Synthesis of Polysubstituted Pyrroles through the Tandem 1,3-Addition/5-endo-dig Cyclization of 1-(1-Alkynyl)cyclopropyl Imines

Article abstract of DOI:10.1002/ejoc.201600985

Cyclopropyl-tethered 3-alkynyl imines react with polarized-covalent-bond-containing compounds to give polyfunctionalized pyrroles. This provides a mild and effective method for the simultaneous introduction of halogen, chalcogen, or hydrogen groups to the

Full text of DOI:10.1002/ejoc.201600985

A Journal of
Accepted Article
Title: Synthesis of Polysubstituted Pyrroles via Tandem 1,3-Addition-5-Endo-Dig Cy-
clization of 1-(1-Alkynyl)Cyclopropyl Imines
Authors: Aurelija Urbanait; Inga Ikotien
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600985
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600985
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European Journal of Organic Chemistry
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Synthesis of Polysubstituted Pyrroles via Tandem 1,3-Addition-5-
Endo-Dig Cyclization of 1-(1-Alkynyl)Cyclopropyl Imines
Aurelija Urbanaitė,[a] Inga Čikotienė*[a]
Abstract: Reactions of cyclopropyl-tethered 3-alkynyl imines with
polarized covalent bond containing compounds lead to formation of
polyfunctionalized pyrroles. Particularly, this observation provides a
mild and effective method for the simultaneous introduction of
halogen, chalcogen or hydrogen groups onto 3rd position of the
pyrrole ring together with incorporation of halogen, azido or
alkoxy/aryloxy groups into side ethyl chain.
we decided to prepare some cyclopropyl-tethered imines and to
evaluate their reactivity towards electrophilic reagents. However,
the obtained results showed
a unique reactivity of 1-
alkynylcyclopropyl imines towards covalent polar bonds
containing molecules and this process cannot be classified as
electrophile-assisted transformations. Herein we present the
results of our investigations.
Results and Discussion
Introduction
The starting 1-arylalkynylcyclopropyl carbaldehydes 1 were
prepared by the known methods.[11a] With prepared starting
aldehydes in hands, for the synthesis of the desired starting
imines, we tried to utilize the classical reaction with primary
Pyrroles are important class of heterocycles with valuable
chemical, biological and photophysical properties. This
heterocycle presents in a number of natural compounds[1],
synthetic bioactive molecules[2] and scaffolds for material
science.[3] Although a wide variation of classical[4] or more
modern transition metal-mediated[5] pyrrole synthetic methods
presents in the literature, the development of new synthetic
methods of polyfunctionalized pyrroles is highly desirable.
Cyclopropyl-tethered functionalized alkynes can be useful
synthones for preparation of five-membered heteroaromatic
compounds. Thus, 1-arylalkynylcyclopropyl carbaldehydes or
ketones were recently introduced as suitable starting materials
for the preparation of various furans. These compounds, due to
their unique structure and reactivity serve as all carbon 1,4-
carbon dipoles,[6] therefore can undergo gold catalyzed reactions
with nucleophiles,[7] [4+2][6,8b] or [4+3][8] cycloadditions, rhodium
catalyzed carbonylative reactions[9] and copper (II) halide
mediated cyclization[10] (Scheme 1). 1-Cyclopropylalkynylimines
or oximes are not used so often, however there are some
reports in the literature about their transition-mediated
transformations to pyrroles.[11] Electrophile-assisted cyclizations
of cyclopropyl-tethered alkynylketones to the corresponding
furanes have been proposed by Huang et al some time ago and
to the best of our knowledges, this is the only example of this
type of ring closure of 1-(1-alkynyl)-cyclopropyl ketones.[12]
amines.
Thus,
1-((4-methoxyphenyl)ethynyl)-
cyclopropanecarbaldehyde 1a and benzylamine was chosen for
the synthesis of cyclopropyl-tethered 3-alkynyl imine 3a.
However no TLC-detectable product was formed during heating
of aldehyde with amine in dichloromethane in the presence of
magnesium sulfate in sealed tube.[11a] So therefore we decided
to utilize microwave assisted synthesis for smoother formation of
imine functionality. After irradiation of solution of starting
aldehyde and benzylamine in 1,2-dichloroethane in the presence
of activated 3Å molecular sieves at 120 oC, a spot of new
product together with spot of unreacted starting material were
detected on TLC. Longer irradiation of the reaction mixture did
not improve the conversion. After preparative column
chromatography 57 % of the starting aldehyde 1a was recovered
and product 2a was isolated in 29 % yield. To our deep surprise,
after structural analysis of product we elucidated that it was 1-
benzyl-4-(2-chloroethyl)-2-(4-methoxyphenyl)-1H-pyrrole
instead of desired imine 3a (Scheme 2).
2a,
We presumed that hydrogen chloride presenting as impurity in
the solvent reacted with in situ formed imine. This reaction could
lead to tandem proton-assisted cyclization to 5-membered
heterocyclic ring and chloride-mediated cyclopropane ring
It is noteworthy, that electrophile-assisted cyclizations have their
scope and some benefits in organic synthesis, because these
methods do not require transition-metal catalysis and the final
products contain halogen, chalcogen or alkoxyarylmethyl
functional groups suitable for further functionalizations.[13] In
continuation of our recent studies in the field of electrophile-
mediated transformations of functionally substituted alkynes,[14]
opening.
Heating
of
solution
of
1-((4-
and
methoxyphenyl)ethynyl)cyclopropanecarbaldehyde
1a
benzylamine in saturated hydrogen chloride solution in
dichloroethane, resulted in higher yield (72%) of compound 2a.
Next, we changed the solvent to non-acidic acetonitrile and
monitored the formation of imine by H NMR spectroscopy. We
noticed, that imine functional group formed successfully after 20
1
o
min heating of reaction solutions at 120 C in microwave oven.
For the full conversion of the aldehyde, two equivalents of
amines were required. However, the purification of the desired
imine by column chromatography led to full product hydrolysis to
the starting aldehyde.
[a]
Department of Organic Chemistry, Faculty of Chemistry, Vilnius
University, Naugarduko 24, LT-03225, Vilnius, Lithuania.
Fax: +370 5 233 09 87
E-mail: inga.cikotiene@chf.vu.lt
Web: http://web.vu.lt/chf/i.cikotiene/
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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Scheme 1. Transition metal catalyzed reactions of cyclopropyl-tethered functionalized alkynes.
minutes. Spectroscopic analysis together with HRMS data of
isolated compound proved the structure of 1-tert-butyl-3-iodo-4-
(2-iodoethyl)-2-(4-methoxyphenyl)-1H-pyrrole (2b) (Table 1,
entry 1). Iodocyclizations/cyclopropane ring cleavage reactions
underwent very smoothly with other substrates, resulting in
formation of di-iodo derivatives 2c-h in good yields (Table 1,
entries 6 - 13). For preparation of polysubstituted pyrroles
containing different functional groups on pyrrole ring and ethyl
chain, we turned our attention to unsymmetric covalent bond
containing reagents. Thus, using of iodine monochloride resulted
in formation of 2-aryl-4-(2-chloroethyl)-3-iodo-1H-pyrroles (2i –
k) (Table 1, entries 14 - 16), phenylselenyl chloride gave the
corresponding
2-aryl-4-(2-chloroethyl)-3-(phenylselanyl)-1H-
pyrroles (2l,m) (Table 1, entries 15,17). Reactions between
intermediate imines and freshly prepared iodine azide or acetyl
hipoiodite resulted in the formation of the corresponding 2-aryl-
4-(2-azidooethyl)-3-iodo-1H-pyrroles (2l,m) and 2-aryl-4-(2-
chloroethyl)-3-(phenylselanyl)-1H-pyrroles (2n,o) and 2-(5-aryl-
4-iodo-1H-pyrrol-3-yl)ethyl acetates (2p, 4) (Table 1, entries 18 –
20). And finally, we were pleasantly surprised to see that when
solutions of the starting aldehydes 1 and amines were irradiated
in microwave oven in the presence of alcohols or phenol, the
selective formation of N-substituted 4-(2-alkoxyethyl)-2-aryl-1H-
pyrroles (2r,t,u) and 1-tert-butyl-4-(2-phenoxyethyl)-2-phenyl-
1H-pyrrole (2s) took place (Table 1, entries 21, 23-25).
Scheme
2.
Reaction
between
1-((4-methoxyphenyl)ethynyl)-
cyclopropanecarbaldehyde 1a and benzylamine in dichloroethane. i: 1.1 eq. of
benzylamine, 1,2-dichloroethane, 3Å MS, MW, 120 oC, 15 min.
So we decided to prepare cyclopropyl tethered alkynyl imines in
situ just before addition of electrophilic reagent. First of all, we
tried to perform iodo-cyclization of intermediate imine. After
heating of starting aldehyde 1a with excess of tert-butylamine in
acetonitrile for 20 min at 120 oC in microwave oven, the obtained
solution was cooled to room temperature and molecular iodine
was added. A very quick consumption of the starting material
was observed by TLC, showing formation of one product in 5
From the obtained results the following mechanism could be
proposed: after the addition of electrophile to the triple bond and
formation of vinylic carbocation A, the subsequent nucleophilic
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European Journal of Organic Chemistry
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anti-attack of imine nitrogen occurs resulting in formation of
intermediate B (Scheme 3, route a). The analogous scenario
was proposed by Huang et al for the synthesis of functionalized
furanes.[12] However, the introduction of an excess of some
external nucleophiles (indole, piperidine, methanol, sodium
azide or potassium iodide) to reaction mixtures (Table 1, entries
2 – 5, 16, 22), did not result in logical incorporation of the
nucleophilic fragment in ethyl chain of final products. In all cases
diiodo compound 2b (entries 2- 5), chloroethyl group containing
compound 2l (entry 16) and methoxyethyl group containing
compound 2r (entry 22) were isolated as sole reaction products.
Moreover, the rate of the cyclization reaction did not depend on
the presence or absence of strong electron donating methoxy
group on the benzene ring, as it usually observed in reactions
proceeding via vinylic carbocations.[14b,c,15] These observations
gave support to route b (Scheme 3). Thus, we believe this
reaction is promoted by formal 1,3-addition reaction of polar
covalent bond containing reagent to Csp-c-Pr fragment, allowing
the consequent 5-endo-dig cyclization to the final pyrroles 2
(Scheme
3,
route
b).
Scheme 3. Reaction between 1-((4-methoxyphenyl)ethynyl)
-
cyclopropanecarbaldehyde 1a and benzylamine in dichloroethane. i: 1.1 eq. of benzylamine, 1,2-
dichloroethane, 3Å MS, MW, 120 oC, 15 min.
Table 1. Data on the synthesis of polysubstituted pyrroles 2.
Entry
Starting aldehyde 1
Amine
RNH2
E-X
Additive
(3 equiv)
Reaction conditions[a]
Product 2 (yield, %)
1a: Ar = 4-MeOC6H4-
R = tBu
R = tBu
R = tBu
R = tBu
R = tBu
R = Bn
I2
-
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method B
Method B
2b (81); E = X = I
2b (56)
1
1a
I2
Indole
2
1a
I2
Piperidine
2b (59)
3
1a
I2
CH3OH
2b (16)
4
1a
I2
NaN3
2b (76)
5
1a
I2
-
-
-
-
-
-
-
-
2c (78); E = X = I
2d (57); E = X = I
2e (46); E = X = I
2f (58); E = X = I
2g (59); E = X = I
2h (64); E = X = I
2i (52); E = I; X = Cl
2j (95); E = I; X = Cl
6
1b: Ar = Ph
R = tBu
R = Bu
I2
7
1b
I2
8
1c: Ar = 4-MeC6H4-
R = tBu
R = Bn
I2
9
1c
1c
1b
1c
I2
10
11
12
13
R = cHex
R = tBu
R = cHex
I2
ICl
ICl
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European Journal of Organic Chemistry
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1c
R = iPr
ICl
-
Method B
Method B
Method B
Method B
Method B
Method B
Method C
Method D
Method D
Method D
Method D
Method D
2k (55); E = I; X = Cl
14
1b
R = tBu
R = tBu
R = tBu
R = cHex
R = tBu
R = tBu
R = Bn
PhSeCl
PhSeCl
PhSeCl
IN3
-
2l (53); E = PhSe; X = Cl
2l (48)
15
1b
KI
-
16
1c
2m (65); E = PhSe; X = Cl
2n (56); E = I; X = N3
2o (76); E = I; X = N3
2p (21); E = I; X = OAc[b]
2r (49); E = H; X = OCH3
2r (47); E = H; X = OCH3
2s (56); E = H; X = OPh
2t (63); E = H; X = OC3H7
2u (70); E = H; X = OCH3
17
1b
-
18
1c
IN3
-
19
1b
IOAc
-
20
1a
HOCH3
HOCH3
HOPh
HOC3H7
HOCH3
-
21
1a
R = Bn
KI
-
22
1b
R = tBu
R = tBu
R = cHex
23
1c
-
24
1c
-
25
[a] Method A. The starting aldehyde, 2 eq. of the corresponding amine, acetonitrile, 3Å MS, MW, 120 oC, 20 min; then addition of molecular iodine (1 equiv) at rt.
Method B. The starting aldehyde, 2 eq. of the corresponding amine, acetonitrile, 3Å MS, MW, 120 oC, 20 min; then evaporation of the solvent and excess of
amine, resolving in fresh acetonitrile and addition of the corresponding reagent. Method C. The starting aldehyde, 2 eq. of the corresponding amine, acetonitrile,
3Å MS, MW, 120 oC, 20 min; then evaporation of the solvent and excess of amine, resolving in fresh chloroform (2 mL) and addition of the resulting mixture to a
solution of freshly prepared acetyl hypoiodite (2 eq.) in chloroform (1 mL). Method D. The starting aldehyde, 2 eq. of the corresponding amine, the corresponding
alcohol (2 mL), 3Å MS, MW, 120 oC, 50 min. [b] Additional product 2-(1-tert-butyl-2,4-diiodo-5-phenyl-1H-pyrrol-3-yl)ethyl acetate (4) was isolated in 19% yield.
Moreover, we performed additional control experiments
including cyclization of starting 1-
compounds and these reactions lead to
a
variety of
polysubstituted pyrroles. Particularly, this observation provides a
mild and effective method for the simultaneous introduction of
halogen, chalcogen or hydrogen groups onto 3rd position of the
pyrrole ring together with incorporation of halogen, azido or
alkoxy/aryloxy groups into side ethyl chain. This unique reactivity
of cyclopropyl-tethered functionalized alkynes towards covalent
polar bonds containing molecules point toward a broad and
divergent synthetic applicability of analogous substrates.
(phenylethynyl)cyclopropanecarbaldehyde 1b and Huang’s 1-
(phenylethynyl)bicyclo[4.1.0]heptan-2-one 6[12] (Scheme 4).
When compound 1b was stirred in methanol-dichloromethane
mixture in the presence of an equivalent of molecular iodine, a
very smooth (5 min) and selective formation of 3-iodo-4-(2-
iodoethyl)-2-phenylfuran 5 took place without any incorporation
of methoxy group from methanol in the structure of the product.
In contrast, Huang’s ketone 6 at the same conditions reacted
more slowly (7 h) and two products were isolated after the work-
up of reaction mixture. The main product, as it was showed by
Huang et al12 was 3-iodo-5-methoxy-2-phenyl-5,6,7,8-
tetrahydro-4H-cyclohepta[b]furan 7 and the minor one contained
iodo group on the cycloheptane ring. Differences in rates as well
as in the outcome of reactions indicate that cyclizations of
cyclopropyl-tethered functionalized alkynes can udergo via
different mechanisms. Unsubstituted cyclopropyl tether favors
the formal 1,3-addition process and smooth subsequent
cyclization, while the presence of bulky cyclohexane ring next to
cyclopropyl tether gives precedent to the classical electrophile-
assisted cyclization with incorporation of external nucleophiles.
Unfortunately, theHuang’s ketone did not form any imine under
the standard conditions, so we were not able to synthesize
derivatives of 5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole.
Conclusions
Scheme 4. Control experiments with 1-arylalkynylcyclopropyl carbaldehyde 1b
and Huang’s ketone 6.
In summary it was shown that 1-(1-alkynyl)cyclopropyl imines
are able to react with polarized covalent bond containing
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European Journal of Organic Chemistry
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m, ArH) ppm. 13C NMR (100 MHz, CDCl3) δ: 31.0 (CH2), 45.3 (CH2Cl),
50.4 (CH2Ph), 55.2 (OCH3), 108.5 (CHpyrrole), 113.8 (ArC), 120.0 (ArC),
120.3 (NCHpyrrole), 125.5 (ArC), 126.4 (ArC), 127.2 (ArC), 128.6 (ArC),
130.0 (ArC), 134.8 (ArC), 138.8 (ArC), 158.8 (ArC) ppm HRMS (ESI):
M+H, found 326.1306. C20H2135ClNO requires 326.1306.
Experimental Section
General information. IR spectra were run in KBr discs on a Perkin-
Elmer FT spectrophotometer Spectrum BX II. 1H and 13C NMR spectra
were recorded with a Brucker (400 MHz) or Varian Unity INOVA (300
MHz) spectrometers in chloroform-d, using residual solvent signal as
internal standard. Signal multiplicity as follows: s (singlet), d (doublet), t
(triplet), q (quartet), quint (quintet), m (multiplet). HRMS spectra were
1-Tert-butyl-3-iodo-4-(2-iodoethyl)-2-(4-methoxyphenyl)-1H-pyrrole
(2b)
White solid, m.p. 129 – 130 оC. Yield 0.206 g, 81 %
obtained on
a mass spectrometer Dual-ESI Q-TOF 6520 (Agilent
1H NMR (400 MHz, CDCl3) δ: 1.38 (9H, s, 3xCH3), 3.01 (2H, t, 3J = 8.0
Hz, CH2), 3.33 (2H, t, 3J = 8.0 Hz, CH2I), 3.87 (3H, s, OCH3), 6.87 (1H, s,
CHpyrrole), 6.94 (2H, d, 3J = 8.0 Hz, ArH), 7.19 (2H, d, 3J = 8.0 Hz, ArH)
ppm. 13C NMR (100 MHz, CDCl3) δ: 6.1 (CH2I), 31.5 (3xCH3), 33.6 (CH2),
55.2 (OCH3), 58.0 (C(CH3)3), 72.5 (CI), 113.2 (ArC), 117.1 (CHpyrrole),
122.8 (ArC), 128.3 (ArC), 133.6 (ArC), 135.0 (ArC), 159.4 (ArC) ppm.
HRMS (ESI): M+H, found 509.9787. C17H22127I2NO requires 509.9785.
Technologies). All reactions and the purity of the synthesized compounds
monitored by TLC using Silica gel 60 F254 aluminium plates (Merck).
Visualization was accomplished by UV light and by treating the plates
with vanillin stain followed by heating.
General procedures for the synthesis of polysubstituted pyrroles 2
Method A. A solution of corresponding cyclopropanecarbaldehyde 1 (0.5
mmol) and amine (1 mmol.) in acetonitrile (2 mL) was irradiated in closed
vessel in scientific microwave oven (CEM Focused Microwave™
Synthesis System, Discover® SP) at 150 W, 120 °C for 20 min. Then the
reaction mixture was cooled to room temperature and molecular iodine
(0.127 g, 0.5 mmol) was added. The resulting solution was stirred at
room temperature and the progress of reaction was monitored by TLC.
After all starting material was consumed, the solvent was evaporated
under reduced pressure. The residue was purified by flash column
chromatography eluting with hexane/ethyl acetate (20 : 1) mixture.
1-Benzyl-3-iodo-4-(2-iodoethyl)-2-(4-methoxyphenyl)-1H-pyrrole (2c)
Yellowish oil. Yield 0.211 g, 78 %
3
1H NMR (400 MHz, CDCl3) δ: 3.02 (2H, t, J = 8.0 Hz, CH2), 3.34 (2H, t,
3J = 8.0 Hz, CH2I), 3.83 (3H, s, OCH3), 4.97 (2H, s, CH2Ph), 6.69 (1H, s,
3
3
CHpyrrole), 6.91 (2H, d, J = 8.0 Hz, ArH), 6.95 (2H, d, J = 8.0 Hz, ArH),
7.19 (2H, d, J = 8.0 Hz, ArH), 7.23 – 7.30 (3H, m, ArH) ppm. 13C NMR
3
(100 MHz, CDCl3) δ: 6.2 (CH2I), 33.3 (CH2), 51.7 (CH2Ph), 55.2 (OCH3),
67.5 (CI), 113.7 (ArC), 120.0 (CHpyrrole), 124.3 (ArC), 125.0 (ArC), 126.6
(ArC), 127.5 (ArC), 128.6 (ArC), 132.1 (ArC), 135.8 (ArC), 138.0 (ArC),
159.5 (ArC) ppm. HRMS (ESI): M+H, found 543.9636. C20H20I2NO
requires 543.9634.
Method B. A solution of corresponding cyclopropanecarbaldehyde 1 (0.5
mmol) and amine (1 mmol) in acetonitrile (2 mL) was irradiated in closed
vessel in scientific microwave oven (CEM Focused Microwave™
Synthesis System, Discover® SP) at 150 W, 120 °C for 20 min. Then the
solvent and the amine were evaporated under reduced pressure. The
residue was dissolved in acetonitrile (2 mL) and the iodine monochloride
(81.25 mg, 0.5 mmol), phenyl hypochloroselenoite (95.5 mg, 0.5 mmol)
or solution of freshly prepared hypoiodyl azide[16] (1 mmol) was added.
The resulting solution was stirred at room temperature and was
monitored by TLC. After all starting material was consumed, the solvent
was evaporated under reduced pressure. The residue was purified by
flash column chromatography eluting with hexane - ethyl acetate (20 :1)
mixture.
1-Tert-butyl-3-iodo-4-(2-iodoethyl)-2-phenyl-1H-pyrrole (2d)
White solid, m.p. 100 – 101 оC. 0.137 g, Yield 57 %
1H NMR (400 MHz, CDCl3) δ: 1.39 (9H, s, 3xCH3), 3.02 (2H, t, 3J = 8.0
Hz, CH2), 3.34 (2H, t, 3J = 8.0 Hz, CH2I), 6.88 (1H, s, CHpyrrole), 7.28 –
7.30 (2H, m, ArH), 7.41 – 7.42 (3H, m, ArH) ppm. 13C NMR (100 MHz,
CDCl3) δ: 6.1 (CH2I), 31.5 (3xCH3), 33.6 (CH2), 58.2 (C(CH3)3), 71.9 (CI),
117.2 (CHpyrrole), 123.0 (ArC), 127.8 (ArC), 128.3 (ArC), 132.5 (ArC),
135.2 (ArC), 136.4 (ArC) ppm. HRMS (ESI): M+H, found 479.9683.
C16H20127I2N requires 479.9680.
Method C. Synthesis of 2-(1-tert-butyl-4-iodo-5-phenyl-1H-pyrrol-3-
yl)ethyl acetate (2p) and 2-(1-tert-butyl-2,4-diiodo-5-phenyl-1H-pyrrol-3-
1-Butyl-3-iodo-4-(2-iodoethyl)-2-phenyl-1H-pyrrole (2e)
yl)ethyl
acetate
(4).
A
solution
of
1-(phenylethynyl)
cyclopropanecarbaldehyde (1b) (67 mg, 0.4 mmol) and tert-butylamine (1
mL, 9.5 mmol, 24 eq.) in acetonitrile (2 mL) was irradiated in closed
vessel in scientific microwave oven (CEM Focused Microwave™
Synthesis System, Discover® SP) at 150 W, 120 °C for 20 min. Then the
solvent and the tert-butylamine were evaporated under reduced pressure.
The residue was dissolved in chloroform (2 mL) and added to a solution
of freshly prepared solution of acetyl hypoiodite[17] (2 eq.) in chloroform (1
mL). The resulting mixture was stirred in the dark at room temperature for
20 min. After reaction was finished, the solution was diluted with DCM
and was washed with saturated sodium thiosulfate solution (2 x 10 mL),
saturated sodium bicarbonate solution (2 x 10 mL) and brine (2 x 10 mL).
The organic layer was dried over sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by flash column
chromatography eluting with hexane - ethyl acetate (20 - 1) mixture.
Colorless oil. Yield 0.11 g, 46 %
1H NMR (400 MHz, CDCl3) δ: 0.79 (3H, t, 3J = 7.6 Hz, CH3), 1.15 (2H,
sexst, 3J = 7.6 Hz, CH2n-Bu), 1.52 (2H, p, 3J = 7.6 Hz, CH2n-Bu), 3.02 (2H, t,
3J = 8.0 Hz, CH2), 3.34 (2H, t, 3J = 8.0 Hz, CH2I), 3.78 (2H, t, 3J = 7.2 Hz,
CH2n-Bu), 6.72 (1H, s, CHpyrrole), 7.32 – 7.34 (2H, m, ArH), 7.34 – 7.46 (3H,
m, ArH) ppm. 13C NMR (100 MHz, CDCl3) δ: 6.2 (CH2I), 13.5 (CH3), 19.6
(CH2n-Bu), 33.3 (CH2), 33.4 (CH2n-Bu), 48.0 (CH2chex), 66.8 (CI), 119.6
(CHpyrrole), 124.7 (ArC), 128.1 (ArC), 128.3 (ArC), 130.8 (ArC), 132.5
(ArC), 135.4 (ArC) ppm. HRMS (ESI): M+H, found 479.9689. C16H20I2N
requires 479.9685.
1-Tert-butyl-3-iodo-4-(2-iodoethyl)-2-p-tolyl-1H-pyrrole (2f)
White solid, m.p. 129 – 130 оC. Yield 0.143 g, 58 %
1H NMR (400 MHz, CDCl3) δ: 1.38 (9H, s, 3xCH3), 2.42 (3H, s, CH3),
3.01 (2H, t, 3J = 8.0 Hz, CH2), 3.33 (2H, t, 3J = 8.0 Hz, CH2I), 6.86 (1H, s,
CHpyrrole), 7.16 (2H, d, 3J = 8.0 Hz, ArH), 7.22 (2H, d, 3J = 8.0 Hz, ArH)
ppm. 13C NMR (100 MHz, CDCl3) δ: 6.1 (CH2I), 21.4 (CH3), 31.5 (3xCH3),
33.6 (CH2), 58.1 (C(CH3)3), 72.0 (CI), 117.1 (CHpyrrole), 122.9 (ArC), 128.6
(ArC), 132.3 (ArC), 133.3 (ArC), 135.3 (ArC), 138.1 (ArC) ppm. HRMS
(ESI): M+H, found 493.9841. C17H22I2N requires 493.9836.
Method D. A solution of corresponding cyclopropanecarbaldehyde 1 (0.5
mmol) and amine (1 mmol) in appropriate alcohol (2 mL) was irradiated
in closed vessel in scientific microwave oven (CEM Focused
Microwave™ Synthesis System, Discover® SP) at 100 – 150 W, 100 –
120 °C for 50 min. After all starting material was consumed; the solvent
was evaporated under reduced pressure. The residue was purified by
flash column chromatography eluting with hexane - ethyl acetate (20 : 1)
mixture.
1-Benzyl-3-iodo-4-(2-iodoethyl)-2-p-tolyl-1H-pyrrole (2g)
1-Benzyl-4-(2-chloroethyl)-2-(4-methoxyphenyl)-1H-pyrrole (2a)
Colorless oil. Yield 0.155 g, 59 %
1H NMR (400 MHz, CDCl3) δ: 2.39 (3H, s, CH3), 3.03 (2H, t, 3J = 8.0 Hz,
CH2), 3.35 (2H, t, 3J = 8.0 Hz, CH2I), 4.98 (2H, s, CH2Ph), 6.69 (1H, s,
CHpyrrole), 6.97 (2H, d, 3J = 6.4 Hz, ArH), 7.16 – 7.21 (4H, m, ArH), 7.25 –
7.30 (3H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3) δ: 6.1 (CH2I), 21.3
(CH3), 33.3 (CH2), 51.7 (CH2Ph), 67.3 (CI), 120.0 (CHpyrrole), 125.2 (ArC),
Yellowish oil. Yield 47.1 mg, 29 %
1H NMR (400 MHz, CDCl3) δ: 2.99 (2H, t, J = 7.6 Hz, CH2), 3.72 (2H, t,
3
3J = 7.6 Hz, CH2Cl), 3.83 (3H, s, OCH3), 5.09 (2H, s, CH2Ph), 6.13 (1H, s,
3
CHpyrrole), 6.60 (1H, br.s, NCHpyrrole), 6.90 (2H, d, J = 8.8 Hz, ArH), 7.05
(2H, d, 3J = 7.2 Hz, ArH), 7.26 (2H, d, 3J = 8.4 Hz, ArH), 7.28 – 7.35 (3H,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600985
FULL PAPER
126.7 (ArC), 127.5 (ArC), 128.6 (ArC), 129.0 (2xArC), 130.7 (ArC), 136.0
(ArC), 137.9 (ArC), 138.1 (ArC) ppm. HRMS (ESI): M+H, found 527.9689.
C20H20127I2N requires 527.9685.
s, CHpyrrole), 7.07 – 7.09 (3H, m, ArH), 7.10 (4H, br.s, ArH), 7.13 – 7.16
(2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3) δ: 21.3 (CH3), 30.7 (CH2),
31.7 (3xCH3), 45.0 (CH2Cl), 57.9 (C(CH3)3), 106.7 (ArC), 117.8 (CHpyrrole),
121.3 (ArC), 125.0 (ArC), 128.1 (ArC), 128.7 (ArC), 131.9 (ArC), 132.6
(ArC), 135.3 (ArC), 137.7 (ArC), 139.2 (ArC) ppm. HRMS (ESI): M+H,
found 432.0982. C23H2735ClNSe requires 432.0990.
1-Cyclohexyl-3-iodo-4-(2-iodoethyl)-2-p-tolyl-1H-pyrrole (2h)
Colorless oil. Yield 0.166 g, 64 %
4-(2-Azidoethyl)-1-cyclohexyl-3-iodo-2-phenyl-1H-pyrrole (2n)
1H NMR (400 MHz, CDCl3) δ: 1.14 – 1.18 (2H, m, CH2chex), 1.52 – 1.65
(4H, m, CH2chex), 1.78 – 1.80 (2H, m, CH2chex), 1.91 (2H, d, 2J = 12.0 Hz,
CH2chex), 2.43 (3H, s, CH3), 3.03 (2H, t, 3J = 8.0 Hz, CH2), 3.34 (2H, t, 3J
= 8.0 Hz, CH2I), 3.78 (1H, tt, 3J = 12.0 Hz, 3J = 3.6 Hz, CHchex), 6.79 (1H,
Yellowish oil. Yield 0.118 g, 56 %
R (KBr): υmax = 2098 (N=N+=N-) cm-1.
3
s, CHpyrrole), 7.20 (2H, d, 3J = 8.0 Hz, ArH), 7.26 (2H, d, J = 8.0 Hz, ArH)
1H NMR (400 MHz, CDCl3) 1.16 – 1.20 (2H, m, CH2chex), 1.53 – 1.64 (4H,
m, CH2chex), 1.78 – 1.80 (2H, m, CH2chex), 1.92 (2H, d, 2J = 12.4 Hz,
ppm. 13C NMR (100 MHz, CDCl3) δ: 6.1 (CH2I), 21.4 (CH3), 25.3
(CH2chex), 25.7 (CH2chex), 33.6 (CH2), 34.6 (CH2chex), 56.5 (CHchex), 66.5
(CI), 115.8 (CHpyrrole), 124.6 (ArC), 129.0 (ArC), 129.6 (ArC), 130.7 (ArC),
134.8 (ArC), 137.8 (ArC) ppm. HRMS (ESI): M+H, found 519.9987.
C19H24127I2N requires 519.9993.
3
CH2chex), 2.77 (2H, t, 3J = 7.2 Hz, CH2), 3.47 (2H, t, J = 7.2 Hz, CH2N3),
3.77 (1H, tt, 3J = 12.0 Hz, 3J = 3.6 Hz, CHchex), 6.80 (1H, s, CHpyrrole), 7.31
– 7.35 (2H, m, ArH), 7.39 – 7.49 (3H, m, ArH) ppm. 13C NMR (100 MHz,
CDCl3) δ: 25.2 (CH2chex), 25.7 (CH2chex), 28.4 (CH2), 34.6 (CH2chex), 51.4
(CH2N3), 56.6 (CHchex), 67.1 (CI), 116.3 (CHpyrrole), 121.3 (ArC), 128.1
(ArC), 128.3 (ArC), 130.9 (ArC), 132.7 (ArC), 134.9 (ArC) ppm. HRMS
(ESI): M+H, found 421.0901. C18H22127IN4 requires 421.0884.
1-Tert-butyl-4-(2-chloroethyl)-3-iodo-2-phenyl-1H-pyrrole (2i)
Brownish solid, m.p. 147 – 148 оC. Yield 0.101 g, 52 %
1H NMR (400 MHz, CDCl3) δ: 1.38 (9H, s, 3xCH3), 2.91 (2H, t, 3J = 8.0
4-(2-Azidoethyl)-1-tert-butyl-3-iodo-2-p-tolyl-1H-pyrrole (2o)
Yellowish solid, m.p. 92 – 93 оC. Yield 0.155 g, 76 %
IR (KBr): υmax = 2096 (N=N+=N-) cm-1.
3
Hz, CH2), 3.69 (2H, t, J = 8.0 Hz, CH2Cl), 6.88 (1H, s, CHpyrrole), 7.27 –
7.30 (2H, m, ArH), 7.41 – 7.42 (3H, m, ArH) ppm. 13C NMR (100 MHz,
CDCl3) δ: 31.5 (3xCH3), 32.3 (CH2), 44.3 (CH2Cl), 58.2 (C(CH3)3), 72.4
(CI), 117.6 (CHpyrrole), 120.0 (ArC), 127.8 (ArC), 128.3 (ArC), 132.5 (ArC),
135.2 (ArC), 136.5 (ArC) ppm. HRMS (ESI): M+H, found 388.0328.
C16H2035Cl127IN requires 388.0323.
1H NMR (400 MHz, CDCl3) δ: 1.39 (9H, s, 3xCH3), 2.42 (3H, s, CH3),
2.75 (2H, t, 3J = 7.2 Hz, CH2), 3.46 (2H, t, 3J = 7.2 Hz, CH2N3), 6.87 (1H,
3
s, CHpyrrole), 7.17 (2H, d, 3J = 8.0 Hz, ArH), 7.22 (2H, d, J = 8.0 Hz, ArH)
4-(2-Chloroethyl)-1-cyclohexyl-3-iodo-2-p-tolyl-1H-pyrrole (2j)
White solid, m.p. 118 – 119 оC. Yield 0.203 g, 95 %
ppm. 13C NMR (100 MHz, CDCl3) δ: 21.4 (CH3), 28.4 (CH2), 31.5 (3xCH3),
51.4 (CH2N3), 58.1 (C(CH3)3), 72.5 (CI), 117.5 (CHpyrrole), 119.4 (ArC),
128.6 (ArC), 132.3 (ArC), 133.4 (ArC), 135.4 (ArC), 138.1 (ArC) ppm.
HRMS (ESI): M+H, found 409.0890. C17H22N4I requires 409.0884.
1H NMR (400 MHz, CDCl3) 1.16 – 1.18 (2H, m, CH2chex), 1.52 – 1.65 (4H,
m, CH2chex), 1.78 – 1.79 (2H, m, CH2chex), 1.91 (2H, d, 2J = 12.0 Hz,
CH2chex), 2.43 (3H, s, CH3), 2.93 (2H, t, 3J = 7.6 Hz, CH2), 3.69 (2H, t, 3J
= 7.6 Hz, CH2Cl), 3.78 (1H, tt, 3J = 12.0 Hz, 3J = 3.6 Hz, CHchex), 6.79
2-(1-tert-butyl-4-iodo-5-phenyl-1H-pyrrol-3-yl)ethyl acetate (2p)
3
(1H, s, CHpyrrole), 7.20 (2H, d, 3J = 8.0 Hz, ArH), 7.26 (2H, d, J = 8.0 Hz,
Yellow oil. Yield 43.2 mg, 21 %
ArH) ppm. 13C NMR (100 MHz, CDCl3) δ: 21.4 (CH3), 25.3 (CH2chex), 25.7
(CH2chex), 32.4 (CH2), 34.6 (CH2chex), 44.3 (CH2Cl), 56.5 (CHchex), 66.9
(CI), 116.2 (CHpyrrole), 121.6 (ArC), 129.1 (ArC), 129.6 (ArC), 130.7 (ArC),
134.8 (ArC), 137.9 (ArC) ppm. HRMS (ESI): M+H, found 428.0641.
C19H24ClIN requires 428.0642.
IR (KBr): υmax = 1738 (C=O) cm-1.
1H NMR (400 MHz, CDCl3) δ: 1.37 (9H, s, 3xCH3), 2.09 (COCH3), 2.77
3
(2H, t, 3J = 7.6 Hz, CH2CH2O), 4.25 (2H, t, J = 7.6 Hz, CH2CH2O), 6.83
(1H, s, CHpyrrole), 7.27 – 7.29 (2H, m, ArH), 7.40 – 7.41 (3H, m, ArH) ppm.
13C NMR (100 MHz, CDCl3) δ: 21.1 (COCH3), 28.0 (CH2CH2O), 31.6
(3xCH3), 58.1 (C(CH3)3), 64.4 (CH2CH2O), 72.9 (CI), 117.2 (CHpyrrole),
119.4 (ArC), 127.8 (ArC), 128.3 (ArC), 132.6 (ArC), 135.1 (ArC), 136.6
(ArC), 171.1 (CO) ppm. HRMS (ESI): M+H, found 412.0771.
C18H23127INO2 requires 412.0768.
4-(2-Chloroethyl)-3-iodo-1-isopropyl-2-p-tolyl-1H-pyrrole (2k)
White solid, m.p. 121 – 122 оC. Yield 0.106 g, 55 %
1H NMR (400 MHz, CDCl3) 1.30 (6H, d, 3J = 6.8 Hz, CH3i-Pr), 2.42 (3H, s,
CH3), 2.93 (2H, t, 3J = 7.6 Hz, CH2), 3.69 (2H, t, 3J = 8.0 Hz, CH2Cl), 4.23
(1H, sept, 3J = 6.8 Hz, CHi-Pr), 6.79 (1H, s, CHpyrrole), 7.20 (2H, d, 3J = 8.0
Hz, ArH), 7.26 (2H, d, 3J = 8.0 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
δ: 21.3 (CH3), 23.8 (CH3i-Pr), 32.4 (CH2), 44.3 (CH2Cl), 48.6 (CHi-Pr), 67.0
(CI), 115.3 (CHpyrrole), 122.0 (ArC), 129.1 (ArC), 129.7 (ArC), 130.8 (ArC),
134.9 (ArC), 138.0 (ArC) ppm. HRMS (ESI): M+H, found 388.0326.
C16H2035ClIN requires 388.0323.
1-Benzyl-4-(2-methoxyethyl)-2-(4-methoxyphenyl)-1H-pyrrole (2r)
Yellowish wax. Yield 78.6 mg, 49 %
1H NMR (400 MHz, CDCl3) δ: 2.81 (2H, t, 3J = 7.2 Hz, CH2CH2OCH3),
3.41 (3H, s, CH2CH2OCH3), 3.63 (2H, t, 3J = 7.2 Hz, CH2CH2OCH3), 3.81
(3H, s, OCH3), 5.06 (2H, s, CH2Ph), 6.12 (1H, d, 4J = 1.2 Hz, CHpyrrole),
3
3
6.57 (1H, br.s, NCHpyrrole), 6.87 (2H, d, J = 8.4 Hz, ArH), 7.05 (2H, d, J
= 7.6 Hz, ArH), 7.24 – 7.33 (5H, m, ArH) ppm. 13C NMR (100 MHz,
CDCl3) δ: 27.5 (CH2CH2OCH3), 50.3 (CH2Ph), 55.1 (OCH3), 58.5
(CH2CH2OCH3), 73.7 (CH2CH2OCH3), 108.7 (CHpyrrole), 113.7 (ArC),
120.1 (NCHpyrrole), 120.4 (ArC), 125.8 (ArC), 126.4 (ArC), 127.1 (ArC),
128.5 (ArC), 130.0 (ArC), 134.5 (ArC), 139.0 (ArC), 158.6 (ArC) ppm.
HRMS (ESI): M+H, found 322.1804. C21H24NO2 requires 322.1802.
1-Tert-butyl-4-(2-chloroethyl)-2-phenyl-3-(phenylselanyl)-1H-pyrrole
(2l)
White solid, m.p. 122 – 123 оC. Yield 0.111 g, 53 %
1H NMR (400 MHz, CDCl3) δ: 1.44 (9H, s, 3xCH3), 2.95 (2H, t, 3J = 7.6
3
Hz, CH2), 3.60 (2H, t, J = 7.6 Hz, CH2Cl), 6.97 (1H, s, CHpyrrole), 7.06 –
7.10 (3H, m, ArH), 7.12 – 7.16 (2H, m, ArH), 7.20 – 7.23 (2H, m, ArH),
7.27 – 7.29 (2H, m, ArH), 7.34 (1H, t, 3J = 7.2 Hz, ArH) ppm. 13C NMR
(100 MHz, CDCl3) δ: 30.7 (CH2), 31.7 (3xCH3), 45.0 (CH2Cl), 58.0
(C(CH3)3), 106.8 (ArC), 117.9 (CHpyrrole), 121.4 (ArC), 125.0 (ArC), 127.3
(ArC), 128.0 (ArC), 128.1 (ArC), 128.7 (ArC), 132.1 (ArC), 135.3 (ArC),
135.7 (ArC), 139.1 (ArC) ppm. HRMS (ESI): M+H, found 418.0830.
C22H2535ClNSe requires 418.0834.
1-Tert-butyl-4-(2-phenoxyethyl)-2-phenyl-1H-pyrrole (2s)
White solid, m.p. 72 – 73 оC. Yield 89.3 mg, 56 %
1H NMR (400 MHz, CDCl3) δ: 1.47 (9H, s, 3xCH3), 3.04 (2H, t, 3J = 7.4
Hz, CH2CH2OPh), 3.04 (2H, t, 3J = 7.5 Hz, CH2CH2OPh), 6.01 (1H, d, 4J
= 1.9 Hz, CHpyrrole), 6.84 (1H, d, 4J = 1.8 Hz, NCHpyrrole), 6.97 – 7.01 (3H,
m, ArH), 7.32 – 7.36 (2H, m, ArH), 7.38 – 7.39 (3H, m, ArH), 7.45 – 7.47
(2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3) δ: 27.2 (CH2CH2OPh),
31.9 (3xCH3), 56.9 (C(CH3)3), 68.8 (CH2CH2OPh), 112.2 (CHpyrrole), 114.5
(ArC), 116.8 (ArC), 117.0 (NCHpyrrole), 120.4 (ArC), 127.3 (ArC), 127.4
(ArC), 129.3 (ArC), 131.6 (ArC), 133.8 (ArC), 137.3 (ArC), 159.0 (ArC)
ppm. HRMS (ESI): M+H, found 320.2011. C22H25NO requires 320.2014.
1-Tert-butyl-3-iodo-4-(2-iodoethyl)-2-p-tolyl-1H-pyrrole (2m)
White solid, m.p. 137 – 138 оC. Yield 0.14 g, 65 %
1H NMR (400 MHz, CDCl3) δ: 1.44 (9H, s, 3xCH3), 2.37 (3H, s, CH3),
2.94 (2H, t, 3J = 7.6 Hz, CH2), 3.58 (2H, t, 3J = 7.6 Hz, CH2Cl), 6.96 (1H,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600985
FULL PAPER
1-Tert-butyl-4-(2-propoxyethyl)-2-p-tolyl-1H-pyrrole (2t)
CHH2CH(OCH3)(CH2)3), 2.74 – 2.81 (1H, m, CH2CH(OCH3)(CH2)2CHH),
2.84 – 2.90 (2H, m, CHHCH(OCH3)(CH2)2CHH), 3.35 (1H, tt, 3J = 9.0 Hz,
3
3J = 2.8 Hz, CH2CH(OCH3)(CH2)3), 3.41 (3H, s, OCH3), 7.30 (1H, t, J =
Yellowish oil. Yield 94.2 mg, 63 %
7.4 Hz, ArH), 7.40 (2H, t, 3J = 7.6 Hz, ArH), 7.93 – 7.95 (2H, m, ArH) ppm.
1H NMR (400 MHz, CDCl3) δ: 0.94 (3H, t, 3J = 7.6 Hz, OCH2CH2CH3),
1.41 (9H, s, 3xCH3), 1.63 (2H, sexst, 3J = 7.2 Hz, OCH2CH2CH3), 2.39
(3H, s, CH3), 2.77 (2H, t, 3J = 7.6 Hz, CH2CH2O), 3.44 (2H, t, 3J = 6.8 Hz,
OCH2CH2CH3), 3.64 (2H, t, 3J = 7.6 Hz, CH2CH2O), 5.87 (1H, d, 4J = 2.0
Hz, CHpyrrole), 6.72 (1H, d, 3J = 2.0 Hz, NCHpyrrole), 7.14 (2H, d, 3J = 7.6
Hz, ArH), 7.27 (2H, d, 3J = 8.0 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
δ: 10.6 (OCH2CH2CH3), 21.2 (CH3), 22.9 (OCH2CH2CH3), 27.6
(CH2CH2O), 31.9 (3xCH3), 56.8 (C(CH3)3), 71.9 (CH2CH2O), 72.5
(OCH2CH2CH3), 112.2 (CHpyrrole), 116.6 (NCHpyrrole), 117.5 (ArC), 128.0
(ArC), 131.5 (ArC), 133.6 (ArC), 134.5 (ArC), 137.0 (ArC) ppm. HRMS
(ESI): M+H, found 300.2320. C20H30NO requires 300.2322.
13C NMR (100 MHz, CDCl3) δ: 22.3 (CH2CH(OCH3)CH2CH2CH2), 28.3
(CH2CH(OCH3)CH2CH2CH2),
31.9
(CH2CH(OCH3)(CH2)3),
35.5
(CH2CH(OCH3)CH2(CH2)2), 56.3 (OCH3), 70.5 (CI), 78.9 (CH2CH(OCH3)
(CH2)3), 119.7 (ArC), 125.9 (ArC), 127.6 (ArC), 128.3 (ArC), 130.6 (ArC),
148.7 (ArC), 152.7 (ArC) ppm. HRMS (ESI): M+H, found 369.0358.
C16H18127I2O requires 369.0351.
3-Iodo-4-(2-iodoethyl)-2-phenylfuran (8)
White solid, m.p. 97 – 99 оC. Yield 23.2 mg, 10 %
1H NMR (400 MHz, CDCl3) δ: 1.67 – 1.77 (1H, m, CH2CHICH2CH2CH2),
1-Cyclohexyl-4-(2-methoxyethyl)-2-p-tolyl-1H-pyrrole (2u)
1.84 – 1.93 (1H, m, CH2CHICH2CH2CH2), 2.30 – 2.39 (1H, m,
CH2CHICH2(CH2)2), 2.41 – 2.48 (1H, m, CH2CHICH2(CH2)2), 2.79 – 2.91
(1H, m, CH2CHICH2(CH2)2), 3.13 (1H, dd, 2J = 15.8 Hz, 3J = 9.0 Hz,
CH2CHI(CH2)3), 3.22 (1H, dd, 2J = 15.8 Hz, 3J = 3.2 Hz, CH2CHI(CH2)3),
4.54 (2H, tt, 3J = 9.0 Hz, 3J = 3.0 Hz, CH2CHI(CH2)3), 7.31 (1H, t, 3J = 7.4
Hz, ArH), 7.41 (2H, t, 3J = 7.6 Hz, ArH), 7.95 – 7.97 (2H, m, ArH) ppm.
13C NMR (100 MHz, CDCl3) δ: 26.5 (CH2CHICH2CH2CH2), 28.2
(CH2CHI(CH2)2CH2), 31.0 (CH2CHI(CH2)3), 39.5 (CH2CHI(CH2)3), 43.2
(CH2CHICH2(CH2)2), 69.4 (CI), 123.7 (ArC), 125.9 (ArC), 127.7 (ArC),
128.3 (ArC), 130.4 (ArC), 148.6 (ArC), 153.2 (ArC) ppm. HRMS (ESI):
M+H, found 464.9214. C15H15127I2O requires 464.9212.
Yellowish oil. Yield 0.104 g, 70 %
1H NMR (400 MHz, CDCl3) δ: 1.19 – 1.27 (2H, m, CH2chex), 1.60 – 1.70
(4H, m, CH2chex), 1.83 (2H, d, 2J = 12.8 Hz, CH2chex), 2.00 (2H, d, 2J =
3
12.8 Hz, CH2chex), 2.41 (3H, s, CH3), 2.81 (2H, t, J = 7.2 Hz, CH2CH2O),
3.41 (3H, s, OCH3), 3.63 (2H, t, 3J = 7.2 Hz, CH2CH2O), 3.98 (1H, tt, 3J =
12.0 Hz, 3J = 3.6 Hz, CHchex), 6.00 (1H, d, 4J = 1.6 Hz, CHpyrrole), 6.70 (1H,
3
3
br.s, NCHpyrrole), 7.21 (2H, d, J = 8.4 Hz, ArH), 7.25 (2H, d, J = 7.6 Hz,
ArH) ppm. 13C NMR (100 MHz, CDCl3) δ: 21.1 (CH3), 25.4 (CH2chex), 25.9
(CH2chex), 27.6 (CH2CH2O), 34.9 (CH2chex), 55.0 (CHchex), 58.5 (OCH3),
73.8 (CH2CH2O), 108.3 (CHpyrrole), 115.8 (NCHpyrrole), 119.6 (ArC), 128.9
(ArC), 129.0 (ArC), 131.0 (ArC), 133.6 (ArC), 136.3 (ArC) ppm. HRMS
(ESI): M+H, found 298.2162. C20H28NO requires 298.2165.
Keywords: pyrrole • cyclization • cyclopropyl-tethered •
alkynylimines • 5-endo-dig
2-(1-Tert-butyl-2,4-diiodo-5-phenyl-1H-pyrrol-3-yl)ethyl acetate (4)
[1]
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264. (b) I. B. Seiple, S. Su, I. S. Young, A. Nakamura, J. Yamaguchi, L.
Jørgensen, R. A. Rodriguez, D. P. O Malley, T. Gaich, M. Kçck, P. S.
Baran, J. Am. Chem. Soc. 2011, 133, 14710. (c) J. T. Gupton, Pyrrole
Natural Products with Antitumor Properties, in: Heterocyclic Antitumor
Antibiotics, Topics in Heterocyclic Chemistry, (Ed.: M. Lee), Vol. 2,
Springer, Heidelberg, Berlin, 2006, pp 53–92. (d) M. Movassaghi, D. S.
Siegel, S. Han, Chem. Sci. 2010, 1, 561. (e) D. X. Hu, D. M. Withall, G.
L. Challis, R. J. Thomson, Chem. Rev., 2016, 116, 7818. (f) X.-B. Ding,
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M. D. Clift, R. J. Thomson, J. Am. Chem. Soc., 2009, 131, 14579. (h)
S.-E. Motuhi, M. Mehiri, C. E. Payri, S. L. Barre, S. Bach, Mar. Drugs
2016, 14, 58.
Yellow oil. Yield 51 mg, 19 %
IR (KBr): υmax = 1739 (C=O) cm-1.
1H NMR (400 MHz, CDCl3) δ: 1.57 (9H, s, 3xCH3), 2.09 (COCH3), 2.92
(2H, t, 3J = 7.6 Hz, CH2CH2O), 4.17 (2H, t, J = 7.6 Hz, CH2CH2O), 7.19
3
– 7.22 (2H, m, ArH), 7.36 – 7.38 (3H, m, ArH) ppm. 13C NMR (100 MHz,
CDCl3) δ: 21.2 (COCH3), 31.5 (CH2CH2O), 33.2 (3xCH3), 62.1 (C(CH3)3),
63.3 (CH2CH2O), 67.2 (CI), 73.3 (CI), 127.9 (ArC), 128.2 (2xArC), 131.6
(ArC), 138.8 (ArC), 140.4 (ArC), 171.0 (CO) ppm. HRMS (ESI): M+H,
found 537.9745. C18H22127I2NO2 requires 537.9734.
General procedure for the synthesis of furanes 5, 7 and 8.
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1b (85 mg, 0.5 mmol) or 1-(phenylethynyl)bicyclo[4.1.0]heptan-2-one 6
(105 mg, 0.5 mmol) in dichloromethane (2 mL) methanol (0.202 mL, 5
mmol) and molecular iodine (0.127 g, 0.5 mmol) were added. The
resulting solution was stirred at room temperature and the progress of
reaction was monitored by TLC. After all starting material was consumed,
the solvent was evaporated under reduced pressure. The residue was
purified by flash column chromatography eluting with hexane/ethyl
acetate (20 : 1) mixture.
[3]
[4]
3-Iodo-4-(2-iodoethyl)-2-phenylfuran (5)
Yellow oil. Yield 0.157 g, 74 %
3
1H NMR (400 MHz, CDCl3) δ: 3.00 (2H, t, J = 7.5 Hz, CH2), 3.36 (2H, t,
3J = 7.5 Hz, CH2I), 7.36 (1H, tt, 3J = 7.2 Hz, 4J = 2.0 Hz, ArH), 7.42 – 7.46
(3H, m, ArH and CHfuran), 7.96 – 7.99 (2H, m, ArH) ppm. 13C NMR (100
MHz, CDCl3) δ: 3.6 (CH2I), 31.0 (CH2), 66.5 (CI), 126.3 (ArC), 128.3
(ArC), 128.4 (ArC), 128.6 (ArC), 130.1 (ArC), 139.0 (CHfuran), 152.2 (ArC)
ppm. HRMS (ESI): M+H, found 424.8902. C12H11127I2O requires
424.8899.
[5]
3-Iodo-5-methoxy-2-phenyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan
(7)
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Colorless oil. Yield 0.151 g, 82 %
1H NMR (400 MHz, CDCl3) δ: 1.59
–
1.68 (1H, m,
CH2CH(OCH3)CH2CHHCH2),
CH2CH(OCH3)CHH(CH2)2),
CH2CH(OCH3)CH2CHHCH2),
1.75
1.94
2.14
–
–
–
1.83
2.03
2.19
(1H,
(1H,
(1H,
m,
m,
m,
[8]
CH2CH(OCH3)CHH(CH2)2), 2.55 (1H, dd, 2J = 15.3 Hz, 3J = 9.2 Hz,
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European Journal of Organic Chemistry
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Unusual tandem 1,3-addition-5-endo-
dig cyclisation of cyclopropyl-tethered
alkynyl imines to polysubstituted
pyrroles
Synthetic methods
Aurelija Urbanaitė, Inga Čikotienė*
Page No. – Page No.
Synthesis of Polysubstituted Pyrroles
via Tandem 1,3-Addition -5-Endo-Dig
Cyclisation of 1-(1-Alkynyl)-
Cyclopropyl Imines
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