ C); 1.41 1.19 (m, 8 CH2). 13C-NMR:179.09 ( s,
CˆO); 124.66 (s, C(3) of pyrrole); 117.53 (d, C(2) of pyrrole); 114.79 (d, C(5) of pyrrole); 108.54 (d, C(4) of
pyrrole); 33.87 (t, CH2CO2H); 31.20 (t, CH2C(C)ˆC); 29.58 (t, CH2); 29.55 (t, CH2); 29.51 (t, CH2); 29.41 (t,
‡
CH2); 29.22 (t, CH2); 29.04 (t, CH2); 26.92 (t, CH2CH2C(C)ˆC); 24.67 (t, CH2CH2COOH). MS:265 (17, M ),
‡
‡
94 (24), 80 (100). HR-MS:265.204160 ( M , C16H27NO2 ; calc. 265.204179).
8-[1-(Phenylsulfonyl)-1H-pyrrol-3-yl]octanamide (10a). A soln. of 7a (7 g, 19 mmol) in MeOH (50 ml)
was cooled to 08 (ice bath), and NH3 was bubbled through this soln. for 10 min. The reaction flask was sealed
with a septum, and the mixture was stirred at r.t. Every second day, the mixture was cooled again to 08, and NH3
was bubbled through the soln. for 10 min, before the flask was sealed again. After 10 d, the resulting colorless
precipitate was filtered off, washed with cold Et2O, and dried in vacuo to afford 10a (4.66 g, 69%). TLC
(hexanes/AcOEt 7:3): Rf 0.08. IR (KBr):3433 s, 3395m, 3337m, 3220m, 3116m, 3101w, 3057w, 3006w, 2924m,
2908m, 2849m, 2579w, 2488w, 2421w, 2362w, 1658s, 1618m, 1584w, 15.27w, 1471m, 1448m, 1415m, 1369s, 1323w,
1285w, 1261m, 1216w, 1169s, 1111s, 1060s, 791m, 732s, 681m, 622s, 582s, 554m. 1H-NMR:7.88 7.80 ( m, 2 arom.
H); 7.63 7.56 (m, arom. H); 7.54 7.46 (m, 2 arom. H); 7.11 7.05 (m, HÀC(2) of pyrrole); 6.93 6.88 (m,
HÀC(5) of pyrrole); 6.18 6.14 (dd, J ˆ 1.7, 1.7, HÀC(4) of pyrrole); 5.58 5.14 (m, NH2); 2.41 2.32 (m,
CH2C(C)ˆC); 2.18 2.25 (m, CH2CONH2); 1.69 1.61 (m, CH2CH2CONH2); 1.56 1.44 (m,
CH2CH2C(C)ˆC); 1.37 1.20 (m, 3 CH2). 13C-NMR:133.60 ( d, arom. CH); 130.07 (s, C(3) of pyrrole);
129.27 (d, arom. CH); 126.64 (d, arom. CH); 120.91 (d, C(2) of pyrrole); 117.22 (d, C(5) of pyrrole); 114.89 (d,
C(4) of pyrrole); 35.79 (t, CH2CONH2); 29.79 (t, CH2C(C)ˆC); 29.07 (t, CH2); 29.01 (t, CH2); 28.94 (t, CH2);
‡
‡
26.66 (t, CH2CH2C(C)ˆC); 25.39 (t, CH2CH2CONH2). MS:348 (0.8, M ), 77 (100). HR-MS:349.1579 ( M ,
‡
C18H24N2O3S ; calc. 349.1585).
12-[1-(Phenylsulfonyl)-1H-pyrrol-3-yl]dodecanamide (10b). Prepared in analogy to 10a, but starting from
7b. The title compound was isolated as a colorless solid in 77% yield. TLC (CH2Cl2/MeOH 9 :1): Rf 0.68.
1H-NMR:7.88 7.78 ( m, 2 arom. H); 7.63 7.56 (m, arom. H); 7.54 7.46 (m, 2 arom. H); 7.09 7.06 (dd, J ˆ 2.2,
2.2, HÀC(2) of pyrrole); 6.93 6.88 (m, HÀC(5) of pyrrole); 6.18 6.14 (dd, J ˆ 1.7, 1.7, HÀC(4) of pyrrole);
5.51 5.15 (m, NH2); 2.41 2.32 (m, CH2C(C)ˆC); 2.27 2.18 (m, CH2CONH2); 1.70 1.60 (m
CH2CH2CONH2); 1.55 1.43 (m, CH2CH2C(C)ˆC); 1.38 1.18 (m, 7 CH2).
8-(1H-Pyrrol-3-yl)octanamine (9a). LiAlH4 was added to a well-stirred soln. of 10a (0.71 g, 2 mmol) in anh.
THF (20 ml) over a period of 2.5 h. The mixture was heated at reflux for 16 h. The reaction was quenched with
2m aq. NaOH soln., until gas evolution ceased. Then, distilled H2O was added, and the mixture was stirred at r.t.
for 4 h. The THF was removed on a rotatory evaporator, and to the remaining −wet× solid, distilled H2O and
CH2Cl2 were added. The org. layer was separated, dried (MgSO4), and concentrated under reduced pressure to
afford 9a (0.38 g, 95%) as an oil. IR (KBr):3400 m, 3215m, 2920s, 2850s, 1561s, 1535s, 1485s, 1469s, 1431m,
1341m, 1065m, 765s. 1H-NMR:8.14 7.75 ( m, NH2); 6.75 6.65 (m, HÀC(2) of pyrrole); 6.60 6.50 (m, HÀC(5)
of pyrrole); 6.12 6.00 (m, HÀC(4) of pyrrole); 2.71 2.59 (m, CH2NH2); 2.52 2.39 (m, CH2C(C)ˆC); 1.64
1.51 (m, CH2CH2NH2); 1.50 1.18 (m, 6 CH2, CH2CH2C(C)ˆC). 13C-NMR:124.58 ( s, C(3) of pyrrole); 117.53
(d, C(2) of pyrrole); 114.78 (d, C(5) of pyrrole); 108.49 (d, C(4) of pyrrole); 42.25 (t, CH2NH2); 33.86 (t,
CH2CH2NH2); 31.18 (t, CH2C(C)ˆC); 29.67 (t, CH2); 29.50 (t, CH2); 29.45 (t, CH2); 26.92 (t, CH2CH2C(C)ˆC);
‡
‡
‡
26.88 (t, CH2CH2CH2NH2). MS:194 (60, M ), 94 (51), 80 (100). HR-MS:195.1856 ( M , C12H22N2 ; calc.
195.1861).

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Helvetica Chimica Acta Vol. 88 (2005)
12-(1H-Pyrrol-3-yl)dodecanamine (9b). Prepared in analogy to 9a, but from 10b. The title compound was
isolated as a colorless solid in 77% yield. IR (KBr):3399 (br.), 2918 s, 2850s, 1566m, 1471m, 1070m, 767m.
1H-NMR:8.25 7.91 ( m, NH2); 6.73 (q, J ˆ 2.4, HÀC(2) of pyrrole); 6.61 6.50 (m, HÀC(5) of pyrrole); 6.13
6.02 (m, HÀC(4) of pyrrole); 2.72 2.65 (m, CH2NH2); 2.53 2.44 (m, CH2C(C)ˆC); 1.66 1.52 (m,
CH2CH2NH2); 1.50 1.14 (m, 9 CH2). 13C-NMR:124.67 ( s, C(3) of pyrrole); 117.53 (d, C(2) of pyrrole);
114.79 (d, C(5) of pyrrole); 108.53 (d, C(4) of pyrrole); 42.28 (t, CH2NH2); 33.89 (t, CH2CH2NH2); 31.21 (t,
CH2C(C)ˆC); 29.64 (t, CH2); 29.62 (t, CH2); 29.60 (t, CH2); 29.53 (t, CH2); 29.52 (t, CH2); 29.50 (t, CH2); 26.94
‡
(t, CH2CH2C(C)ˆC); 26.89 (t, CH2CH2CH2NH2). MS:250 (40, M ), 94 (28), 80 (100). HR-MS:250.240660
‡
‡
(M , C16H30N2 ; calc. 250.240899).
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Received March 14, 2005