A synthesis of functionalized dihydro-1H-pyrroles from Nef-isocyanide adducts and enamines

Article abstract of DOI:10.1055/s-0031-1290369

α-Ketoimidoyl chlorides, obtained from α-addition of acyl chlorides onto alkyl isocyanides, are treated with enamines to afford 5-(alkylimino)-4-hydroxy-4,5-dihydro-1H-pyrrole-2,3,4-tricarboxylates and 2-(alkylimino)-3-hydroxy-2,3-dihydro-1H-pyrrole-3,4-dicarboxylates in good to excellent yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290369

1662▌
LETTER
lAetteSr ynthesis of Functionalized Dihydro-1H-pyrroles from Nef-Isocyanide
Adducts and Enamines
Synthesis of Functionalized Dihydro-1H-pyrroles
Issa Yavari,* Reza Hosseinpour, Ramin Pashazadeh
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)82883455; E-mail: yavarisa@modares.ac.ir
Received: 14.03.2012; Accepted after revision: 23.04.2012
in the synthesis of various heterocycles.7 A number of iso-
Abstract: α-Ketoimidoyl chlorides, obtained from α-addition of
cyanide reactions have seen their potential largely unex-
acyl chlorides onto alkyl isocyanides, are treated with enamines to
plored, and this is probably the case with the Nef reaction;
afford 5-(alkylimino)-4-hydroxy-4,5-dihydro-1H-pyrrole-2,3,4-tri-
the α-addition of acyl chlorides onto isocyanides forming
imidoyl chlorides.8 Nef-type reactions could also be ob-
tained with highly electrophilic acid derivatives such as
trifluoroacetic anhydride9 or acyl bromides, which are
more reactive than the corresponding chlorides.10,11 Intra-
molecular trapping of the Nef adducts with various nu-
cleophiles have been reported.12–15 The scope of the Nef
reaction could be further extended by adding external
trapping agents that are able to induce new cascade reac-
tions.
carboxylates and 2-(alkylimino)-3-hydroxy-2,3-dihydro-1H-pyr-
role-3,4-dicarboxylates in good to excellent yields.
Key words: Nef-isocyanide adduct, enaminone, imidoyl chloride,
pyrrole, chemoselective reaction
Nitrogen-containing heterocycles are of great importance
in the pharmaceutical industry because they often exhibit
interesting biological activities. Substituted pyrroles are
important heterocycles with useful biological and physi-
cal properties.1,2 For example, tetra- and penta-substituted
pyrroles feature prominently in natural products, pharma-
ceuticals, agrochemicals, fluorescent dyes, and conduct-
ing polymers.3,4 Thus, significant demand exists in drug
discovery and other research programs for novel and
structurally diverse pyrrole derivatives.
One of the main problems of the Nef isocyanide reaction
is the selectivity of the nucleophilic attack on the Nef ad-
ducts; either the imidoyl or the carbonyl function can be
attacked, which may lead to isocyanide elimination. We
anticipated that the use of the α-carboalkoxy substituent
would make the ketone more electrophilic and reduce the
chance of elimination of the isocyanide and consequent
formation of trivial acylation derivatives. This modifica-
tion was found to be successful. Thus, as part of our cur-
rent studies on the development of new routes to
heterocyclic systems,16–18 we report a simple synthesis of
functionalized 4,5-dihydro-1H-pyrroles from the reaction
The unique properties of the isocyano group, which may
function as both an electrophile and as a nucleophile, have
turned these compounds into useful reagents for organic
synthesis.5 Beyond the classical multicomponent reac-
tions,6 the most important applications of isocyanides are
O
O
R1O
neat
r.t.
R1O
Cl
Cy
N
C
+
Cl
R1O2C
HO
CO2R3
CO2R3
O
O
NCy
1
2
5
CO2R3
CyN
N
R2
7
R2HN
MeCN
r.t.
CO2R3
CO2R3
R2NH2
+
3
CO2R3
6
4
R2
Bn
1–4, 7 R1
R3
Yield (%) of 7
a
b
c
d
e
f
Me
Me
Me
Et
Et
Et
Me
Me
70
72
70
76
65
65
70
50
4-MeC6H4CH2
4-MeOC6H4CH2 Me
Bn
Me
Me
Me
Me
Et
4-MeC6H4CH2
allyl
n-Bu
Bn
g
h
Et
Et
Scheme 1 Synthesis of compounds 7
SYNLETT 2012, 23, 1662–1666
Advanced online publication: 14.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290369; Art ID: ST-2012-D0238-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Functionalized Dihydro-1H-pyrroles
1663
between α-ketoimidoyl chlorides and enaminones. As a A plausible pathway may be advanced to rationalize prod-
result, the Nef-isocyanide adducts 5, obtained from alkyl uct formation (Scheme 2). Presumably, the Nef-isocya-
chloroglyoxalates 1 and alkyl isocyanides 2, react with nide adduct 5, formed from acid chloride 1 and isocyanide
enaminones 6 (prepared from alkyl amines 3 and dialkyl 2, is attacked by enaminoester 6 in a chemoselective man-
acetylenedicarboxylates 4 at room temperature, in anhy- ner, to furnish intermediate 8, which undergoes an intra-
drous MeCN), to afford trialkyl 1-alkyl-5-(alkylimino)- molecular proton-transfer reaction to afford 9. This
4,5-dihydro-4-hydroxy-1H-pyrrole-2,3,4-tricarboxylates
intermediate is converted into 7 by imine-enamine tau-
tomerization and cyclization reaction.
7 in 50–76% yields (Scheme 1).19
The structures of compounds 7a–h were deduced from To extend our knowledge of this transformation, we per-
their IR and 1H and 13C NMR spectra. For example, the 1H formed the reaction between Nef-isocyanide adduct 5 and
NMR spectrum of 7a exhibited three single sharp lines enamines 12 derived from 2,4-pentanedione and β-keto
that were readily recognized as arising from methoxy (δ = ester 11 and primary alkylamines 3. These reactions led to
3.60, 3.65 and 3.75 ppm) protons, together with character- the formation of diethyl 1-benzyl-2-(alkylimino)-3-hy-
istic multiplets for cyclohexyl, aryl, and benzylic protons. droxy-5-methyl-2,3-dihydro-1H-pyrrole-3,4-dicarboxylates
A fairly broad single peak was observed for the OH (δ = (13a–c) and alkyl 4-acetyl-1-alkyl-2-(alkylimino)-3-hy-
4.16 ppm) proton. The 1H-decoupled 13C NMR spectrum droxy-5-methyl-2,3-dihydro-1H-pyrrole-3-carboxylates
of 7a showed 21 distinct resonances, in agreement with (13d–i) in 52–82% yields (Scheme 3). Compounds 13
the proposed structure. The mass spectrum of 7a dis- were again fully characterized with their IR, 1H NMR and
played the molecular ion peak (m/z 444). The 1H and 13
C
13C NMR spectra.19
NMR spectra of 7b–h are similar to those for 7a, except
for the alkyl and aryl groups.
In conclusion, Nef-isocyanide adducts are employed in
sequential reactions with enamines to afford functional-
+
1
2
O
R1O
Cl
1
O
R O2C
NCy
Cl
O
NCy
R2HN
R3O2C
R3O2C
CO2R3
CO2R3
5
proton-transfer
reaction
+
3
4
NHR2
6
8
1
OH
1
R O2C
NCy
Cl
OH
R O2C
NCy
Cl
R3O2C
R3O2C
R3O2C
R3O2C
imine–enamine
tautomerization
cyclization
– HCl
7
NR2
NHR2
10
9
Scheme 2 A plausible mechanism for the formation of compounds 7
O
O
R1O
neat
r.t.
R1O
Cl
+
Alk
O
N
C
2
Cl
R1O2C
HO
COZ
O
O
NR3
2
1
5
NAlk
N
R2
13
NHR2
O
O
MeCN
r.t.
R2NH2
+
Z
Z
3
11
12
R1
R2
1,2,3,11,13
Alk
Yield (%) of 13
Z
a
b
c
d
e
f
g
h
i
Et Cy
Et t-Bu
Et 1,1,3,3-tetramethylbutyl Bn
Et Cy
Et t-Bu
Et Cy
Et Cy
Me Cy
Et Cy
Bn
Bn
OEt
OEt
OEt
Me
78
65
52
75
70
74
78
80
82
Bn
Bn
Me
2-ClC6H4CH2 Me
Bu
Bn
Me
Me
4-MeC6H4CH2 Me
Scheme 3 Synthesis of compounds 13
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1662–1666

1664
I. Yavari et al.
LETTER
C23H28N2O7 (444.19): C, 62.15; H, 6.35; N, 6.30. Found: C,
62.11; H, 6.27; N, 6.34.
ized 4-hydroxy-4,5-dihydro-1H-pyrroles and 3-hydroxy-
2,3-dihydro-1H-pyrrole in a chemoselective manner, in
good yields. Due to the presence of transformable func-
tionalities in these products they are potentially valuable
for further synthetic manipulations.
Trimethyl 5-(Cyclohexylimino)-4,5-dihydro-4-hydroxy-
1-(4-methylbenzyl)-1H-pyrrole-2,3,4-tricarboxylate
(7b): Yield: 0.33 g (72%); cream powder; mp 114–116 °C.
IR (KBr): 3430 (OH), 1751 (C=O), 1663 (C=N) cm–1. 1H
NMR (500 MHz, CDCl3): δ = 1.21–1.72 (m, 10 H, 5 CH2),
2.29 (s, 3 H, Me), 2.78 (br s, 1 H, OH), 3.63 (s, 3 H, MeO),
3.71 (s, 3 H, MeO), 3.77 (s, 3 H, MeO), 4.10–4.25 (m, 1 H,
CH), 4.62 (d, 2J = 15.5 Hz, 1 H, CH2N), 4.78 (d, 2J =
15.5 Hz, 1 H, CH2N), 6.90–7.20 (m, 5 H, 5 CH). 13C NMR
(125 MHz, CDCl3): δ = 20.9 (Me), 24.0 (2 CH2), 25.5 (CH2),
34.0 (CH2), 34.5 (CH2), 45.0 (CH), 51.2 (MeO), 52.8 (MeO),
53.3 (MeO), 57.5 (CH2N), 77.2 (C-OH), 104.2 (C), 127.3 (2
CH), 128.9 (2 CH), 133.4 (C), 137.0 (C), 150.6 (C), 152.8
(C=N), 161.6 (C=O), 162.0 (C=O), 170.8 (C=O). MS (EI):
m/z (%) = 458 (2) [M]+, 399 (48), 367 (40), 293 (12), 239
(10), 211 (28), 151 (10), 105 (100), 79 (12), 55 (12). Anal.
Calcd. for C24H30N2O7 (458.21): C, 62.87; H, 6.59; N, 6.11.
Found: C, 62.81; H, 6.62; N, 6.19.
Trimethyl 5-(Cyclohexylimino)-4,5-dihydro-4-hydroxy-
1-(4-methyloxybenzyl)-1H-pyrrole-2,3,4-tricarboxylate
(7c): Yield: 0.33 g (70%); cream powder; mp 96–98 °C. IR
(KBr): 3429 (OH), 1747 (C=O), 1664 (C=N) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 1.24–1.74 (m, 10 H, 5 CH2), 2.28 (s,
3 H, Me), 3.63 (s, 3 H, MeO), 3.73 (s, 3 H, MeO), 3.77 (s,
3 H, MeO), 3.78 (s, 3 H, MeO), 3.64–3.68 (m, 1 H, CH),
4.62 (d, 2J = 15.4 Hz, 1 H, CH2N), 4.64 (br s, 1 H, OH), 4.75
(d, 2J = 15.4 Hz, 1 H, CH2N), 6.80 (d, 3J = 8.6 Hz, 2 H, 2
CH), 7.13 (d, 3J = 8.6 Hz, 2 H, 2 CH). 13C NMR (125.7
MHz, CDCl3): δ = 24.1 (CH2), 24.2 (CH2), 25.7 (CH2), 34.2
(CH2), 34.7 (CH2), 44.9 (CH), 51.4 (MeO), 53.0 (MeO), 53.5
(MeO), 55.2 (MeO), 57.7 (CH2N), 76.6 (C-OH), 104.3 (C),
113.7 (2 CH), 128.7 (C), 128.8 (2 CH), 150.8 (C), 153.0 (C),
159.9 (C=N), 161.8 (C=O), 162.1 (C=O), 170.9 (C=O). MS
(EI): m/z (%) = 474 (10) [M]+, 415 (18), 383 (9), 293 (6), 211
(12), 136 (7), 151 (10), 121 (100), 83 (9), 55 (15). Anal.
Calcd. for C24H30N2O8 (474.2): C, 60.57; H, 6.37; N, 5.90.
Found: C, 60.68; H, 6.25; N, 5.83.
4-Ethyl 2,3-Dimethyl 1-benzyl-5-(cyclohexylimino)-4,5-
dihydro-4-hydroxy-1H-pyrrole-2,3,4-tricarboxylate
(7d): Yield: 0.35 g (76%); cream powder; mp 105–107 °C.
IR (KBr): 3431 (OH), 1750 (C=O), 1667 (C=N) cm–1. 1H
NMR (500 MHz, CDCl3): δ = 1.18–1.75 (m, 10 H, 5 CH2),
1.24 (t, 3J = 7.0 Hz, 3 H, Me), 3.62 (s, 3 H, MeO), 3.69 (s,
3 H, MeO), 3.86–3.88 (m, 1 H, CH), 4.21 (q, 3J = 7.1 Hz,
2 H, OCH2), 4.57 (d, 2J = 15.8 Hz, 1 H, CH of CH2N), 4.88
(br s, 1 H, OH), 5.91 (d, 2J = 15.8 Hz, 1 H, CH of CH2N),
7.23–7.29 (m, 5 H, 5 CH). 13C NMR (125 MHz, CDCl3): δ =
12.6 (Me), 23.5 (CH2), 23.5 (CH2), 25.0 (CH2), 33.5 (CH2),
34.0 (CH2), 44.3 (CH), 49.9 (MeO), 51.7 (MeO), 56.8
(OCH2), 61.6 (CH2N), 76.6 (C-OH), 105.2 (C), 126.6 (2
CH), 126.7 (CH), 127.5 (2 CH), 136.3 (C), 150.4 (C), 154.8
(C=N), 161.4 (C=O), 161.8 (C=O), 169.1 (C=O). MS (EI):
m/z (%) = 458 (2) [M]+, 385 (60), 353 (80), 307 (10), 271
(37), 225 (17), 181 (10), 126 (12), 91 (100), 55 (18). Anal.
Calcd. for C24H30N2O7 (458.21): C, 62.87; H, 6.59; N, 6.11.
Found: C, 62.74; H, 6.27; N, 6.02.
References and Notes
(1) Taylor, E. C.; Jones, R. A. Pyrroles; Wiley: New York,
1990.
(2) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry
II; Vol. 4; Kartritzky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1996, 380–382.
(3) Gupton, J. T. Top. Heterocycl. Chem. 2006, 2, 53.
(4) Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891.
(5) Suginome, M.; Ito, Y. In Science of Synthesis; Vol. 19;
Murahashi, S.-I., Ed.; Thieme: Stuttgart, 2004, 445.
(6) Dömling, A. Chem. Rev. 2006, 106, 17.
(7) Lygin, A. V.; Meiere, A. D. Angew. Chem. Int. Ed. 2010, 49,
9094.
(8) Nef, J. U. Justus Liebigs Ann. Chem. 1892, 270, 267.
(9) El Kaim, L.; Pinot-Périgord, E. Tetrahedron 1998, 54, 3799.
(10) Westling, M.; Smith, R.; Livinghouse, T. J. Org. Chem.
1986, 51, 1159.
(11) Lee, C. H.; Westling, M.; Livinghouse, T.; Williams, A. C.
J. Am. Chem. Soc. 1992, 114, 4089.
(12) Ugi, I.; Fetzer, U. Chem. Ber. 1961, 94, 1116.
(13) Coffinier, D.; El Kaim, L.; Grimaud, L. Org. Lett. 2009, 11,
1825.
(14) Coffinier, D.; El Kaim, L.; Grimaud, L. Synlett 2010, 2474.
(15) Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2010,
12, 820.
(16) Yavari, I.; Mirzaei, A.; Moradi, L.; Khalili, G. Tetrahedron
Lett. 2010, 51, 396.
(17) Yavari, I.; Khalili, G. Synlett 2010, 1862.
(18) Yavari, I.; Souri, S.; Syrouspour, M.; Bayat, M. J. Synlett
2009, 1921.
(19) Synthesis of 7 and 13; General Procedure: To a
magnetically stirred solution of alkylamine 3 (1 mmol) in
anhydrous MeCN (2 mL), was added either dialkyl
acetylenedicarboxylate 4 (1 mmol) or 1,3-dicarbonyl
compound 11 (1 mmol). This solution was added to
α-ketoimidoyl chloride 5 [obtained from the alkyl
chloroglyoxalate 1 (1 mmol) and alkyl isocyanide 2 (1
mmol) at room temperature]. After completion of the
reaction [ca. 6 h; reaction monitored by TLC (EtOAc–
hexane, 1:5)], the cream precipitate was separated, washed
with hexane–Et2O, and neutralized with Et3N in a mixture of
H2O–MeOH to the give product.
Trimethyl 1-Benzyl-5-(cyclohexylimino)-4,5-dihydro-4-
hydroxy-1H-pyrrole-2,3,4-tricarboxylate (7a): Yield:
0.31 g (70%); cream powder; mp 124–126 °C. IR (KBr):
3431 (OH), 1749 (C=O), 1675 (C=N) cm–1. 1H NMR (500
MHz, CDCl3): δ = δ = 1.22–1.93 (m, 10 H, 5 CH2), 3.05–
3.10 (m, 1 H, CH), 3.60 (s, 3 H, MeO), 3.65 (s, 3 H, MeO),
3.75 (s, 3 H, MeO), 4.16 (br s, 1 H, OH), 4.63 (d, 2J =
15.6 Hz, 1 H, CH2N), 4.80 (d, 2J = 15.6 Hz, 1 H, CH2N),
7.17 (t, 3J = 7.0 Hz, 2 H, 2 CH), 7.20 (t, 3J = 7.0 Hz, 1 H,
CH), 7.24 (d, 3J = 7.0 Hz, 2 H, 2 CH). 13C NMR (125 MHz,
CDCl3): δ = 23.9 (CH2), 24.0 (CH2), 25.5 (CH2), 34.0 (CH2),
34.5 (CH2), 45.2 (CH), 51.2 (MeO), 52.8 (MeO), 53.3
(MeO), 57.5 (CH2N), 77.3 (C-OH), 104.3 (C), 127.3 (2 CH),
128.1 (2 CH), 128.7 (CH), 136.4 (C), 150.6 (C), 152.8
(C=N), 161.6 (C=O), 161.9 (C=O), 170.7 (C=O). MS (EI):
m/z (%) = 444 (2) [M]+, 385 (48), 353 (65), 293 (15), 271
(30), 211 (35), 151 (5), 91 (100), 55 (15). Anal. Calcd. for
4-Ethyl 2,3-Dimethyl 5-(cyclohexylimino)-4,5-dihydro-4-
hydroxy-1-(4-methylbenzyl)-1H-pyrrole-2,3,4-
tricarboxylate (7e): Yield: 0.31 g (65%); cream powder;
mp 96–98 °C. IR (KBr): 3426 (OH), 1753 (C=O), 1665
(C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.03 (t, 3J =
7.1 Hz, 3 H, Me), 1.21–1.73 (m, 10 H, 5 CH2), 2.27 (s, 3 H,
Me), 3.60–3.70 (m, 1 H, CH), 3.61 (s, 3 H, MeO), 3.68 (s,
3 H, MeO), 4.21 (br s, 1 H, OH), 4.26 (q, 3J = 7.1 Hz, 2 H,
OCH2), 4.52 (d, 2J = 15.6 Hz, 1 H, CH2N), 4.86 (d, 2J =
Synlett 2012, 23, 1662–1666
© Georg Thieme Verlag Stuttgart · New York

LETTER
15.6 Hz, 1 H, CH2N), 7.03 (d, 3J = 7.9 Hz, 2 H, 2 CH), 7.07
Synthesis of Functionalized Dihydro-1H-pyrroles
1665
64.18; H, 7.04; N, 5.76. Found: C, 64.12; H, 6.98; N, 5.73.
Diethyl 1-Benzyl-2-(cyclohexylimino)-2,3-dihydro-3-
hydroxy-5-methyl-1H-pyrrole-3,4-dicarboxylate (13a):
Yield: 0.33 g (78%); colorless solid; mp 85–87 °C. IR
(KBr): 3357 (OH), 1729 (C=O), 1641 (C=O), 1604
(C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.20 –1.80
(m, 10 H, 5 CH2), 1.24 (t, 3J = 7.1 Hz, 3 H, Me), 1.30 (t, 3J =
7.1 Hz, 3 H, Me), 2.31 (s, 3 H, Me), 2.29 (s, 3 H, Me), 3.63–
3.72 (m, 1 H, CH), 4.13 (br s, 1 H, OH), 4.21 (m, 2 H,
OCH2), 4.27 (m, 2 H, OCH2), 4.64 (d, 2J = 16.1 Hz, 1 H,
CH2N), 5.05 (d, 2J = 16.1 Hz, 1 H, CH2N), 7.15–7.30 (m,
5 H, 5 CH of aryl). 13C NMR (125 MHz, CDCl3): δ = 12.8
(Me), 14.1 (Me), 14.3 (Me), 24.3 (2 CH2), 25.7 (CH2), 34.3
(CH2), 34.7 (CH2), 43.8 (CH), 57.4 (OCH2), 59.3 (OCH2),
62.4 (CH2N), 82.0 (C-OH), 103.6 (C), 126.4 (CH), 127.1
(CH), 128.5 (CH), 137.5 (CH), 154.2 (C), 160.6 (C=N),
163.8 (C=O), 171.5 (C=O). MS (EI): m/z (%) = 428 (2) [M]+,
355 (72), 309 (100), 283 (12), 227 (60), 200 (10), 132 (19),
91 (94), 69 (54), 55 (51). Anal. Calcd. for C24H32N2O5
(428.23): C, 67.27; H, 7.53; N, 6.54. Found: C, 67.22; H,
7.46; N, 6.48.
(d, 3J = 7.9 Hz, 2 H, 2 CH). 13C NMR (125 MHz, CDCl3):
δ = 13.9 (Me), 21.0 (Me), 24.1 (CH2), 24.2 (CH2), 25.7
(CH2), 34.2 (CH2), 34.7 (CH2), 45.0 (CH), 51.2 (MeO), 52.8
(MeO), 57.6 (OCH2), 62.8 (CH2N), 76.9 (C-OH), 104.6 (C),
127.4 (2 CH), 128.9 (2 CH), 133.6 (C), 137.0 (C), 150.7 (C),
153.1 (C=N), 161.8 (C=O), 162.0 (C=O), 170.3 (C=O). MS
(EI): m/z (%) = 472 (2) [M]+, 399 (34), 367 (34), 307 (10),
285 (14), 225 (15), 181 (5), 143 (4), 105 (100), 55 (12). Anal.
Calcd. for C25H32N2O7 (472.22): C, 63.54; H, 6.83; N, 5.93.
Found: C, 63.65; H, 6.73; N, 5.85.
4-Ethyl 2,3-Dimethyl 1-allyl-5-(cyclohexylimino)-4,5-
dihydro-4-hydroxy-1H-pyrrole-2,3,4-tricarboxylate(7f):
Yield: 0.26 g (65%); cream powder; mp 82–84 °C. IR (KBr):
3430 (OH), 1753 (C=O), 1666 (C=N) cm–1. 1H NMR (500
MHz, CDCl3): δ = 1.20 (t, 3J = 7.1 Hz, 3 H, Me), 1.23–1.68
(m, 10 H, 5 CH2), 3.54–3.58 (m, 1 H, CH), 3.60 (s, 3 H,
MeO), 3.84 (s, 3 H, MeO), 4.00–4.04 (m, 1 H, CH2N), 4.06–
4.08 (br s, 1 H, OH), 4.13–4.17 (m, 1 H, CH2N), 4.22 (q,
3J = 7.1 Hz, 2 H, OCH2), 5.05 (d, 3J = 10.3 Hz, 1 H, H2C=),
5.08 (d, 2J = 17.1 Hz, 1 H, H2C=), 5.65–5.72 (m, 1 H, =CH-
). 13C NMR (125 MHz, CDCl3): δ = 13.8 (Me), 23.9 (CH2),
24.0 (CH2), 25.5 (CH2), 34.0 (CH2), 34.5 (CH2), 44.0 (CH),
51.1 (MeO), 52.8 (MeO), 57.5 (OCH2), 62.7 (CH2N), 77.2
(C-OH), 104.2 (C), 116.8 (H2C=), 131.7 (=CH-), 150.7 (C),
152.4 (C=N), 161.6 (C=O), 161.9 (C=O), 170.2 (C=O). MS
(EI): m/z (%) = 408 (2) [M]+, 355 (20), 303 (100), 253 (80),
221 (95), 166 (28), 126 (24), 105 (8), 55 (25). Anal. Calcd.
for C20H28N2O7 (408.19): C, 58.81; H, 6.91; N, 6.86. Found:
C, 58.71; H, 6.82; N, 6.83.
4-Ethyl 2,3-Dimethyl 1-butyl-5-(cyclohexylimino)-4,5-
dihydro-4-hydroxy-1H-pyrrole-2,3,4-tricarboxylate
(7g): Yield: 0.30 g (70%); cream powder; mp 94–96 °C. IR
(KBr): 3414 (OH), 1753 (C=O), 1660 (C=N) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 0.84 (t, 3J = 7.3 Hz, 3 H, Me), 1.15–
1.70 (m, 14 H, 7 CH2), 1.21 (t, 3J = 7.1 Hz, 3 H, CH3), 3.32–
3.37 (m, 1 H, CH), 3.86–3.55 (d, 3J = 7.1 Hz, 2 H, CH2N),
3.62 (s, 3 H, MeO), 3.91 (s, 3 H, MeO), 4.10 (br s, 1 H, OH),
4.20 (q, 3J = 7.1 Hz, 2 H, OCH2). 13C NMR (125 MHz,
CDCl3): δ = 13.6 (Me), 13.9 (Me), 19.5 (CH2), 24.0 (CH2),
24.1 (CH2), 25.7 (CH2), 30.3 (CH2), 34.2 (CH2), 34.7 (CH2),
42.2 (CH), 51.1 (MeO), 53.1 (MeO), 57.7 (OCH2), 62.7
(CH2N), 77.3 (C-OH), 103.5 (C), 151.6 (C), 153.0 (C=N),
162.0 (C=O), 162.1 (C=O), 170.4 (C=O). MS (EI): m/z (%)
= 424 (2) [M]+, 351 (33), 319 (100), 287 (10), 263 (10), 237
(10), 182 (14), 142 (8), 126 (5), 57 (15). Anal. Calcd. for
C21H32N2O7 (424.22): C, 59.42; H, 7.60; N, 6.60. Found: C,
59.46; H, 7.68; N, 6.72.
Triethyl 1-Benzyl-5-(cyclohexylimino)-4,5-dihydro-4-
hydroxy-1H-pyrrole-2,3,4-tricarboxylate (7h): Yield:
0.25 g (50%); cream powder; mp 80–82 °C. IR (KBr): 3430
(OH), 1733 (C=O), 1672 (C=N) cm–1. 1H NMR (500 MHz,
CDCl3): δ = 1.10 (t, 3J = 7.1 Hz, 3 H, Me), 1.19 (t, 3J =
7.1 Hz, 3 H, Me), 1.26 (t, 3J = 7.1 Hz, 3 H, Me), 1.25–1.89
(m, 10 H, 5 CH2), 3.60–3.66 (m, 1 H, CH), 4.11 (q, 3J =
7.1 Hz, 2 H, OCH2), 4.15 (q, 3J = 7.1 Hz, 2 H, OCH2), 4.23
(q, 3J = 7.1 Hz, 2 H, OCH2), 4.57 (br s, 1 H, OH), 4.63 (d,
2J = 15.8 Hz, 1 H, CH2N), 4.90 (d, 2J = 15.8 Hz, 1 H, CH2N),
7.22–7.26 (m, 5 H, 5 CH). 13C NMR (125 MHz, CDCl3): δ =
15.0 (Me), 15.4 (Me), 15.6 (Me), 25.5 (CH2), 25.6 (CH2),
27.1 (CH2), 35.6 (CH2), 36.2 (CH2), 46.6 (CH), 59.1
(OCH2), 61.4 (OCH2), 63.9 (OCH2), 64.3 (CH2N), 78.1 (C-
OH), 105.9 (C), 128.7 (2 CH), 128.8 (2 CH), 129.7 (CH),
138.2 (C), 152.1 (C), 154.5 (C=N), 162.8 (C=O), 163.1
(C=O), 171.9 (C=O). MS (EI): m/z (%) = 486 (2) [M]+, 413
(2), 367 (4), 299 (15), 207 (18), 178 (8), 105 (10), 91 (100),
77 (5), 52 (4). Anal. Calcd. for C26H34N2O7 (486.24): C,
Diethyl 1-Benzyl-2-(tert-butylimino)-2,3-dihydro-3-
hydroxy-5-methyl-1H-pyrrole-3,4-dicarboxylate (13b):
Yield: 0.26 g (65%); colorless crystals; mp 80–82 °C.
IR (KBr): 3373 (OH), 1749 (C=O), 1656 (C=O), 1612
(C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3J =
7.1 Hz, 3 H, Me), 1.23 (t, 3J = 7.1 Hz, 3 H, Me), 1.24 (s, 9 H,
CMe3), 2.35 (s, 3 H, Me), 4.10–4.28 (m, 4 H, 2 OCH2), 4.43
(br s, 1 H, OH), 4.58 (d, 2J = 15.8 Hz, 1 H, CH2N), 5.10–5.19
(d, 2J = 15.8 Hz, 1 H, CH2N), 7.20–7.35 (m, 5 H, 5 CH). 13
NMR (125 MHz, CDCl3): δ = 13.2 (Me), 14.0 (Me), 14.4
C
(Me), 31.0 (CMe3), 51.9 (CMe3), 59.5 (OCH2), 62.2 (OCH2),
62.5 (CH2N), 77.9 (C-OH), 102.1 (C), 126.6 (CH), 127.1
(CH), 128.5 (CH), 138.5 (CH), 160.1 (C), 161.2 (C=N),
164.5 (C=O), 172.0 (C=O). MS (EI): m/z (%) = 402 (10)
[M]+, 329 (74), 283 (79), 227 (100), 181 (22), 131 (28), 91
(83), 57 (55). Anal. Calcd. for C22H30N2O5 (402.22): C,
65.65; H, 7.51; N, 6.96. Found: C, 65.71; H, 7.62; N, 7.03.
Diethyl 1-Benzyl-2,3-dihydro-3-hydroxy-5-methyl-2-
(1,1,3,3-tetramethylbutylimino)-1H-pyrrole-3,4-
dicarboxylate (13c): Yield: 0.24 g (52%); yellow oil.
IR (KBr): 3393 (OH), 1743 (C=O), 1676 (C=O), 1608
(C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.83 (s, 3 H,
CMe2), 1.27 (t, 3J = 7.1 Hz, 3 H, Me), 0.98 (s, 3 H, CMe2),
1.23 (m, 3 H, Me), 1.25 (s, 9 H, CMe3), 1.26 (m, 3 H, Me),
1.40 (d, 2J = 12.1 Hz, 1 H, CH2), 1.43 (d, 2J = 12.1 Hz, 1 H,
CH2), 1.90 (s, 3 H, Me), 4.08 (q, 3J = 7.1 Hz, 2 H, OCH2),
4.12 (br s, 1 H, OH), 4.20 (q, 3J = 7.1 Hz, 2 H, OCH2), 4.58
(d, 3J = 16.4 Hz, 1 H, CH2N), 5.22 (d, 3J = 16.4 Hz, 1 H,
CH2N), 7.15–7.35 (m, 5 H, 5 CH). 13C NMR (125 MHz,
CDCl3): δ = 13.2 (Me), 14.1 (Me), 14.6 (Me), 29.7 (CMe3),
31.4 (CMe2), 31.6 (CMe2), 31.9 (CH2), 51.8 (CMe3), 55.8
(CMe2), 58.6 (OCH2), 59.2 (OCH2), 62.0 (CH2N), 79.0 (C-
OH), 103.1 (C), 126.2 (CH), 126.7 (CH), 127.3 (CH), 138.1
(CH), 160.0 (C), 161.7 (C=N), 164.2 (C=O), 171.3 (C=O).
MS (EI): m/z (%) = 458 (5) [M]+, 385 (11), 341 (14), 273
(24), 227 (31), 196 (27), 172 (26), 147 (37), 131 (22), 91
(100). Anal. Calcd. for C26H38N2O5 (458.28): C, 68.10; H,
8.35; N, 6.11. Found: C, 68.05; H, 8.29; N, 6.17.
Ethyl 4-Acetyl-1-benzyl-2-(cyclohexylimino)-2,3-
dihydro-3-hydroxy-5-methyl-1H-pyrrole-3-carboxylate
(13d): Yield: 0.29 g (75%); cream powder; mp 110–112 °C.
IR (KBr): 3243 (OH), 1749 (C=O), 1686 (C=O), 1615
(C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.15–1.75 (m,
10 H, 5 CH2), 1.28 (t, 3J = 7.2 Hz, 3 H, Me), 2.19 (s, 3 H,
Me), 2.29 (s, 3 H, Me), 3.74–3.75 (m, 1 H, CH), 4.16–4.29
(m, 2 H, OCH2), 4.40 (br s, 1 H, OH), 4.63 (d, 2J = 16.2 Hz,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1662–1666

1666
I. Yavari et al.
LETTER
1 H, CH2N), 5.13 (d, 2J = 16.5 Hz, 1 H, CH2N), 7.20 (d, 3J =
7.2 Hz, 2 H, 2 CH), 7.24 (t, 3J = 7.2 Hz, 1 H, CH), 7.28 (d,
3J = 7.2 Hz, 2 H, 2 CH). 13C NMR (125 MHz, CDCl3): δ =
14.8 (Me), 14.9 (Me), 25.0 (CH2), 25.1 (CH2), 26.6 (CH2),
30.1 (Me), 35.1 (CH2), 35.6 (CH2), 44.8 (CH), 58.1 (OCH2),
63.4 (CH2N), 78.9 (C-OH), 116.6 (C), 127.3 (CH), 128.1
(CH), 129.5 (CH), 138.1 (CH), 155 (C), 160.1 (C=N), 172.5
(C=O), 191.9 (C=O). MS (EI): m/z (%) = 398 (2) [M]+, 325
(100), 283 (4), 243 (45), 229 (10), 201 (12), 106 (15), 91
(96), 79 (14), 58 (45). Anal. Calcd. for C23H30N2O4 (398.22):
C, 69.62; H, 8.06; N, 7.11. Found: C, 69.74; H, 8.14; N, 7.18.
Ethyl 4-Acetyl-1-benzyl-2-(tert-butylimino)-2,3-dihydro-
3-hydroxy-5-methyl-1H-pyrrole-3-carboxylate (13e):
Yield: 0.26 g (70%,); cream powder; mp 115–117 °C.
IR (KBr): 3395 (OH), 1738 (C=O), 1687 (C=O), 1572
(C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.23 (t,
3J =7.1 Hz, 3 H, Me), 1.28 (s, 9 H, CMe3), 2.21 (s, 3 H, Me),
2.29 (s, 3 H, Me), 3.70 (br s, 1 H, OH), 4.12–4.30 (m, 2 H,
OCH2), 4.58 (d, 2J = 16.1 Hz, 1 H, CH2N), 5.23 (d, 2J =
16.1 Hz, 1 H, CH2N), 7.22 (d, 3J = 7.7 Hz, 2 H, 2 CH), 7.23
(d, 3J = 7.7 Hz, 2 H, 2 CH), 7.28 (d, 3J = 7.7 Hz, 2 H, 2 CH).
13C NMR (125 MHz, CDCl3): δ = 13.9 (Me), 14.3 (Me), 29.4
(Me), 30.9 (CMe3), 41.2 (CMe3), 55.0 (OCH2), 61.8 (CH2N),
78.4 (C-OH), 114.2 (C), 126.4 (CH), 126.7 (CH), 126.9
(CH), 128.5 (CH), 137.6 (C), 149.8 (C), 158.9 (C=N), 171.1
(C=O), 190.9 (C=O). MS (EI): m/z (%) = 372 (22) [M]+, 299
(25), 243 (100), 195 (40), 149 (23), 117 (38), 106 (98), 106
(70), 90 (98), 79 (18), 57 (35). Anal. Calcd. for C21H28N2O4
(372.2): C, 67.72; H, 7.58; N, 7.52. Found: C, 67.81; H, 7.64;
N, 7.58.
(C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.99 (t, 3J =
7.2 Hz, 3 H, Me), 1.26 (t, 3J = 7.2 Hz, 3 H, Me), 1.20–1.86
(m, 14 H, 7 CH2), 2.33 (s, 3 H, Me), 2.58 (s, 3 H, Me), 3.54–
3.70 (m, 1 H, CH), 3.93 (d, 2J = 16.0 Hz, 1 H, CH2N), 4.20
(br s, 1 H, OH), 4.28 (d, 2J = 16.0 Hz, 1 H, CH2N), 4.30–4.35
(m, 2 H, OCH2). 13C NMR (125 MHz, CDCl3): δ = 14.8
(Me), 14.9 (Me), 25.0 CH2), 25.1 (CH2), 26.6 (CH2), 30.1
(Me), 35.1 (CH2), 35.6 (CH2), 44.8 (CH), 58.1 (OCH2), 63.4
(CH2N), 78.9 (C-OH), 116.6 (C), 127.3 (CH), 128.1 (CH),
129.5 (CH), 138.1 (CH), 155 (C), 160.1 (C=N), 172.5
(C=O), 191.9 (C=O). MS (EI): m/z (%) = 364 (2) [M]+, 291
(100), 236 (10), 210 (96), 183 (10), 154 (15), 127 (10), 98
(20), 84 (18), 67 (25), 57 (59). Anal. Calcd. for C20H32N2O4
(364.24): C, 65.91; H, 8.85; N, 7.69. Found: C, 65.93; H,
8.89; N, 7.64.
Methyl 4-Acetyl-1-benzyl-2-(cyclohexylimino)-2,3-
dihydro-3-hydroxy-5-methyl-1H-pyrrole-3-carboxylate
(13h): Yield: 0.31 g (80%); cream powder; mp 98–100 °C.
IR (KBr): 3279 (OH), 1737 (C=O), 1673 (C=O), 1566
(C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.10–2.15 (m,
10 H, 5 CH2), 1.96 (s, 3 H, Me), 2.26 (s, 3 H, Me), 3.74 (br
s, 1 H, OH), 3.85 (s, 3 H, OMe), 3.92–4.08 (m, 1 H, CH),
5.08 (d, 2J = 16.5 Hz, 1 H, CH2N), 5.12 (d, 2J = 16.5 Hz, 1 H,
CH2N), 7. 20–7.26 (m, 5 H, 5 CH). 13C NMR (125 MHz,
CDCl3): δ = 14.7 (Me), 26.0 (CH2), 26.1 (CH2), 26.7 (CH2),
31.2 (Me), 33.3 (CH2), 33.4 (CH2), 49.0 (CH), 56.1 (OCH2),
59.1 (CH2N), 83.0 (C-OH), 123.4 (C), 128.0 (CH), 126.7
(CH), 129.6 (CH), 129.0 (CH), 130.4 (C), 134.8 (C), 157.2
(C), 167.5 (C=N), 168.5 (C=O), 194.1 (C=O). MS (EI): m/z
(%) = 384 (2) [M]+, 291 (100), 229 (34), 209 (14), 164 (12),
127 (20), 99 (35), 83 (50), 70 (25), 55 (96). Anal. Calcd. for
C23H30N2O4 (398.22): C, 69.32; H, 7.59; N, 7.03. Found: C,
69.33; H, 7.62; N, 6.64.
Ethyl 4-acetyl-2-(cyclohexylimino)-2,3-dihydro-3-
hydroxy-5-methyl-1-(4-methylbenzyl)-1H-pyrrole-3-
carboxylate (13i): Yield: 0.34 g (82%); cream powder;
mp 124–126 °C. IR (KBr): 3250 (OH), 1748 (C=O), 1662
(C=O), 1610 (C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ =
1.15–2.07 (m, 10 H, 5 CH2), 1.20 (t, 3J =7.1 Hz, 3 H, Me),
2.22 (s, 3 H, Me), 2.26 (s, 3 H, Me), 2.33 (s, 3 H, Me), 3.64
(br s, 1 H, OH), 3.90–3.93 (m, 1 H, CH), 4.10–4.32 (m, 2 H,
OCH2), 4.89 (d, 2J = 16.3 Hz, 1 H, CH2N), 5.91 (d, 2J =
16.3 Hz, 1 H, CH2N), 7.03 (d, 3J = 7.8 Hz, 2 H, 2 CH), 7.07
(d, 3J = 7.8 Hz, 2 H, 2 CH). 13C NMR (125 MHz, CDCl3):
δ = 14.7 (Me), 15.3 (Me), 22.4 (Me), 25.7 (CH2), 25.8 (CH2),
31.1 (Me), 31.2 (CH2), 32.2 (CH2), 48.2 (CH), 59.0 (OCH2),
65.1 (CH2N), 82.9 (C-OH), 123.3 (C), 127.9 (CH), 130.8
(CH), 130.9 (C), 139.3 (C), 157.2 (C), 167.4 (C=N), 168.1
(C=O), 194.0 (C=O). MS (EI): m/z (%) = 412 (22) [M]+, 339
(100), 297 (24), 257 (22), 204 (23), 120 (60), 105 (97), 84
(60), 67 (30), 56 (47). Anal. Calcd. for C24H32N2O4 (412.24):
C, 69.88; H, 7.82; N, 6.79. Found: C, 69.82; H, 7.87; N, 6.72.
Ethyl 4-Acetyl-1-(2-chlorobenzyl)-2-(cyclohexylimino)-
2,3-dihydro-3-hydroxy-5-methyl-1H-pyrrole-3-
carboxylate (13f): Yield: 0.32 g (74%); cream powder; mp
109–111 °C. IR (KBr): 3272 (OH), 1750 (C=O), 1651
(C=O), 1543 (C=N) cm–1. 1H NMR (500 MHz, CDCl3): δ =
1.11–1.97 (m, 10 H, 5 CH2), 1.27 (d, 3J =7.1 Hz, 3 H, Me),
2.18 (s, 3 H, Me), 2.24 (s, 3 H, Me), 3.74 (br s, 1 H, OH),
3.90–4.18 (m, 1 H, CH), 4.16–4.30 (m, 2 H, OCH2), 4.74 (d,
2J = 17.1 Hz, 1 H, CH2N), 5.08 (d, 2J = 17.1 Hz, 1 H, CH2N),
7.09–7.36 (m, 4 H, 4CH). 13C NMR (125 MHz, CDCl3): δ =
13.7 (Me), 14.0 (Me), 23.7 (Me), 23.8 (CH2), 25.2 (CH2),
28.8 (Me), 33.7 (CH2), 34.2 (CH2), 41.2 (CH), 56.7 (OCH2),
62.1 ((CH2N), 77.5 (C-OH), 115.5 (C), 126.6 (CH), 126.7
(CH), 127.9 (CH), 129.0 (CH), 131.6 (C), 133.9 (C), 153.6
(C), 158.6 (C=N), 171.1 (C=O), 190.8 (C=O). MS (EI): m/z
(%) = 432 (2) [M]+, 359 (100), 301 (14), 277 (70), 228 (20),
148 (55), 127 (98), 106 (78), 89 (65), 77 (35), 55 (24). Anal.
Calcd. for C23H29ClN2O4 (432.18): C, 63.81; H, 6.75; N,
6.47. Found: C, 63.89; H, 6.83; N, 6.5.
Ethyl 4-Acetyl-1-buyl-2-(cyclohexylimino)-2,3-dihydro-
3-hydroxy-5-methyl-1H-pyrrole-3-carboxylate (13g):
Yield: 0.28 g (78%); cream powder; mp 124–126 °C.
IR (KBr): 3240 (OH), 1749 (C=O), 1661 (C=O), 1600
Synlett 2012, 23, 1662–1666
© Georg Thieme Verlag Stuttgart · New York

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