Furan ring opening-pyrrole ring closure: Simple route to 5-alkyl-2-(aminomethyl)pyrroles

Article abstract of DOI:10.1055/s-0030-1258165

A simple route to 5-alkyl-2-(aminomethyl)pyrroles is proposed that is based on hydrolytic ring opening of 5-alkylfurfurylamines followed by pyrrole ring closure under Paal-Knorr conditions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258165

PAPER
2969
Furan Ring Opening–Pyrrole Ring Closure: Simple Route to 5-Alkyl-2-
(aminomethyl)pyrroles
5
-Alkyl-2-(aminom
l
ethyl)
e
pyrroles xander V. Butin,*a Tatyana A. Nevolina,a Vitaly A. Shcherbinin,a Maxim G. Uchuskin,a Olga V. Serdyuk,b
Igor V. Trushkovc,d
a
Research Institute of Heterocyclic Compounds Chemistry, Kuban State Technological University,
Moskovskaya st. 2, Krasnodar 350072, Russian Federation
Department of Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don, 344090, Russian Federation
Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russian Federation
b
c
d
Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology, and Immunology,
Leninskii av. 117/2, Moscow 105062, Russian Federation
Fax +7(861)2596592.; E-mail: alexander_butin@mail.ru; E-mail: av_butin@yahoo.com
Received 20 April 2010; revised 27 April 2010
stricted,1i,11,13 because of difficulties in preparing the nec-
essary 1,4-diketones. 1-Phthalimido-2,5-diketones have
been synthesized by a benzoin condensation-like addition
of aldehydes to vinyl ketones in the presence of thiazoli-
um salts as catalysts,29 or by a three-step transformation of
2-(phthalimidomethyl)furans through formation of the
corresponding 2,5-dimethoxy-2,5-dihydrofurans, ring
opening, and double-bond hydrogenation.11 An alterna-
tive route to these aminodiketones involves the reaction of
N-(tert-butoxycarbonyl)glycine with potassium ethyl ma-
lonate followed by alkylation of the intermediate with a
bromomethyl ketone.1i 1,4-Diketones can also be pre-
pared by acid-catalyzed cleavage of a furan ring.30
Abstract: A simple route to 5-alkyl-2-(aminomethyl)pyrroles is
proposed that is based on hydrolytic ring opening of 5-alkylfur-
furylamines followed by pyrrole ring closure under Paal–Knorr
conditions.
Key words: furans, ring opening, ring closure, pyrroles, polycycles
2-(Aminomethyl)pyrroles have a broad range of biologi-
cal activities1 and have been shown to be potential anti-
inflammatory,2 analgesic,3 antidepressant,4 antipsychotic,5
or antitumor agents.6 2-(Aminomethyl)pyrroles have also
been used in the treatment of attention-deficit hyperactive
disorder;7 they have also been used in the preparation of
conformationally restricted peptidomimetics8,9 and anion-
binding receptors,9,10 and for the synthesis of
pyrrolodiazepines11–13 and other bioactive molecules con-
taining pyrrole units annulated to other heterocycles.1i,13–15
The 2-(aminomethyl)pyrrole moiety is present in a variety
of natural compounds such as porphobilinogen, an impor-
tant intermediate in the biosynthesis of porphyrins, cor-
rins, and chlorophylls.16 2-(Aminomethyl)pyrroles can be
transformed into porphyrinogens,17 pyrrodimethanes,18
porphyrins, or porphocyanins.19
When the starting furan contains a substituent that is ap-
propriate for further transformation into an aminoalkyl
group, a common sequence that involves cleavage of the
furan ring followed by closure of the pyrrole ring can be
used to provide an efficient synthesis of 2-(aminometh-
yl)pyrroles. Here, we describe an application of this ap-
proach to the transformation of 5-alkylfurfurylamines into
the corresponding 5-alkyl-2-(aminomethyl)pyrroles by
formation of 2-(phthalimidomethyl)furans as intermedi-
ates that undergo ring cleavage to give phthalimido di-
ketones that are subjected to Paal–Knorr cyclization and
removal of the phthalimide protecting group.
2-(Aminomethyl)pyrroles are usually synthesized by the
reduction of the corresponding oximes,1b,g,6a,9,10,20 ni-
triles,1e,6a,19c,20b,21 azides,1d,8b,12,14,22 or amides.5a Other ap-
proaches to 2-(aminomethyl)pyrroles include the
reductive amination of pyrrole-2-carbaldehydes,8d,23 the
transformation of pyrrole-2-carbaldehydes into imines
followed by addition of nucleophilic reagents,24 ami-
noalkylation of pyrroles,22b,25 nucleophilic substitution of
bromine in 2-(bromomethyl)pyrroles,5a,18a,26 and a variety
of intramolecular condensation reactions.8g,27
The starting N-furfurylphthalimides 3a–e were synthe-
sized in 65–79% yields by refluxing a mixture of the cor-
responding furfurylamine 1a–e31 with commercially
available phthalic anhydride (2) in acetic acid for 15–30
minutes (Scheme 1).11b The furan ring can be subjected to
acid-catalyzed cleavage by a variety of methods.30 We
used treatment with a mixture of acetic acid and hydro-
chloric acid, as we have shown that this method is effi-
cient in a variety of furan recyclization reactions.32 We
found that furans 3b–d, which have an alkyl group on the
C5 atom, were transformed into the corresponding di-
ketones 4b–d in high yields when they were stirred in a mix-
ture of acetic acid and hydrochloric acid at room
temperature (Scheme 1). In contrast, under the same con-
ditions imide 3a failed to give 4a, and instead of the di-
ketone we obtained a resinous material, and when 3a was
heated to reflux in a mixture of the two acids, significant
One of the oldest and best-known methods for the synthe-
sis of pyrroles is the Paal–Knorr reaction, i.e., the reaction
of 1,4-diketones or their analogues with primary amines
or ammonia.28 However, the application of this approach
to the synthesis of 2-(aminomethyl)pyrroles is very re-
SYNTHESIS 2010, No. 17, pp 2969–2978
x
x.
x
x
.
2
0
1
0
Advanced online publication: 12.07.2010
DOI: 10.1055/s-0030-1258165; Art ID: Z10310SS
© Georg Thieme Verlag Stuttgart · New York

2970
A. V. Butin et al.
PAPER
tarring occurred. We also found that the transformation of were obtained (Scheme 2, Table 1). This transformation
3e into 4e was inefficient under these reaction conditions. proceeded in moderate-to-good yields with aliphatic or
At room temperature, the reaction was too slow, and only aromatic amines, benzohydrazide, or 4-tolylsulfono-
traces of 4e were observed in the reaction mixture by TLC hydrazide. Treatment of pyrroles 6a–g with hydrazine hy-
analysis after a solution of 3e had been stirred in a mixture drate in methanol at room temperature33 gave the
of acetic acid and hydrochloric acid for one week. By in- corresponding deprotected amines 7a–g, which were
creasing the temperature, we were able to isolate 4e in a characterized after transformation into the corresponding
small yield, but the conversion of 3e was low even after N-butoxycarbonylderivatives 8a–g(Scheme 2 andTable 1).
refluxing the mixture for one day; increasing the reaction
time had no effect on the efficiency of this reaction. We
believe that in the case of 3e, the reaction equilibrium is
O
R1
AcOH
R1
reflux
O
N
R2
shifted toward the reagents side as a result of conjugation
between the furan and chlorophenyl rings.
+
R2NH2
O
N
N
O
O
5
O
O
4b–d
6a–r
reflux
O
O
+
R
N2H4
EtOH, r.t.
AcOH
O
NH2
1a–e
2
H
N
O
NH2
Boc2O
R1
Boc
R1
N
R
N
R2
R
R2
7a–g
O
HCl, AcOH
O
O
N
N
8a–g
O
O
O
r.t. (reflux for 3e)
Scheme 2 Synthesis of 2-(phthalimidomethyl)pyrroles 6 by the
Paal–Knorr reaction, and their transformation into the corresponding
2-[(N-butoxycarbonylamino)methyl]pyrroles 8
3a R = H (79%)
4a R = H (0%)
3b R = Me (74%)
3c R = Et (72%)
3d R = t-Bu (71%)
4b R = Me (92%)
4c R = Et (88%)
4d R = t-Bu (90%)
This approach was also used in the synthesis of pyrro-
lo[1,2-a][1,4]benzodiazepines 11a–c. A solution of di-
ketone 4b in benzene was refluxed with anilines 9a–c in
the presence of catalytic amount of trichloroacetic acid to
give the corresponding pyrroles 10a–c. On heating with
ethanolic hydrazine hydrate, pyrroles 10a–c were trans-
formed into the corresponding pyrrolo[1,2-a][1,4]benzo-
diazepines 11a–c (Scheme 3).
3e R = 4-ClC6H4 (65%)
4e R = 4-ClC6H4 (15%)
Scheme 1 Synthesis of N-furfurylphthalimides 3 and 1-phthalimido-
2,5-diketones 4
When mixtures of diketones 4b–d with amines 5 were re-
fluxed in acetic acid, the corresponding pyrroles 6a–r
Table 1 Synthesis of 2-(Phthalimidomethyl)pyrroles 6a–r and 2-[(N-Butoxycarbonylamino)methyl]pyrroles 8a–g
R1
R2
Yield (%)
R1
R2
Yield (%)
6
8
6
a
Me
85
82
j
Me
4-O2NC6H4
68
O
b
c
Me
Me
Me
Bn
90
83
78
89
72
63
k
l
Me
Me
Me
4-MeOC6H4
84
71
80
4-F3CC6H4
3-MeOC6H4
d
n-Bu
m
2,4-(MeO)2C6H3
O
O
e
Me
80
67
n
Me
73
O
f
Me
Me
Me
NHC(O)Ph
4-ClC6H4
90
85
55
76
88
o
p
q
Et
4-ClC6H4
78
85
82
g
h
t-Bu
Me
4-ClC6H4
NHTs
CH2CH2CO2H
i
Me
2-F3CC6H4
83
r
Me
65
O
Synthesis 2010, No. 17, 2969–2978 © Thieme Stuttgart · New York

PAPER
5-Alkyl-2-(aminomethyl)pyrroles
2971
O
N
R
N
MeO
MeO
NH2
MeO
MeO
N2H4
Cl3CCO2H
N
O
O
4b
+
R
Δ, benzene
Δ, EtOH
N
O
R
MeO
11a R = Me (50%)
11b R = Ph (46%)
11c R = 4-MeC6H4 (30%)
9a–c
OMe
10a R = Me (52%)
10b R = Ph (68%)
10c R = 4-MeC6H4 (80%)
Scheme 3 Synthesis of pyrrolo[1,2-a][1,4]benzodiazepines 11
O
O
N
N
N2H4
Δ, EtOH, DMF
HCl
H2N
NaOAc
+
4b
N
OEt
O
Δ, EtOH
NH
12
O
14 (30%)
O
OEt
13 (76%)
Scheme 4 Synthesis of pyrrolo[1,2-a]diazepine 14 from diketone 4b and b-glycine ethyl ester 12
reaction was monitored by TLC. The mixture was poured into cold
H2O (150 mL) and neutralized with NaHCO3 to pH ~7. The precip-
itate was filtered off, washed with cold H2O, air dried, and recrys-
tallized (EtOAc–PE).
By using a similar procedure, we also prepared the pyrro-
lo[1,2-a]diazepine 14. The diketone 4b, on heating with
b-glycine ethyl ester hydrochloride (12) in the presence of
sodium acetate, gave the pyrrole 13, which on treatment
with hydrazine hydrate in ethanol and N,N-dimethyl-
formamide gave the required product 14 (Scheme 4).13
2-[(5-Methyl-2-furyl)methyl]-1H-isoindole-1,3(2H)-dione (3b)
White solid; yield: 16.05 g (74%); mp 95 °C.
To summarize, we have developed a simple and efficient
method for the synthesis of 2-(aminomethyl)pyrroles
from readily available furfurylamines. The approach per-
mits the synthesis of N-alkyl- and N-arylpyrroles in good
yields. The transformation is compatible with a variety of
functional groups, including ketone, ester, and carboxy
groups. 2-(Phthalimidomethyl)pyrroles containing a car-
bonyl function attached to the substituent at the nitrogen
atom can be further transformed into pyrrolodiazepine de-
rivatives by deprotection and cyclization in situ; this sig-
nificantly broadens the value of the method.
IR (KBr): 1717, 1560, 1465, 1421, 1387, 1334, 1219, 1089, 1023,
964, 787, 752, 711 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.21 (s, 3 H, Me), 4.78 (s, 2 H,
CH2), 5.85 (d, J = 3.0 Hz, 1 H, HFur), 6.22 (d, J = 3.0 Hz, 1 H, HFur),
7.66–7.72 (m, 2 H, HPht), 7.80–7.86 (m, 2 H, HPht).
MS (EI, 70 eV): m/z (%) = 241 (100) [M+], 226 (12), 198 (31), 104
(14), 95 (32), 76 (36), 53 (16), 50 (43), 43 (45).
Anal. Calcd for C14H11NO3: C, 69.70; H, 4.60; N, 5.81. Found: C,
69.83; H, 4.91; N, 5.79.
2-[(5-Ethyl-2-furyl)methyl]-1H-isoindole-1,3(2H)-dione (3c)
White solid; yield: 16.52 g (72%); mp 93 °C.
IR (KBr): 1715, 1433, 1397, 1314, 1195, 1109, 1019, 951, 804, 736
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.16 (t, J = 7.5 Hz, 3 H, CH2CH3),
2.57 (q, J = 7.5 Hz, 2 H, CH2CH3), 4.79 (s, 2 H, CH2), 5.87 (d,
J = 3.0 Hz, 1 H, HFur), 6.23 (d, J = 3.0 Hz, 1 H, HFur), 7.66–7.73 (m,
2 H, HPht), 7.81–7.87 (m, 2 H, HPht).
NMR spectra were recorded on a Bruker DPX 300 spectrometer
(300 MHz for 1H; 75 MHz for 13C NMR) at r.t.; the chemical shifts
(d) were measured in ppm with respect to the solvent (CDCl3, 1H:
1
d = 7.26 ppm, 13C: d = 77.13 ppm; DMSO-d6, H: d = 2.50 ppm,
13C: d = 39.7 ppm). Coupling constants (J) are given in Hz. IR spec-
tra were recorded by using KBr plates on InfraLUM FT-02 and In-
fraLUM FT-801 instruments. Mass spectra were recorded on a
Kratos MS-30 instrument with EI ionization at 70 eV and 200 °C.
Melting points (uncorrected) were determined in capillaries with an
Electrothermal 9100 capillary melting-point apparatus. Column
chromatography was performed on silica gel KSK (50–160 mm,
LTD Sorbpolymer). All the reactions were carried out by using
freshly distilled and dry solvents.
MS (EI, 70 eV): m/z (%) = 255 (100) [M+], 240 (15), 226 (88), 198
(21), 108 (23), 104 (21), 78 (81), 65 (18), 50 (35), 43 (26).
Anal. Calcd for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C,
70.73; H, 5.06; N, 5.42.
2-[(5-tert-Butyl-2-furyl)methyl]-1H-isoindole-1,3(2H)-dione
(3d)
White solid; yield: 17.83 g (71%); mp 93 °C.
IR (KBr): 1709, 1428, 1400, 1313, 1200, 1104, 949, 786, 733 cm–1.
2-[(2-Furyl)methyl]-1H-isoindole-1,3(2H)-diones 3; General
Procedure
A soln of furfurylamine 1 (90 mmol) and phthalic anhydride 2 (14.8
g, 100 mmol) in AcOH (15 mL) was refluxed for 20 min while the
Synthesis 2010, No. 17, 2969–2978 © Thieme Stuttgart · New York

2972
A. V. Butin et al.
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1H NMR (300 MHz, CDCl3): d = 1.21 (s, 9 H, t-Bu), 4.80 (s, 2 H,
CH2), 5.84 (d, J = 3.0 Hz, 1 H, HFur), 6.18 (d, J = 3.0 Hz, 1 H, HFur),
7.66–7.73 (m, 2 H, HPht), 7.81–7.88 (m, 2 H, HPht).
Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C,
67.73; H, 6.41; N, 4.50.
2-[5-(4-Chlorophenyl)-2,5-dioxopentyl]-1H-isoindole-1,3(2H)-
dione (4e)
White solid; yield: 2.13 g (15%); mp 179 °C.
IR (KBr): 1721, 1681, 1414, 1088, 963, 818, 724 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.97 (t, J = 6.6 Hz, 2 H, CH2),
3.31 (t, J = 6.6 Hz, 2 H, CH2), 4.64 (s, 2 H, CH2), 7.42 (d, J = 9.0
MS (EI, 70 eV): m/z (%) = 283 (45) [M+], 268 (100), 226 (16), 160
(10), 121 (40), 104 (7), 77 (22), 50 (16), 43 (13).
Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C,
72.00; H, 6.12; N, 4.78.
2-{[5-(4-Chlorophenyl)-2-furyl]methyl}-1H-isoindole-1,3(2H)-
dione (3e)
Hz, 2 H, HAr), 7.69–7.76 (m, 2 H, HPht), 7.82–7.90 (m, 4 H, HPht
,
Beige solid; yield: 19.76 g (65%); mp 166 °C.
HAr).
IR (KBr): 1705, 1424, 1400, 1316, 1092, 944, 829, 794, 732 cm–1.
MS (EI, 70 eV): m/z (%) = 357/355 (1/3) [M+], 197/195 (35/100),
160 (60), 141/139 (27/83), 133 (13), 111 (49), 104 (31), 76 (54), 50
(43).
1H NMR (300 MHz, CDCl3): d = 4.89 (s, 2 H, CH2), 6.44 (d, J = 3.3
Hz, 1 H, HFur), 6.53 (d, J = 3.3 Hz, 1 H, HFur), 7.29 (d, J = 9.0 Hz, 2
H, HAr), 7.53 (d, J = 9.0 Hz, 2 H, HAr), 7.68–7.74 (m, 2 H, HPht),
7.83–7.89 (m, 2 H, HPht).
Anal. Calcd for C19H14ClNO4: C, 64.14; H, 3.97; N, 3.94. Found: C,
64.06; H, 3.89; N, 3.85.
MS (EI, 70 eV): m/z (%) = 339/337 (7/20) [M+], 198 (64), 191 (62),
170 (37), 162 (33), 139 (30), 128 (45), 115 (30), 104 (53), 76 (100),
63 (24), 50 (69).
2-[(1H-Pyrrol-2-yl)methyl]-1H-isoindole-1,3(2H)-diones 6a–q;
General Procedure
A mixture of diketone 4 (11 mmol) and amine 5 (12 mmol) in
AcOH (15 mL) was refluxed for 40–90 min while the reaction was
monitored by TLC, then poured into cold H2O (150 mL) and neu-
tralized to pH ~7 with NaHCO3. The product was extracted with
CH2Cl2 (3 × 30 mL), and the combined organic fractions were
washed with H2O, dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by column chromatography (sil-
ica gel), and the solvent was evaporated to one third of the original
volume and kept until the product crystallized.
Anal. Calcd for C19H12ClNO3: C, 67.57; H, 3.58; N, 4.15. Found: C,
67.35; H, 3.52; N, 4.11.
N-(2,5-Dioxoalkyl)-1H-isoindole-1,3(2H)-diones 4b–e; General
Procedure
An isoindoledione 3b–e (40 mmol) was dissolved in a mixture of
glacial AcOH (50 mL) and concd HCl (30 mL), and the mixture was
stirred for 24 h (72 h for 4d) at r.t. (reflux for 4e), while the reaction
was monitored by TLC. The mixture was then poured into cold H2O
(300 mL) and neutralized to pH ~7 with NaHCO3. The precipitate
was filtered off, washed with cold H2O, air dried, and recrystallized
(CH2Cl2–PE).
2-({5-Methyl-1-[(5-methyl-2-furyl)methyl]-1H-pyrrol-2-
yl}methyl)-1H-isoindole-1,3(2H)-dione (6a)
Eluent: CH2Cl2–PE (1:5); white solid; yield: 3.12 g (85%); mp
107 °C.
2-(2,5-Dioxohexyl)-1H-isoindole-1,3(2H)-dione (4b)
IR (KBr): 1707, 1426, 1388, 1326, 1196, 1089, 1020, 932, 786, 713
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.02 (s, 3 H, Me), 2. 21 (s, 3 H,
Me), 4.89 (s, 2 H, CH2), 5.15 (s, 2 H, CH2), 5.69 (d, J = 3.3 Hz, 1 H,
White solid; yield: 9.53 g (92%); mp 119 °C (Lit.11a 118–119.5 °C).
IR (KBr): 1721, 1680, 1414, 1228, 1192, 1092, 1042, 992, 971, 720
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.14 (s, 3 H, Me), 2.76 (s, 4 H,
CH2CH2), 4.53 (s, 2 H, CH2), 7.65–7.73 (m, 2 H, HPht), 7.77–7.85
(m, 2 H, HPht).
MS (EI, 70 eV): m/z (%) = 216 (2) [M+ – 43], 160 (68), 133 (12),
104 (27), 99 (100), 76 (40), 71 (27), 50 (26), 43 (87).
HFur), 5.83 (d, J = 3.3 Hz, 1 H, HPyr), 5.85 (d, J = 3.3 Hz, 1 H, HFur),
6.26 (d, J = 3.3 Hz, 1 H, HPyr), 7.63–7.70 (m, 2 H, HPht), 7.75–7.82
(m, 2 H, HPht).
MS (EI, 70 eV): m/z (%) = 334 (10) [M+], 240 (12), 104 (4), 95
(100), 43 (20).
Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C,
71.91; H, 5.45; N, 8.20.
2-(2,5-Dioxoheptyl)-1H-isoindole-1,3(2H)-dione (4c)
White solid; yield: 9.61 g (88%); mp 110 °C (Lit.29 109–110 °C).
IR (KBr): 1725, 1416, 1192, 1092, 1049, 969, 720 cm–1.
2-[(1-Benzyl-5-methyl-1H-pyrrol-2-yl)methyl]-1H-isoindole-
1,3(2H)-dione (6b)
Eluent: CH2Cl2–PE (1:4); pale brown solid; yield: 3.27 g (90%); mp
127–128 °C.
1H NMR (300 MHz, CDCl3): d = 1.03 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.44 (q, J = 7.2 Hz, 2 H, CH2CH3), 2.70–2.82 (m, 4 H, CH2CH2),
4.54 (s, 2 H, CH2), 7.67–7.74 (m, 2 H, HPht), 7.80–7.87 (m, 2 H,
IR (KBr): 1710, 1425, 1389, 1340, 1300, 1100, 934, 748, 711 cm–1.
HPht).
MS (EI, 70 eV): m/z (%) = 216 (6) [M+ – 57], 160 (44), 133 (8), 113
(100), 104 (17), 95 (12), 85 (11), 77 (24), 57 (49), 50 (12).
1H NMR (300 MHz, CDCl3): d = 2.12 (s, 3 H, Me), 4.74 (s, 2 H,
CH2), 5.28 (s, 2 H, CH2), 5.95 (d, J = 3.6 Hz, 1 H, HPyr), 6.36 (d,
J = 3.6 Hz, 1 H, HPyr), 6.69–6.72 (m, 2 H, HAr), 6.89–6.94 (m, 1 H,
HAr), 7.03–7.08 (m, 2 H, HAr), 7.55–7.66 (m, 4 H, HPht).
MS (EI, 70 eV): m/z (%) = 330 (24) [M+], 239 (100), 182 (10), 104
(7), 76 (14), 65 (27), 51 (11).
2-(6,6-Dimethyl-2,5-dioxoheptyl)-1H-isoindole-1,3(2H)-dione
(4d)
Colorless prisms; yield: 10.84 g (90%); mp 113 °C.
IR (KBr): 1716, 1419, 1315, 1192, 1071, 990, 907, 725 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.12 (s, 9 H, t-Bu), 2.73–2.78 (m,
2 H, CH2), 2.82–2.86 (m, 2 H, CH2), 4.55 (s, 2 H, CH2), 7.67–7.74
(m, 2 H, HPht), 7.81–7.87 (m, 2 H, HPht).
MS (EI, 70 eV): m/z (%) = 244 (9) [M+ – 57], 216 (28), 160 (45),
141 (100), 133 (11), 113 (84), 104 (25), 77 (37), 57 (74), 50 (22), 41
(80).
Anal. Calcd for C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C,
76.06; H, 5.40; N, 8.47.
2-({5-Methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrrol-2-
yl}methyl)-1H-isoindole-1,3(2H)-dione (6c)
Eluent: CH2Cl2–PE (1:5); white solid; yield: 3.51 g (83%); mp
124 °C.
Synthesis 2010, No. 17, 2969–2978 © Thieme Stuttgart · New York

PAPER
5-Alkyl-2-(aminomethyl)pyrroles
2973
IR (KBr): 1718, 1612, 1426, 1394, 1329, 1176, 1109, 951, 849, 713
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.99 (s, 3 H, Me), 4.63 (s, 2 H,
CH2), 5.96 (d, J = 3.6 Hz, 1 H, HPyr), 6.22 (d, J = 3.6 Hz, 1 H, HPyr),
7.41 (d, J = 8.1 Hz, 2 H, HAr), 7.64–7.79 (m, 6 H, HAr + HPht).
MS (EI, 70 eV): m/z (%) = 384 (41) [M+], 238 (100), 222 (28), 196
(10), 168 (12), 145 (17), 130 (20), 105 (17), 76 (32), 50 (23).
1H NMR (300 MHz, CDCl3): d = 1.97 (s, 3 H, Me), 4.61 (s, 2 H,
CH2), 5.92 (d, J = 3.6 Hz, 1 H, HPyr), 6.19 (d, J = 3.6 Hz, 1 H, HPyr),
7.20 (d, J = 8.7 Hz, 2 H, HAr), 7.43 (d, J = 8.7 Hz, 2 H, HAr), 7.64–
7.71 (m, 2 H, HPht), 7.73–7.81 (m, 2 H, HPht).
MS (EI, 70 eV): m/z (%) = 352/350 (2/5) [M+], 239 (15), 206/204
(34/100), 188 (14), 168 (18), 154 (27), 130 (22), 111 (19), 104 (16),
76 (47), 50 (33).
Anal. Calcd for C20H15ClN2O2: C, 68.48; H, 4.31; N, 7.99. Found:
C, 68.32; H, 4.28; N, 8.18.
Anal. Calcd for C21H15F3N2O2: C, 65.62; H, 3.93; N, 7.29. Found:
C, 65.40; H, 3.77; N, 7.39.
3-{2-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-meth-
yl-1H-pyrrol-1-yl}propanoic Acid (6h)
Eluent: CH2Cl2–PE (1:4); beige solid; yield: 1.89 g (55%); mp
>250 °C (dec).
2-[(1-Butyl-5-methyl-1H-pyrrol-2-yl)methyl]-1H-isoindole-
1,3(2H)-dione (6d)
Eluent: CH2Cl2–PE (1:10); pale brown solid; yield: 2.54 g (78%);
mp 89–90 °C.
IR (KBr): 1720, 1436, 1400, 1328, 1300, 1088, 1120, 960, 748, 732,
712 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.15 (s, 3 H, Me), 2.55 (t,
J = 7.8 Hz, 2 H, CH2), 4.20 (t, J = 7.8 Hz, 2 H, CH2), 4.73 (s, 2 H,
CH2), 5.66 (d, J = 3.6 Hz, 1 H, HPyr), 5.83 (d, J = 3.6 Hz, 1 H, HPyr),
7.77–7.90 (m, 4 H, HPht).
MS (EI, 70 eV): m/z (%) = 312 (100) [M+], 297 (16), 239 (85), 166
(93), 152 (30), 130 (22), 120 (36), 104 (47), 94 (37), 76 (81), 65
(22), 50 (61).
IR (KBr): 1701, 1427, 1394, 1342, 1090, 930, 749, 713 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 7.2 Hz, 3 H, Me),
1.35–1.49 (m, 2 H, CH2), 1.52–1.64 (m, 2 H, CH2), 2.19 (s, 3 H,
CH3), 4.00 (t, J = 7.5 Hz, 2 H, CH2), 4.81 (s, 2 H, CH2), 5.80 (d,
J = 3.6 Hz, 1 H, HPyr), 6.21 (d, J = 3.6 Hz, 1 H, HPyr), 7.64–7.72 (m,
2 H, HPht), 7.76–7.84 (m, 2 H, HPht).
MS (EI, 70 eV): m/z (%) = 296 (100) [M+], 254 (20), 239 (81), 150
(50), 136 (72), 130 (20), 107 (59), 94 (91), 76 (47), 50 (30).
Anal. Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C,
73.00; H, 6.86; N, 9.54.
Anal. Calcd for C17H16N2O4: C, 65.38; H, 5.16; N, 8.97. Found: C,
65.44; H, 4.82; N, 8.58.
2-{[5-Methyl-1-(3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1H-pyr-
rol-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (6e)
Eluent: CH2Cl2–PE (1:1); beige solid; yield: 3.27 g (80%); mp 163–
164 °C.
2-({5-Methyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrrol-2-
yl}methyl)-1H-isoindole-1,3(2H)-dione (6i)
Eluent: CH2Cl2–PE (1:5); cream solid; yield: 3.51 g (83%); mp
128 °C.
IR (KBr): 1765, 1711, 1494, 1415, 1357, 1177, 1111, 1053, 995,
939, 718 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.96 (s, 3 H, Me), 4.60 (br s, 2 H,
CH2), 5.41 (s, 2 H, CH2), 5.94 (d, J = 3.6 Hz, 1 H, HPyr), 6.27 (d,
J = 3.6 Hz, 1 H, HPyr), 7.56–7.76 (m, 7 H, HAr).
MS (EI, 70 eV): m/z (%) = 372 (48) [M+], 239 (14), 226 (100), 181
(18), 130 (16), 104 (15), 76 (37), 50 (26).
IR (KBr): 1712, 1502, 1461, 1421, 1390, 1314, 1131, 1033, 768,
712 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.88 (s, 3 H, Me), 4.36 (d, J = 15.3
Hz, 1 H, CHAHB), 4.67 (d, J = 15.3 Hz, 1 H, CHAHB), 5.94 (d,
J = 3.6 Hz, 1 H, HPyr), 6.28 (d, J = 3.6 Hz, 1 H, HPyr), 7.26–7.34 (m,
1 H, HAr), 7.58–7.70 (m, 4 H, HPht, HAr), 7.71–7.79 (m, 2 H, HPht),
7.80–7.87 (m, 1 H, HAr).
MS (EI, 70 eV): m/z (%) = 384 (18) [M+], 238 (100), 222 (15), 168
(17), 145 (16), 130 (18), 105 (19), 76 (35), 50 (24).
Anal. Calcd for C22H16N2O4: C, 70.96; H, 4.33; N, 7.52. Found: C,
70.79; H, 4.23; N, 7.48.
Anal. Calcd for C21H15F3N2O2: C, 65.62; H, 3.93; N, 7.29. Found:
C, 65.84; H, 3.94; N, 7.46.
N-{2-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-
methyl-1H-pyrrol-1-yl}benzamide (6f)
Eluent: CH2Cl2–PE (1:5); colorless prisms; yield: 3.55 g (90%); mp
217–218 °C.
2-{[5-Methyl-1-(4-nitrophenyl)-1H-pyrrol-2-yl]methyl}-1H-
isoindole-1,3(2H)-dione (6j)
Eluent: EtOAc–PE (1:5); yellow needles; yield: 2.70 g (68%); mp
203 °C.
IR (KBr): 3331, 1764, 1710, 1673, 1521, 1422, 1391, 1332, 1270,
1099, 930, 744, 706 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.00 (s, 3 H, Me), 4.58 (d,
J = 15.0 Hz, 1 H, CHAHB), 4.69 (d, J = 15.0 Hz, 1 H, CHAHB), 5.79
(d, J = 3.6 Hz, 1 H, HPyr), 6.05 (d, J = 3.6 Hz, 1 H, HPyr), 7.51–7.57
(m, 2 H, HAr), 7.61–7.67 (m, 1 H, HAr), 7.76–7.84 (m, 4 H, HPht),
7.87–7.90 (m, 2 H, HAr), 11.27 (s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 359 (35) [M+], 254 (25), 239 (81), 211
(12), 193 (16), 160 (10), 130 (19), 105 (97), 77 (100), 65 (14), 51
(57).
IR (KBr): 1717, 1595, 1519, 1339, 1109, 941, 874 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.00 (s, 3 H, Me), 4.62 (s, 2 H,
CH2), 5.98 (d, J = 3.6 Hz, 1 H, HPyr), 6.28 (d, J = 3.6 Hz, 1 H, HPyr),
7.45 (d, J = 9.0 Hz, 2 H, HAr), 7.64–7.71 (m, 2 H, HPht), 7.72–7.79
(m, 2 H, HPht), 8.35 (d, J = 9.0 Hz, 2 H, HAr).
MS (EI, 70 eV): m/z (%) = 361 (5) [M+], 239 (18), 215 (100), 199
(16), 167 (35), 154 (29), 130 (30), 104 (28), 76 (85), 50 (53).
Anal. Calcd for C20H15N3O4: C, 66.48; H, 4.18; N, 11.63. Found: C,
66.24; H, 4.22; N, 11.90.
Anal. Calcd for C21H17N3O3: C, 70.18; H, 4.77; N, 11.69. Found: C,
70.12; H, 4.78; N, 11.51.
2-{[1-(4-Methoxyphenyl)-5-methyl-1H-pyrrol-2-yl]methyl}-
1H-isoindole-1,3(2H)-dione (6k)
Eluent: CH2Cl2–PE (1:6.5); pale yellow prisms; yield: 3.20 g
2-{[1-(4-Chlorophenyl)-5-methyl-1H-pyrrol-2-yl]methyl}-1H-
isoindole-1,3(2H)-dione (6g)
Eluent: CH2Cl2–PE (1:6); white solid; yield: 3.28 g (85%); mp
(84%); mp 131–132 °C.
159 °C.
IR (KBr): 1718, 1516, 1426, 1392, 1292, 1251, 1189, 1113, 1027,
950, 837, 741, 709 cm–1.
IR (KBr): 1722, 1492, 1426, 1391, 1088, 1001, 949, 836, 732 cm–1.
Synthesis 2010, No. 17, 2969–2978 © Thieme Stuttgart · New York

2974
A. V. Butin et al.
PAPER
2-{[1-(4-Chlorophenyl)-5-ethyl-1H-pyrrol-2-yl]methyl}-1H-
isoindole-1,3(2H)-dione (6o)
Eluent: CH2Cl2–PE (1:2); white solid; yield: 3.13 g (78%); mp
119 °C.
1H NMR (300 MHz, CDCl3): d = 1.96 (s, 3 H, Me), 3.85 (s, 3 H,
OMe), 4.62 (s, 2 H, CH2), 5.90 (d, J = 3.6 Hz, 1 H, HPyr), 6.15 (d,
J = 3.6 Hz, 1 H, HPyr), 6.95 (d, J = 8.7 Hz, 2 H, HAr), 7.18 (d, J = 8.7
Hz, 2 H, HAr), 7.63–7.70 (m, 2 H, HPht), 7.73–7.81 (m, 2 H, HPht).
MS (EI, 70 eV): m/z (%) = 346 (40) [M+], 239 (18), 200 (100), 184
IR (KBr): 1723, 1492, 1427, 1392, 1088, 1003, 950, 838, 730 cm–1.
(18), 130 (12), 77 (26), 50 (14).
1H NMR (300 MHz, CDCl3): d = 1.06 (t, J = 7.5 Hz, 3 H, CH2CH3),
2.28 (q, J = 7.5 Hz, 2 H, CH2CH3), 4.60 (s, 2 H, CH2), 5.94 (d,
J = 3.6 Hz, 1 H, HPyr), 6.22 (d, J = 3.6 Hz, 1 H, HPyr), 7.21 (d, J = 8.7
Hz, 2 H, HAr), 7.43 (d, J = 8.7 Hz, 2 H, HAr), 7.64–7.71 (m, 2 H,
Anal. Calcd for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C,
72.72; H, 5.26; N, 8.06.
2-{[1-(3-Methoxyphenyl)-5-methyl-1H-pyrrol-2-yl]methyl}-
1H-isoindole-1,3(2H)-dione (6l)
Eluent: CH2Cl2–PE (1:6); cream solid; yield: 2.70 g (71%); mp
HPht), 7.74–7.81 (m, 2 H, HPht).
MS (EI, 70 eV): m/z (%) = 366/364 (10/31) [M+], 220/218 (33/100),
204/202 (12/35), 190/188 (13/38), 167 (59), 160 (17), 154 (30), 130
(34), 104 (34), 76 (81), 50 (52).
134 °C.
IR (KBr): 1718, 1597, 1394, 1326, 1243, 1180, 1114, 1031, 949,
857, 794, 747 cm–1.
Anal. Calcd for C21H17ClN2O2: C, 69.14; H, 4.70; N, 7.68. Found:
C, 69.00; H, 4.67; N, 7.66.
1H NMR (300 MHz, CDCl3): d = 2.00 (s, 3 H, Me), 3.76 (s, 3 H,
OMe), 4.66 (s, 2 H, CH2), 5.92 (d, J = 3.6 Hz, 1 H, HPyr), 6.17 (d,
J = 3.6 Hz, 1 H, HPyr), 6.77–6.79 (m, 1 H, HAr), 6.83–6.86 (m, 1 H,
HAr), 6.94–6.98 (m, 1 H, HAr), 7.32–7.37 (m, 1 H, HAr), 7.62–7.70
(m, 2 H, HPht), 7.72–7.81 (m, 2 H, HPht).
2-{[5-tert-Butyl-1-(4-chlorophenyl)-1H-pyrrol-2-yl]methyl}-
1H-isoindole-1,3(2H)-dione (6p)
Eluent: CH2Cl2–PE (1:4); white solid; yield: 3.67 g (85%); mp 155–
156 °C.
MS (EI, 70 eV): m/z (%) = 346 (34) [M+], 239 (13), 200 (100), 184
(24), 130 (13), 77 (23), 50 (13).
IR (KBr): 1714, 1492, 1422, 1390, 1319, 1092, 932, 840, 784, 732
cm–1.
Anal. Calcd for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C,
72.68; H, 5.12; N, 8.06.
1H NMR (300 MHz, CDCl3): d = 1.08 (s, 9 H, t-Bu), 4.42 (s, 2 H,
CH2), 5.98 (d, J = 3.9 Hz, 1 H, HPyr), 6.12 (d, J = 3.9 Hz, 1 H, HPyr),
7.29 (d, J = 8.7 Hz, 2 H, HAr), 7.40 (d, J = 8.7 Hz, 2 H, HAr), 7.64–
7.72 (m, 2 H, HPht), 7.74–7.82 (m, 2 H, HPht).
MS (EI, 70 eV): m/z (%) = 394/392 (9/26) [M+], 379/377 (27/86),
232/230 (17/51), 215 (31), 180 (46), 160 (98), 130 (52), 104 (53),
77 (100), 50 (55).
2-{[1-(2,5-Dimethoxyphenyl)-5-methyl-1H-pyrrol-2-yl]meth-
yl}-1H-isoindole-1,3(2H)-dione (6m)
Eluent: CH2Cl2–PE (1:6); cream solid; yield: 3.31 g (80%); mp
174 °C.
IR (KBr): 1714, 1510, 1422, 1390, 1277, 1229, 1099, 1048, 933,
806, 755, 729 cm–1.
Anal. Calcd for C23H21ClN2O2: C, 70.31; H, 5.39; N, 7.13. Found:
C, 70.17; H, 5.27; N, 7.19.
1H NMR (300 MHz, CDCl3): d = 1.92 (s, 3 H, Me), 3.48 (s, 3 H,
OMe), 3.70 (s, 3 H, OMe), 4.56 (d, J = 15.3 Hz, 1 H, CHAHB), 4.69
(d, J = 15.3 Hz, 1 H, CHAHB), 5.94 (d, J = 3.6 Hz, 1 H, HPyr), 6.28
(d, J = 3.6 Hz, 1 H, HPyr), 6.73 (d, J = 3.0 Hz, 1 H, HAr), 6.82 (d,
J = 9.0 Hz, 1 H, HAr), 6.93 (dd, J = 9.0 Hz, J = 3.0 Hz, 1 H, HAr),
7.61–7.68 (m, 2 H, HPht), 7.69–7.76 (m, 2 H, HPht).
N-{2-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-
methyl-1H-pyrrol-1-yl}-4-methylbenzenesulfonamide (6q)
Eluent: CH2Cl2–PE (1:5); cream solid; yield: 3.69 g (82%); mp
222–223 °C.
IR (KBr): 3407, 1699, 1612, 1435, 1400, 1351, 1158, 1091, 897,
749 cm–1.
MS (EI, 70 eV): m/z (%) = 376 (51) [M+], 239 (14), 230 (100), 216
(37), 198 (14), 130 (13), 105 (12), 77 (23), 51 (15).
1H NMR (300 MHz, DMSO-d6): d = 1.42 (s, 3 H, Me), 2.41 (s, 3 H,
Me), 4.48 (d, J = 15.9 Hz, 1 H, CHAHB), 4.66 (d, J = 15.9 Hz, 1 H,
CHAHB), 5.57 (d, J = 3.6 Hz, 1 H, HPyr), 5.68 (d, J = 3.6 Hz, 1 H,
Anal. Calcd for C22H20N2O4: C, 70.20; H, 5.36; N, 7.44. Found: C,
69.95; H, 5.29; N, 7.38.
HPyr), 7.45 (d, J = 8.1 Hz, 2 H, HAr), 7.61 (d, J = 8.1 Hz, 2 H, HAr),
2-({5-Methyl-1-[2-(5-methyl-2-furyl)phenyl]-1H-pyrrol-2-
yl}methyl)-1H-isoindole-1,3(2H)-dione (6n)
Eluent: CH2Cl2–PE (1:5); cream solid; yield: 3.18 g (73%); mp
126–127 °C.
7.81–7.90 (m, 4 H, HPht), 11.12 (s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 409 (1) [M+], 254 (64), 236 (15), 160
(14), 130 (39), 104 (27), 91 (93), 77 (100), 65 (55), 51 (29).
Anal. Calcd for C21H19N3O4S: C, 61.60; H, 4.68; N, 10.26; S, 7.83.
Found: C, 61.93; H, 4.51; N, 9.97; S, 7.64.
IR (KBr): 1719, 1538, 1492, 1427, 1386, 1338, 1299, 1102, 1044,
935, 763, 713 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.81 (s, 3 H, Me), 1.99 (s, 3 H,
Me), 4.41 (d, J = 15.3 Hz, 1 H, CHAHB), 4.55 (d, J = 3.3 Hz, 1 H,
HFur), 4.66 (d, J = 15.3 Hz, 1 H, CHAHB), 5.63 (d, J = 3.3 Hz, 1 H,
2-({5-Methyl-1-[2-(5-methyl-2-furyl)ethyl]-1H-pyrrol-2-
yl}methyl)-1H-isoindole-1,3(2H)-dione (6r)
A soln of diketone 4b (2.86 g, 11 mmol) and 2-(2-furyl)ethanamine
(1.38 g, 11 mmol) in EtOH (30 mL) was refluxed for 1 h (TLC mon-
itoring). The solvent was evaporated and the residue was recrystal-
lized (EtOAc–acetone) to give a white solid; yield: 2.50 g (65%);
mp 137–138 °C.
HFur), 6.02 (d, J = 3.6 Hz, 1 H, HPyr), 6.41 (d, J = 3.6 Hz, 1 H, HPyr),
7.21–7.24 (m, 1 H, HAr), 7.32–7.37 (m, 1 H, HAr), 7.45–7.50 (m, 1
H, HAr), 7.58 (s, 4 H, HPht), 7.77–7.81 (m, 1 H, HAr).
MS (EI, 70 eV): m/z (%) = 396 (100) [M+], 353 (61), 250 (72), 236
(84), 221 (25), 206 (60), 191 (24), 180 (17), 105 (17), 76 (29), 59
(16).
IR (KBr): 1716, 1568, 1468, 1424, 1388, 1332, 1304, 1204, 1096,
1020, 932, 808, 780, 748 cm–1.
Anal. Calcd for C25H20N2O3: C, 75.74; H, 5.08; N, 7.07. Found: C,
75.95; H, 4.99; N, 7.15.
1H NMR (300 MHz, CDCl3): d = 2.15 (s, 3 H, Me), 2.26 (s, 3 H,
Me), 2.87 (t, J = 7.5 Hz, 2 H, CH2), 4.29 (t, J = 7.5 Hz, 2 H, CH2),
4.69 (s, 2 H, CH2), 5.80 (d, J = 3.6 Hz, 1 H, HPyr), 5.85 (d, J = 3.3
Hz, 1 H, HFur), 5.89 (d, J = 3.3 Hz, 1 H, HFur), 6.17 (d, J = 3.6 Hz, 1
H, HPyr), 7.64–7.71 (m, 2 H, HPht), 7.76–7.84 (m, 2 H, HPht).
Synthesis 2010, No. 17, 2969–2978 © Thieme Stuttgart · New York

PAPER
5-Alkyl-2-(aminomethyl)pyrroles
2975
MS (EI, 70 eV): m/z (%) = 348 (42) [M+], 253 (23), 241 (13), 201
(12), 160 (44), 106 (100), 94 (17), 79 (18), 65 (15), 53 (12).
HPyr), 5.99 (d, J = 3.3 Hz, 1 H, HPyr), 6.96 (br t, J = 5.4 Hz, 1 H,
NH), 7.51 (d, J = 8.4 Hz, 2 H, HAr), 7.85 (d, J = 8.4 Hz, 2 H, HAr).
Anal. Calcd for C21H20N2O3: C, 72.40; H, 5.79; N, 8.04. Found: C,
72.44; H, 5.66; N, 8.11.
13C NMR (75 MHz, DMSO-d6): d = 12.6, 28.1 (3C), 36.4, 77.5,
106.7, 107.6, 124.1 (q, JCF = 272.6 Hz), 126.3 (2C, q, JCF = 3.8 Hz),
128.1 (q, JCF = 32.2 Hz), 128.7, 128.9 (2C), 130.3, 141.4, 155.0.
2-[(tert-Butoxycarbonylamino)methyl]pyrroles 8; General Pro-
cedure
MS (EI, 70 eV): m/z (%) = 354 (7) [M+], 297 (80), 253 (15), 238
(100), 226 (20), 154 (21), 145 (15), 94 (21), 57 (80).
N2H4·H2O (5 mL) was added to a soln of compound 6 (6.0 mmol)
in MeOH (40 mL), and the mixture was stirred at r.t. for 1 h while
the reaction was monitored by TLC. The solvent was evaporated
and H2O (30 mL) was added to the residue and adjusted to pH ~5
with AcOH. The precipitate was filtered off and aq NH3 was added
to the filtrate to adjust the pH to ~10. The mixture was extracted
with EtOAc (4 × 50 mL), and the combined organic fractions were
washed with H2O, dried (Na2SO4), and concentrated under reduced
pressure. (Boc)2O (1.64 g 7.5 mmol) was added to the resulting 2-
(aminomethyl)pyrrole, and the mixture was stirred at r.t. for 30 min
(TLC monitoring). H2O (30 mL) was added and the precipitate was
filtered off, washed with H2O, and air-dried. The residue was puri-
fied by column chromatography [EtOAc–PE (1:3)], and the sol-
vents were evaporated under reduced pressure to give a crude
product that was crystallized (PE).
Anal. Calcd for C18H21F3N2O2: C, 61.01; H, 5.97; N, 7.91. Found:
C, 61.11; H, 6.10; N, 7.97.
tert-Butyl [(1-Butyl-5-methyl-1H-pyrrol-2-yl)methyl]carbam-
ate (8d)
White solid; yield: 1.13 g (63%); mp 63–64 °C.
IR (KBr): 3358, 1684, 1518, 1361, 1244, 1167, 1026, 941, 864, 754
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 7.2 Hz, 3 H, Me),
1.30–1.40 (m, 2 H, CH2), 1.44 (s, 9 H, t-Bu), 1.55–1.65 (m, 2 H,
CH2), 2.21 (s, 3 H, Me), 3.74–3.79 (m, 2 H, CH2), 4.27 (d, J = 5.4
Hz, 2 H, CH2), 4.58 (br s, 1 H, NH), 5.78 (d, J = 3.3 Hz, 1 H, HPyr),
5.93 (d, J = 3.3 Hz, 1 H, HPyr).
13C NMR (75 MHz, CDCl3): d = 12.3, 13.8, 20.1, 28.3 (3C), 33.5,
36.9, 43.7, 79.3, 105.5, 107.1, 127.9, 129.4, 155.3.
tert-Butyl ({5-Methyl-1-[(5-methyl-2-furyl)methyl]-1H-pyrrol-
2-yl}methyl)carbamate (8a)
Colorless needles; yield: 1.50 g (82%); mp 75–76 °C.
MS (EI, 70 eV): m/z (%) = 266 (38) [M+], 209 (80), 165 (25), 150
(70), 136 (25), 108 (26), 94 (61), 57 (93), 53 (21), 41 (100).
IR (KBr): 3371, 1681, 1523, 1269, 1248, 1170, 1019, 938, 868, 773
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 9 H, t-Bu), 2.23 (s, 3 H,
Me), 2.26 (s, 3 H, Me), 4.35 (d, J = 5.4 Hz, 2 H, CH2), 4.82 (br t,
J = 5.4 Hz, 1 H, NH), 4.91 (s, 2 H, CH2), 5.81 (d, J = 3.6 Hz, 1 H,
HPyr), 5.85 (d, J = 3.3 Hz, 1 H, HFur), 5.97–6.02 (m, 2 H, HPyr, HFur).
Anal. Calcd for C15H26N2O2: C, 67.63; H, 9.84; N, 10.52. Found: C,
67.41; H, 10.04; N, 10.36.
tert-Butyl {[5-Methyl-1-(3-oxo-1,3-dihydro-2-benzofuran-5-yl)-
1H-pyrrol-2-yl]methyl}carbamate (8e)
White solid; yield: 1.23 g (67%); mp 118 °C (CH2Cl2–PE).
13C NMR (75 MHz, CDCl3): d = 12.3, 13.5, 28.3 (3C), 36.7, 40.6,
79.1, 105.8, 106.1, 107.6, 108.2, 128.3, 130.0, 148.9, 151.9, 155.4.
IR (KBr): 3377, 1770, 1688, 1501, 1412, 1363, 1251, 1163, 1054,
995, 912, 863, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.31 (s, 9 H, t-Bu), 2.00 (s, 3 H,
Me), 4.06 (d, J = 5.4 Hz, 2 H, CH2), 4.47 (br s, 1 H, NH), 5.38 (s, 2
H, CH2), 5.94 (d, J = 3.3 Hz, 1 H, HPyr), 6.11 (d, J = 3.3 Hz, 1 H,
HPyr), 7.54 (dd, J = 7.8 Hz, J = 1.8 Hz, 1 H, HAr), 7.60 (d, J = 7.8 Hz,
1 H, HAr), 7.77 (d, J = 1.8 Hz, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 12.7, 28.1 (3C), 36.7, 69.5, 79.2,
106.7, 108.3, 123.2, 125.3, 127.0, 129.7, 130.6, 134.0, 139.2, 145.9,
154.8, 169.9.
MS (EI, 70 eV): m/z (%) = 304 (7) [M+], 153 (12), 95 (100), 57 (15).
Anal. Calcd for C17H24N2O3: C, 67.08; H, 7.95; N, 9.20. Found: C,
67.07; H, 8.23; N, 9.13.
tert-Butyl [(1-Benzyl-5-methyl-1H-pyrrol-2-yl)methyl]carbam-
ate (8b)
White solid; yield: 1.62 g (89%); mp 85 °C.
IR (KBr): 3371, 1684, 1523, 1450, 1359, 1246, 1165, 1020, 930,
860, 755 cm–1.
MS (EI, 70 eV): m/z (%) = 342 (3) [M+], 285 (34), 241 (83), 226
(95), 214 (19), 182 (21), 167 (24), 94 (28), 89 (19), 57 (100).
1H NMR (300 MHz, DMSO-d6): d = 1.29 (s, 9 H, t-Bu), 2.00 (s, 3
H, Me), 3.99 (d, J = 5.7 Hz, 2 H, CH2), 5.11 (s, 2 H, CH2), 5.74 (d,
J = 3.3 Hz, 1 H, HPyr), 5.85 (d, J = 3.3 Hz, 1 H, HPyr), 6.85–6.88 (m,
2 H, HAr), 7.10 (br t, J = 5.7 Hz, 1 H, NH), 7.18–7.31 (m, 3 H, HAr).
Anal. Calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found: C,
66.71; H, 6.32; N, 8.22.
tert-Butyl {[1-(Benzoylamino)-5-methyl-1H-pyrrol-2-yl]meth-
yl}carbamate (8f)
White solid; yield: 1.39 g (76%); mp 140 °C (CH2Cl2–PE).
13C NMR (75 MHz, DMSO-d6): d = 12.1, 28.1 (3C), 36.0, 46.1,
77.6, 105.6, 106.8, 125.7 (2C), 126.7, 128.3, 128.5 (2C), 129.7,
139.0, 155.3.
IR (KBr): 3298, 3161, 1700, 1666, 1547, 1277, 1166, 1056, 919,
863, 760 cm–1.
MS (EI, 70 eV): m/z (%) = 300 (11) [M+], 243 (39), 184 (23), 153
(47), 91 (100), 65 (17), 57 (35).
1H NMR (300 MHz, DMSO-d6): d = 1.32 (s, 9 H, t-Bu), 2.03 (s, 3
H, Me), 3.96 (dd, J = 5.7 Hz, J = 15.3 Hz, 1 H, CHAHB), 4.03 (dd,
J = 5.7 Hz, J = 15.3 Hz, 1 H, CHAHB), 5.75 (d, J = 3.6 Hz, 1 H,
HPyr), 5.84 (d, J = 3.6 Hz, 1 H, HPyr), 6.85 (br t, J = 5.7 Hz, 1 H,
NH), 7.50–7.57 (m, 2 H, HAr), 7.59–7.67 (m, 1 H, HAr), 7.93–7.99
(m, 2 H, HAr), 11.23 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 10.8, 28.2 (3C), 35.3, 77.7,
103.3, 104.4, 127.7 (2C), 128.3, 128.5 (2C), 129.2, 131.9, 132.2,
155.2, 166.0.
Anal. Calcd for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33. Found: C,
71.97; H, 8.09; N, 9.23.
tert-Butyl ({5-Methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrrol-
2-yl}methyl)carbamate (8c)
White solid; yield: 1.33 g (72%); mp 128 °C (CH2Cl2–PE).
IR (KBr): 3340, 1675, 1530, 1325, 1166, 1120, 1069, 854, 765
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.28 (s, 9 H, t-Bu), 1.97 (s, 3
H, Me), 3.91 (d, J = 5.4 Hz, 2 H, CH2), 5.89 (d, J = 3.3 Hz, 1 H,
MS (EI, 70 eV): m/z (%) = 329 (2) [M+], 228 (19), 213 (12), 152
(32), 122 (20), 105 (100), 77 (70), 57 (51), 51 (22).
Synthesis 2010, No. 17, 2969–2978 © Thieme Stuttgart · New York

2976
A. V. Butin et al.
PAPER
Anal. Calcd for C18H23N3O3: C, 65.63; H, 7.04; N, 12.76. Found: C,
65.58; H, 7.18; N, 12.69.
7.51 (m, 2 H, HAr), 7.57–7.64 (m, 1 H, HAr), 7.68–7.73 (m, 2 H,
HAr), 7.75–7.85 (m, 4 H, HPht).
13C NMR (75 MHz, DMSO-d6): d = 12.5, 34.0, 55.5, 55.9, 105.9,
108.4, 112.0, 113.4, 123.0 (2C), 127.7, 128.4 (2C), 129.0, 129.3
(2C), 130.0, 130.1, 131.5 (2C), 133.2, 134.4 (2C), 136.7, 148.0,
150.7, 167.0 (2C), 194.0.
tert-Butyl {[1-(4-Chlorophenyl)-5-methyl-1H-pyrrol-2-yl]meth-
yl}carbamate (8g)
White solid; yield: 1.61 g (88%); mp 114 °C (CH2Cl2–PE).
IR (KBr): 3409, 1697, 1670, 1538, 1490, 1268, 1166, 1089, 1015,
874, 838, 762 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.31 (s, 9 H, t-Bu), 1.94 (s, 3
H, Me), 3.86 (d, J = 5.4 Hz, 2 H, CH2), 5.85 (d, J = 3.3 Hz, 1 H,
MS (EI, 70 eV): m/z (%) = 480 (55) [M+], 462 (70), 447 (10), 334
(57), 320 (26), 239 (45), 228 (76), 214 (15), 198 (18), 105 (100), 91
(17), 77 (21), 59 (12).
Anal. Calcd for C29H24N2O5: C, 72.49; H, 5.03; N, 5.83. Found: C,
72.47; H, 5.22; N, 5.66.
HPyr), 5.94 (d, J = 3.3 Hz, 1 H, HPyr), 6.94 (br t, J = 5.4 Hz, 1 H,
NH), 7.30 (d, J = 8.7 Hz, 2 H, HAr), 7.54 (d, J = 8.7 Hz, 2 H, HAr).
13C NMR (75 MHz, DMSO-d6): d = 12.5, 28.2 (3C), 36.4, 77.5,
106.3, 107.0, 128.6, 129.2 (2C), 129.9 (2C), 130.2, 132.4, 136.6,
155.1.
2-({1-[4,5-Dimethoxy-2-(4-methylbenzoyl)phenyl]-5-methyl-
1H-pyrrol-2-yl}methyl)-1H-isoindole-1,3(2H)-dione (10c)
Beige solid; yield: 4.35 g (80%); mp 200 °C (EtOH–acetone).
MS (EI, 70 eV): m/z (%) = 322/320 (3/8) [M+], 265/263 (34/100),
206/204 (30/90), 192 (20), 169 (21), 154 (43), 111 (15), 94 (25), 75
(20), 57 (80).
IR (KBr): 1715, 1660, 1602, 1519, 1439, 1388, 1337, 1256, 1207,
1172, 1103, 1038, 940, 889, 864, 751, 714 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.92 (s, 3 H, Me), 2.39 (s, 3 H,
Me), 3.67 (s, 3 H, OMe), 3.91 (s, 3 H, OMe), 4.56 (d, J = 15.6 Hz,
1 H, CHAHB), 4.63 (d, J = 15.6 Hz, 1 H, CHAHB), 5.76 (d, J = 3.6
Hz, 1 H, HPyr), 6.08 (d, J = 3.6 Hz, 1 H, HPyr), 6.76 (s, 1 H, HAr), 7.02
Anal. Calcd for C17H21ClN2O2: C, 63.65; H, 6.60; N, 8.73. Found:
C, 63.53; H, 6.77; N, 8.69.
2-{[1-(2-Aroylphenyl)-5-methyl-1H-pyrrol-2-yl]methyl}-1H-
isoindole-1,3(2H)-diones 10; General Procedure
(s, 1 H, HAr), 7.21 (d, J = 8.1 Hz, 2 H, HAr), 7.62–7.79 (m, 6 H, HPht,
HAr).
Cl3CCO2H (0.6 g) was added to a soln of diketone 4b (11 mmol)
and amine 9 (11 mmol) in benzene (20 mL), and the mixture was
refluxed for 40–90 min while the reaction was monitored by TLC.
The mixture was then poured into cold H2O (150 mL) and neutral-
ized to pH ~7 with NaHCO3. The product was extracted with ben-
zene (3 × 30 mL), and the combined organic fractions were washed
with H2O, dried (Na2SO4), and concentrated under reduced pres-
sure. The residue was purified by column chromatography [silica
gel, EtOAc–PE (1:3)], and the solvent was evaporated to one third
of its starting volume and kept until the product crystallized.
13C NMR (75 MHz, CDCl3): d = 12.7, 21.6, 34.3, 56.0, 56.2, 106.3,
109.2, 112.0, 113.3, 123.0 (2C), 127.8, 128.9 (2C), 129.9 (2C),
130.1, 130.7, 130.9, 132.1 (2C), 133.7 (2C), 134.5, 143.8, 148.0,
150.7, 167.4 (2C), 193.8.
MS (EI, 70 eV): m/z (%) = 494 (44) [M+], 476 (16), 348 (19), 334
(32), 242 (57), 228 (22), 197 (12), 119 (100), 105 (82), 91 (26), 50
(14).
Anal. Calcd for C30H26N2O5: C, 72.86; H, 5.30; N, 5.66. Found: C,
72.79; H, 5.21; N, 5.61.
2-{[1-(2-Acetyl-4,5-dimethoxyphenyl)-5-methyl-1H-pyrrol-2-
yl]methyl}-1H-isoindole-1,3(2H)-dione (10a)
Beige solid; yield: 2.40 g (52%); mp 179 °C.
Substituted 8,9-Dimethoxy-1-methyl-4H-benzo[f]pyrrolo[1,2-
a][1,4]diazepines 11; General Procedure
A mixture of compound 10 (5.0 mmol), N2H4·H2O (2 mL), and
EtOH (40 mL) was stirred at r.t. or the reflux temperature until ho-
mogeneous. Ethanolic HCl (33%) was added to adjust the pH to ~5.
The precipitate was filtered off and the pH of the filtrate was adjust-
ed to ~10 with aq NH3. The product was extracted with CHCl3
(5 × 50 mL), and the combined organic fractions were washed with
H2O and brine, dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by column chromatography [sil-
ica gel, EtOAc–PE (1:4)]. The solvent was evaporated under re-
duced pressure to one third of its original volume, and the soln was
kept until the product crystallized.
IR (KBr): 1717, 1670, 1599, 1515, 1428, 1390, 1259, 1219, 1170,
1033, 949, 882, 794, 745, 711 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.78 (s, 3 H, Me), 1.92 (s, 3 H,
Me), 3.83 (s, 3 H, OMe), 3.98 (s, 3 H, OMe), 4.55 (d, J = 15.6 Hz,
1 H, CHAHB), 4.63 (d, J = 15.6 Hz, 1 H, CHAHB), 5.96 (d, J = 3.6
Hz, 1 H, HPyr), 6.19 (d, J = 3.6 Hz, 1 H, HPyr), 6.73 (s, 1 H, HAr), 7.45
(s, 1 H, HAr), 7.65–7.73 (m, 2 H, HPht), 7.75–7.83 (m, 2 H, HPht).
13C NMR (75 MHz, CDCl3): d = 12.4, 27.4, 34.0, 56.1, 56.3, 107.4,
109.1, 111.6, 112.4, 123.2 (2C), 127.1, 130.1, 130.3, 130.6, 131.9
(2C), 134.0 (2C), 148.9, 152.3, 167.4 (2C), 197.8.
8,9-Dimethoxy-1,6-dimethyl-4H-pyrrolo[1,2-a][1,4]benzo-
diazepine (11a)
Reaction stirred at r.t. Pale yellow solid; yield 0.68 g (50%); mp
MS (EI, 70 eV): m/z (%) = 418 (100) [M+], 403 (30), 400 (60), 385
(24), 272 (75), 258 (54), 228 (60), 216 (81), 200 (20), 125 (16), 110
(17), 76 (19), 59 (37).
150–151 °C.
Anal. Calcd for C24H22N2O5: C, 68.89; H, 5.30; N, 6.69. Found: C,
68.69; H, 5.13; N, 6.68.
IR (KBr): 1628, 1608, 1516, 1448, 1420, 1372, 1312, 1252, 1208,
1172, 1044, 884, 796, 764 cm–1.
2-{[1-(2-Benzoyl-4,5-dimethoxyphenyl)-5-methyl-1H-pyrrol-2-
yl]methyl}-1H-isoindole-1,3(2H)-dione (10b)
Pale yellow solid; yield: 3.60 g (68%); mp 181–182 °C.
1H NMR (300 MHz, CDCl3): d = 2.32 (s, 3 H, Me), 2.37 (s, 3 H,
Me), 3.80 (d, J = 12.6 Hz, 1 H, CHAHB), 3.91 (s, 3 H, OMe), 3.95
(s, 3 H, OMe), 4.71 (d, J = 12.6 Hz, 1 H, CHAHB), 6.01 (d, J = 3.3
Hz, 1 H, HPyr), 6.04 (d, J = 3.3 Hz, 1 H, HPyr), 6.81 (s, 1 H, HAr), 6.97
(s, 1 H, HAr).
13C NMR (75 MHz, CDCl3): d = 14.4, 26.3, 48.0, 56.0, 56.1, 104.1,
108.0, 109.7, 110.1, 123.6, 127.7, 131.0, 135.4, 146.1, 149.6, 166.7.
IR (KBr): 1716, 1660, 1596, 1516, 1456, 1428, 1388, 1360, 1336,
1260, 1208, 1128, 1104, 1044, 940, 868, 720 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.84 (s, 3 H, Me), 3.53 (s, 3 H,
OMe), 3.82 (s, 3 H, OMe), 4.42 (d, J = 15.6 Hz, 1 H, CHAHB), 4.48
(d, J = 15.6 Hz, 1 H, CHAHB), 5.59 (d, J = 3.6 Hz, 1 H, HPyr), 5.83
(d, J = 3.6 Hz, 1 H, HPyr), 6.79 (s, 1 H, HAr), 7.10 (s, 1 H, HAr), 7.44–
MS (EI, 70 eV): m/z (%) = 270 (30) [M+], 255 (100), 240 (33), 211
(27), 182 (11), 170 (16).
Synthesis 2010, No. 17, 2969–2978 © Thieme Stuttgart · New York

PAPER
5-Alkyl-2-(aminomethyl)pyrroles
2977
Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C,
71.08; H, 6.86; N, 10.49.
MS (EI, 70 eV): m/z (%) = 340 (29) [M+], 253 (12), 239 (67), 193
(74), 180 (67), 160 (60), 147 (73), 130 (23), 120 (88), 108 (70), 93
(68), 76 (100).
8,9-Dimethoxy-1-methyl-6-phenyl-4H-pyrrolo[1,2-a][1,4]ben-
zodiazepine (11b)
Reaction stirred at r.t. White solid; yield 0.76 g (46%); mp 165–
Anal. Calcd for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: C,
67.04; H, 5.92; N, 8.19.
166 °C.
7-Methyl-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-
one (14)
IR (KBr): 1604, 1564, 1516, 1448, 1424, 1364, 1312, 1252, 1208,
1176, 1128, 1044, 1028, 864, 796, 768 cm–1.
A mixture of ester 13 (2 g, 6.0 mmol), DMF (6 mL), N2H4·H2O (2.5
mL), and EtOH (50 mL) was refluxed for 45 min (TLC monitoring).
The solvent was then evaporated under reduced pressure and the
residue was washed with CHCl3 (3 × 30 mL). The combined organ-
ic fractions were washed with H2O, dried (Na2SO4), and concentrat-
ed under reduced pressure. The residue was purified by column
chromatography [silica gel, EtOAc–PE (1:3)], the solvent was
evaporated under reduced pressure to one third of the original vol-
ume, and the soln was kept until the product crystallized.
1H NMR (300 MHz, CDCl3): d = 2.39 (s, 3 H, Me), 3.75 (s, 3 H,
OMe), 3.96 (s, 3 H, OMe), 3.98 (d, J = 12.3 Hz, 1 H, CHAHB), 4.99
(d, J = 12.3 Hz, 1 H, CHAHB), 6.03 (d, J = 3.3 Hz, 1 H, HPyr), 6.05
(d, J = 3.3 Hz, 1 H, HPyr), 6.76 (s, 1 H, HAr), 6.89 (s, 1 H, HAr), 7.30–
7.43 (m, 3 H, HPh), 7.56–7.63 (m, 2 H, HPh).
13C NMR (75 MHz, CDCl3): d = 14.3, 48.6, 56.0, 56.1, 104.5,
107.8, 109.6, 112.7, 122.0, 127.7, 127.9 (2C), 129.3 (2C), 129.9,
133.0, 135.6, 139.8, 145.5, 149.9, 167.8.
White solid; yield: 0.52 g (30%); mp 194–195 °C.
MS (EI, 70 eV): m/z (%) = 332 (42) [M+], 317 (100), 302 (15), 273
(10), 257 (27), 239 (10), 154 (11), 143 (10).
IR (KBr): 3200, 1664, 1508, 1476, 1440, 1424, 1388, 1348, 1312,
1248, 1200, 1172, 1100, 776 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.19 (s, 3 H, Me), 2.90–2.94 (m,
2 H, CH2), 4.00–4.05 (m, 2 H, CH2), 4.31 (d, J = 5.7 Hz, 2 H, CH2),
5.79 (d, J = 3.3 Hz, 1 H, HPyr), 5.85 (d, J = 3.3 Hz, 1 H, HPyr), 7.16
(br t, J = 5.7 Hz, 1 H, NH).
Anal. Calcd for C21H20N2O2: C, 75.88; H, 6.06; N, 8.43. Found: C,
75.67; H, 6.20; N, 8.27.
8,9-Dimethoxy-1-methyl-6-(4-methylphenyl)-4H-pyrrolo[1,2-
a][1,4]benzodiazepine (11c)
Reaction stirred at reflux. White solid; yield 0.52 g (30%); mp 150–
151 °C.
13C NMR (75 MHz, CDCl3): d = 12.2, 34.1, 39.3, 40.9, 105.3,
105.8, 126.9, 129.9, 174.3.
IR (KBr): 1603, 1519, 1451, 1415, 1363, 1254, 1207, 1129, 1048,
871, 825, 760 cm–1.
MS (EI, 70 eV): m/z (%) = 164 (60) [M+], 162 (51), 149 (39), 136
(30), 120 (67), 109 (100), 106 (90), 95 (42), 93 (48), 77 (47), 66
(41), 59 (29), 55 (66), 42 (46).
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H, Me), 2.38 (s, 3 H,
Me), 3.76 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 3.96 (d, J = 12.3 Hz,
1 H, CHAHB), 4.96 (d, J = 12.3 Hz, 1 H, CHAHB), 6.03 (d, J = 3.3
Hz, 1 H, HPyr), 6.05 (d, J = 3.3 Hz, 1 H, HPyr), 6.77 (s, 1 H, HAr), 6.87
(s, 1 H, HAr), 7.14 (d, J = 8.1 Hz, 2 H, HAr), 7.49 (d, J = 8.1 Hz, 2 H,
HAr).
Anal. Calcd for C9H12N2O: C, 65.83; H, 7.37; N, 17.06. Found: C,
65.67; H, 7.30; N, 17.06.
Acknowledgment
13C NMR (75 MHz, CDCl3): d = 14.3, 21.3, 48.5, 56.0, 56.1, 104.5,
107.8, 109.6, 112.9, 122.1, 127.7, 128.7 (2C), 129.3 (2C), 133.0,
135.7, 137.0, 140.0, 145.5, 149.8, 167.8.
We thank the Russian Foundation of Basic Research (grants no. 07-
03-00352-a and 10-03-00254-a) and the Federal Agency for Educa-
tion (Rosobrazovanie) (grant 2.1.1/4628) for financial support of
this work.
MS (EI, 70 eV): m/z (%) = 346 (9) [M+], 331 (100), 315 (11), 138
(15), 95 (20), 59 (40).
Anal. Calcd for C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.29; H, 6.31; N, 8.20.
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H.; Baucke, D.; Hornberger, W.; Lange, U. E. W.; Seitz, W.;
Höffken, H. W. Bioorg. Med. Chem. Lett. 2006, 16, 2641.
(i) Vanotti, E.; Amici, R.; Bargiotti, A.; Berthelsen, J.;
Bosotti, R.; Ciavolella, A.; Cirla, A.; Cristiani, C.;
Ethyl 3-{2-[(1,3-Dioxo-1, 3-dihydro-2H-isoindol-2-yl)methyl]-
5-methyl-1H-pyrrol-1-yl}propanoate (13)
A soln of diketone 4b (2.6 g, 10 mmol), ester hydrochloride 12 (6.91
g, 45 mmol), and NaOAc (1.85 g, 22.5 mmol) in EtOH (40 mL) was
refluxed for 4.5 h while the reaction was monitored by TLC. The
mixture was poured into cold H2O (200 mL), and the precipitate was
filtered off, air-dried, and purified by column chromatography [sil-
ica gel, EtOAc–PE (1:3.5)]. The solvent was evaporated to one third
of its original volume, and the soln was kept until the product crys-
tallized.
White solid; yield: 2.59 g (76%); mp 118–119 °C.
IR (KBr): 1720, 1436, 1396, 1356, 1332, 1316, 1296, 1188, 1120,
1016, 960, 748, 740, 712 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.27 (t, J = 7.2 Hz, 3 H, CH2CH3),
2.20 (s, 3 H, Me), 2.62–2.67 (m, 2 H, CH2), 4.16 (q, J = 7.2 Hz, 2
H, CH2CH3), 4.35–4.40 (m, 2 H, CH2), 4.84 (s, 2 H, CH2), 5.81 (d,
J = 3.6 Hz, 1 H, HPyr), 6.18 (d, J = 3.6 Hz, 1 H, HPyr), 7.64–7.72 (m,
2 H, HPht), 7.77–7.85 (m, 2 H, HPht).
13C NMR (75 MHz, CDCl3): d = 12.3, 14.1, 33.2, 35.8, 39.0, 60.8,
106.7, 109.8, 123.2 (2C), 126.0, 128.8, 132.0 (2C), 133.9 (2C),
167.9 (2C), 170.9.
Synthesis 2010, No. 17, 2969–2978 © Thieme Stuttgart · New York

2978
A. V. Butin et al.
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Synthesis 2010, No. 17, 2969–2978 © Thieme Stuttgart · New York