Efficient preparation of [1-15N]-3-cyano-4-methyl-1H-pyrrole by a Wittig-based strategy

Article abstract of DOI:10.1002/ejoc.200800079

3-Cyano-4-methyl-1H-pyrrole (1) was prepared by a new Wittig procedure from simple, commercially available starting materials in four steps with an overall yield of 39%. Similarly, [1-¹⁵N]-3-cyano-4-methyl-1H-pyrrole (1a) was prepared starting from [¹⁵N]-phthalimide. In this synthesis, Wittig coupling was used to form the central C-C bond of intermediate 6, which has nitrile and methyl substituents. Upon deprotection and cyclization pyrrole 1 is obtained directly in one pot. This scheme also allows stable isotope incorporation at any position or a combination of positions. 3-Cyano-4-methyl-1H-pyrrole was converted into the novel 1-benzyl-3-cyano-4- methylpyrrole and the novel 4-methyl-1H-pyrrole-3-aldehyde. It is clear that this novel Wittig procedure has a wide scope that will allow the easy preparation of many new pyrrole systems. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800079

FULL PAPER
DOI: 10.1002/ejoc.200800079
Efficient Preparation of [1-15N]-3-Cyano-4-methyl-1H-pyrrole by a Wittig-
Based Strategy
Prativa B. S. Dawadi*[a] and Johan Lugtenburg[a]
Keywords: Nitrogen heterocycles / Mass spectrometry / NMR spectroscopy
3-Cyano-4-methyl-1H-pyrrole (1) was prepared by a new
Wittig procedure from simple, commercially available start-
ing materials in four steps with an overall yield of 39%. Simi-
at any position or a combination of positions. 3-Cyano-4-
methyl-1H-pyrrole was converted into the novel 1-benzyl-3-
cyano-4-methylpyrrole and the novel 4-methyl-1H-pyrrole-
larly, [1-15N]-3-cyano-4-methyl-1H-pyrrole (1a) was pre- 3-aldehyde. It is clear that this novel Wittig procedure has a
pared starting from [15N]-phthalimide. In this synthesis, Wit-
tig coupling was used to form the central C–C bond of inter-
mediate 6, which has nitrile and methyl substituents. Upon
deprotection and cyclization pyrrole 1 is obtained directly in
one pot. This scheme also allows stable isotope incorporation
wide scope that will allow the easy preparation of many new
pyrrole systems.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
starting from the commercially available [15N]-phthalimide,
and the target molecule was fully characterized spectro-
scopically.
Introduction
The substituted pyrrole ring is the basic building block
in a number of important biological compounds, including
vitamin B12, chlorophyll, haem, etc.[1,2] Many pyrroles have
important biological and pharmaceutical properties.[3]
Access to site-directed stable-isotope-enriched (13C and
15N) sites in these molecules will allow these compounds to
be investigated through the use of isotope-sensitive tech-
niques and without perturbation at the atomic level to de-
termine the role that these systems play in biological fields.
Only very few 15N- and 13C-enriched pyrroles are known
that have isotope incorporation at only one position.[4] [1-
15N]-3-Cyano-4-methylpyrrole is the target of our efforts to
find a simple synthetic scheme that allows this system to be
prepared with a stable isotope label at any position or a
combination of positions up to the uniformly isotope-
labeled form.
Results and Discussion
Synthesis
The conversions in Scheme 1 were first optimized
through reactions with molecules in nonisotopically en-
riched forms. The strategy depicted in Scheme 1 starts with
β-phthalimidopropionitrile (4; 4.05 g, 20 mmol), which can
be prepared efficiently by the Michael addition of phthal-
imide (2; 3.0 g, 20 mmol) to acrylonitrile (3; 10 mL) in the
presence of potassium phthalimide (0.3 g, 1.6 mmol).[5]
Treatment of product 4 in ethanol with hydrazine hydrate
yielded 3-aminopropionitrile in ethanol solution and 2,3-
dihydrophthalazine-1,4-dione as a solid product, which was
separated by simple filtration. The fumaric acid (ethanol
solution) was added to the solution of 3-aminopropionitrile
to obtain 3-aminopropionitrile fumarate (2.30 g, 18 mmol).
The fumarate product was further treated with benzophe-
none imine (3.30 g, 18 mmol) to obtain 3-[(diphenylmethyl-
ene)amino]propionitrile (5; 3.51 g, 15 mmol) as a light-yel-
low crystalline product by a known procedure.[6]
Treatment of 5 (3.51 g, 15 mmol) with lithium diisopro-
pylamide (LDA, 3 equiv.) in THF at –70 °C followed by the
addition of diethyl chlorophosphate (2.58 g, 15 mmol) and
subsequently 1,1-dimethoxyacetone (1.90 g, 16 mmol)
whilst stirring resulted in an E/Z mixture of 2-
{[(diphenylmethylene)amino]methyl}-4,4-dimethoxy-3-meth-
ylbut-2-enenitrile (6) in a 3:2 ratio. The E/Z mixture of 6
We have chosen [1-15N]-3-cyano-4-methylpyrrole as a
3,4-disubstituted pyrrole with two different substituents at
the 3,4-positions, because these systems are not easily
accessible with known synthetic procedures. They are also
essential building blocks to prepare biologically important
protoporphyrins, chlorophyll, and vitamin B12. We have
first pioneered a synthetic scheme to obtain 3-cyano-4-
methylpyrrole with natural abundance starting materials
that are also commercially available in the various stable
isotope-enriched forms or can be prepared in stable isotope-
enriched forms by simple synthetic procedures. The study
is completed by preparing [1-15N]-3-cyano-4-methylpyrrole
[a] Leiden Institute of Chemistry, Leiden University,
P. O. Box 9502, 2300 RA Leiden, The Netherlands
E-mail: p.dawadi@chem.leidenuniv.nl
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Eur. J. Org. Chem. 2008, 2288–2292

[1-15N]-3-Cyano-4-methyl-1H-pyrroles by a Wittig-Based Strategy
Scheme 1. Preparation of 3-cyano-4-methyl-1H-pyrrole (1) and [1-15N]-3-cyano-4-methyl-1H-pyrrole (1a) starting from phthalimide (2)
and [15N]-phthalimide (2a), respectively.
was purified by column chromatography on silica gel 60 enriched form. However, we prepared 1-chloroacetone in
with ethyl acetate/hexane (1:3) as eluent. The signals of the any isotopically labeled form,[10] which can be converted
methyl group and methylene group in minor compound 6 into the corresponding 2-oxopropan-1-al.[11]
showed an NOE interaction in the 1H NMR spectra, which
establishes this compound as the (Z)-6 isomer and thus the
major as the (E)-6 isomer. Product 6 (4.35 g, 13 mmol) was
stirred in 2.5  HCl (50 mL) for 1 h at room temperature
Discussion
and further work up gave a mixture of 3-cyano-4-methyl-
In Scheme 1, we used the Wittig reaction to couple two
1H-pyrrole (1) and benzophenone. Column chromatog- components in one step so that they form the 3–4 C–C
raphy on silica gel 60 with ethyl acetate/hexane (1:3) gave 1 bond of target molecule 1. Intermediate 6 has substituents
(0.89 g) in 65% yield. The Rf values of 1 and benzophenone in the 1,5-positions. The deprotection and cyclization in
are 0.22 and 0.45, respectively, in ethyl acetate/n-hexane acidic medium is the critical point, which results in pyrrole
(1:3). Our target molecule is now accessible from simple 1 by a one-pot procedure and for which only a simple sepa-
commercially available reagents in 39% overall yield based ration between 1 and benzophenone is needed at the end.
on the starting material 2. All analytical data of 1 are in We first used 2.5  aqueous HCl (method A). Then, we re-
full agreement with those in the literature.[7,8] Repeating this alized that the nonnucleophilic oxalic acid might give better
reaction with commercial [15N]-phthalimide gave [1-15N]-3- results (method B). However, the yield (58%) was lower
cyano-4-methyl-1H-pyrrole (1a) in 36% overall yield. than that obtained by in method A (65%). We then used
The m/z value of 1a is 107.0505, which agrees very well glacial acetic acid (method C), which gave us a mixture of
with calculated value of 107.05309 for the formula the new 1-acetyl-3-cyano-4-methylpyrrole and 3-cyano-4-
1
12C6 H614N15N.
methyl-1H-pyrrole (1) in a 2:3 ratio in 50% yield. This indi-
1
The H NMR chemical shifts of 1a were compared with cates that method A is the preferable one. On the basis of
natural abundance chemical shifts of 1. We observed a char- the aqueous HCl procedure, it is expected that scaling up
acteristic splitting of 97 Hz of NH (δ = 9 ppm) due to the the reaction will not be a problem.
presence of 15N of pyrrole 1a. Within experimental error,
We found that in the third step of the sequence, 3 equiv.
no signal due to 14N incorporation is observed. This result of LDA led to an almost quantitative yield of (E/Z)-6. In
is in agreement with the high (98%) 15N incorporation of the presence of only 2 equiv. of LDA, virtually no (E/Z)-6
the 15N labeled reagent, which showed that during the reac- was formed. The (diphenylmethylene)amino group is an
tion no isotope dilution had taken place. The chemical shift amino protecting group par excellence in the well-known
of 15NH of pyrrole 1a is observed at δ = 153 ppm (com- O’Donnell method for the synthesis of optically active α-
pared to the 15N signal of ammonium nitrate solution). amino acids.[12] For the synthesis of 3-[(diphenylmethylene)-
This value compares well with the reported 15N shift value amino]propionitrile (5), we used amination of acrylonitrile
of natural abundance pyrrole.[9]
with phthalimide as an initial step and protection of free
All the reagents except 1,1-dimethoxyacetone used in amino group of 3-aminopropionitrile with benzophenone
Scheme 1 are commercially available in any stable isotope- imine later. For 15N incorporation we initially chose the
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P. B. S. Dawadi, J. Lugtenburg
FULL PAPER
amination of acrylonitrile with benzophenone imine.[13]
This literature procedure has a long reaction time and low
yield, which induced us to find a better method to prepare
5 starting with phthalimide. The additional advantage of
this method is that phthalimide is commercially available in
the 15N-enriched form.
As far as we know, Wittig coupling has not previously
been used in the synthesis of pyrroles. We feel that this
preparation has a broad scope. A host of protected 3-ami-
0.2 mm: spots were visualized by treating with an oxidizing spray
(2 g of KMnO4 and 4 g of NaHCO3 in 100 mL of water). Column
chromatography was performed on Merck silica gel 60. H NMR
spectra were recorded with a Bruker WM-300 or Bruker AM-600
spectrometer with tetramethylsilane (TMS: δ = 0.00 ppm) as an
internal standard. 1H noise-decoupled 13C spectra were recorded
with Bruker WM-300 at 75 MHz or a Bruker AM-600 at 150 MHz.
15N NMR spectra were recorded with Bruker WM-300 with respect
to external NH4NO3 (saturated in H2O/lock:CDCl3, conversion
constant = 22.3 ppm). Perkin–Elmer Paragon 1000 FTIR was used
1
nopropionitriles will be easily available by amination of for IR measurements (neat). Mass spectra were recorded with a
Finnigan MAT 900 equipped with a direct insertion probe (DIP)
or with a Finnigan MAT 700-TSQ equipped with a custom-made
electron-spray interface (ESI) and electron ionization (EI) in JEOL
JMS SX/SX 102A (four sector mass spectrometer), coupled to a
JEOL MS-MP9021D/UPD system program. All experiments were
carried out under an atmosphere of dry nitrogen. Tetrahydrofuran
(THF) and diethyl ether were distilled from benzophenone ketyl.
Saturated solutions of NaCl and NH4Cl refer to saturated solutions
of the salt in water. All chemicals were purchased from Aldrich
Fluka or Acros Chimica. [15N]-Phthalimide and potassium [15N]-
substituted acrylonitriles for the synthesis of 2-substituted
3-cyano 4-methylpyrroles. Also, a number of 1,1-dimethoxy
ketone derivatives will be easily available by Riley oxidation
of aldehydes and ketones.[14] This allows Scheme 1 to be
extended further to synthesize analogous of 1 with different
substituents in the 4-position.
The 1-NH of the pyrroles can also be easily substituted
by other groups by simple base-catalyzed electrophilic reac-
tions, for example, pyrrole 1 can be simply converted into
the new 1-benzyl-3-cyano-4-methylpyrrole (8) in high yield phthalimide were purchased from Aldrich/Isotech.
by treating it with benzyl bromide in diethyl ether in the
β-Phthalimidopropionitrile (4): Phthalimide (3.0 g, 20 mmol), potas-
presence of KOtBu and 18-crown-6 ether as catalyst
(Scheme 1). All the spectroscopic properties of 8 are in
agreement with the proposed structure. Besides the reaction
of the NH group, the nitrile functionality can be converted
into many other functional groups. The nitrile functional
group of pyrrole 1 reacts with a slight excess of DIBAL-
H to give 4-methyl-1H-pyrrole-3-aldehyde (7) in 82% yield.
sium phthalimide (0.3 g), and acrylonitrile (10 mL) were heated at
reflux for 3 h and excess acrylonitrile was evaporated in vacuo to
obtain product 4 (4.05, 20 mmol) as a colorless solid. 1H NMR
(300 MHz, CDCl3): δ = 2.81 (t, 3JH,H = 6.9 Hz, 2 H, CH2), 4.01 (t,
3JH,H = 6.9 Hz, 2 H, CH2), 7.28–7.91 (m, 4 H, C6H4) ppm. 13C
NMR (75 MHz, CDCl3): δ = 17.10 (CH2), 33.50 (CH2), 116.7
(CN), 123.6 (2ϫCH), 131.6 (2ϫC), 134.6 (2ϫCH), 167.5 (C=O)
ppm. IR: ν = 2254, 1772, 1714, 1699, 1668, 1652, 1467, 1398,
˜
1
Aldehyde 7 is a new compound (see Scheme 1). In the H
1378 cm–1.
and 13C NMR spectra, the characteristic CHO peak is ob-
served at δ = 9.87 and 186 ppm, respectively. The Fermi
doublet resonance at 2768 and 2820 cm–1[15] and the car-
bonyl stretching at 1658 cm–1 in the IR spectrum show the
presence of the aldehyde functional group in the 3-position.
β-[15N]-Phthalimidopropionitrile (4a): Similarly, [15N]-phthalimide
(3.0 g, 20 mmol), potassium [15N]-phthalimide (0.3 g), and acrylo-
nitrile (10 mL) were heated at reflux to obtain product 4a (4.05,
20 mmol) as a colorless solid. 1H NMR (300 MHz, CDCl3): δ =
3
2
2.82 (td, JH,H = 6.9 Hz, JH,15 = 2.2 Hz, 2 H, CH2), 4.02 (td,
N
3JH,H = 6.9 Hz, JH,15 = 1.1 Hz, 2 H, CH2), 7.28–7.91 (m, 4 H,
3
N
C6H4) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.13 (CH2), 33.50
Conclusions
1
(d, JC,15 = 10.5 Hz, CH2), 116.8 (CN), 123.6 (2ϫCH), 131.6 (d,
N
Acrylonitrile was converted into a Wittig reagent in a few
simple steps with high yield. Coupling of this product with
commercially available 1,1-dimethoxyacetone gives an inter-
mediate with reactive groups in the 1,5-positions. Deprotec-
tion and cyclization of these groups in one step gives
the otherwise-difficult-to-access 3-cyano-4-methylpyrrole 1.
This scheme also allows easy, site-directed, stable-isotope
incorporation at any position or a combination of positions.
The scope of this new Wittig approach is very broad, be-
cause many different unsaturated nitriles and 1,1-dimethoxy
ketones are expected to undergo this reaction. Furthermore,
2JC,15N = 8.1 Hz, 2ϫC), 134.6 (2ϫCH), 167.5 (d, 1JC,15N = 12.5 Hz,
C=O) ppm. 15N NMR (30 MHz, CDCl ): δ = 158.5 ppm. IR: ν =
˜
3
2253, 1772, 1713, 1610, 1394, 1367 cm–1. MS (EI+): m/z = 201,
162, 133, 104, 76. HRMS: calcd. for C11H8N15NO2 201.058578;
found 201.0559.
3-[(Diphenylmethylene)amino]propionitrile (5): β-Phthalimidopro-
pionitrile (4; 4.05 g, 20 mmol) in ethanol (100 mL) was heated at
reflux with hydrazine hydrate (50–60%, 7 mL) for 15 min. The solid
was filtered off. The solvent was concentrated and extracted with
diethyl ether (3ϫ200 mL) after adding 10% NaOH (to pH 10).
The solvent was concentrated to 50 mL and an ethanol solution of
Scheme 1 can be extended to synthesize other five-mem- fumaric acid (1.16 g, 10 mmol) was added. The mixture was stirred
for 16 h and filtered to obtain the solid product of 3-aminopro-
bered heterocycles such as furans, thiophenes, selenophenes,
and so on by synthesizing the corresponding nitrile deriva-
tives. The scope of the reaction is even wider for the nitrile
functionality, as it can be easily converted into an aldehyde
that opens a plethora of new systems.
pionitrile fumarate (2.30 g, 18 mmol). 1H NMR (300 MHz,
3
3
CDCl3): δ = 2.64 (t, JH,H = 6.8 Hz, 2 H, CH2), 2.88 (t, JH,H
=
6.7 Hz, 2 H, CH2), 6.42 (s, 2 H, CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 18.82 (CH2), 36.64 (CH2), 119.2 (CN), 135.1 (2ϫCH),
168.0 (C=O) ppm. IR: ν = 2736 (br.), 2256, 1644, 1520, 1506, 1471,
˜
1358, 1219 cm–1.
Experimental Section
General: Reactions were monitored by using thin-layer chromatog-
To a solution of 3-aminopropionitrile fumarate (2.30 g, 18 mmol)
in acetic acid (20 mL) was added benzophenone imine (3.27 g,
18 mmol) at room temperature. The reaction mixture was stirred
raphy (TLC) on Merck F254 silica gel 60 aluminium sheets,
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[1-15N]-3-Cyano-4-methyl-1H-pyrroles by a Wittig-Based Strategy
for 16 h at room temperature. Ethyl acetate/n-hexane (1:3, 100 mL)
was added to the solution and stirred further for 1 h at room tem-
perature. The mixture was filtered and washed with ethyl acetate/n-
hexane (1:3). The filtrate was concentrated to 50 mL and n-hexane
(20 mL) was added to obtain a colorless crystalline solid. The prod-
uct was filtered, dissolved in CH2Cl2 (20 mL), and washed with
10% NaHCO3, dried with MgSO4, and filtered, and the solvent
was evaporated to obtain product 5 (3.51 g, 83%). 1H NMR
(300 MHz, CDCl3): δ = 2.74 (t, 3JH,H = 6.7 Hz, 2 H, CH2), 3.60 (t,
3JH,H = 6.7 Hz, 2 H, CH2), 7.16–7.64 (m, 10 H, 2ϫC6H5) ppm.
13C NMR (75 MHz, CDCl3): δ = 19.77 (CH2), 48.91 (CH2), 118.7
(CN), 127.5, 128.0, 128.5, 128.7, 128.8, 130.4, 135.9, 138.9
mers], 152.1 (CH3-C=), 170.4 (-C=N) ppm. 1H NMR [300 MHz,
CDCl3 (Z) isomer]: δ = 1.74 (s, 3 H, CH3), 3.43 (s, 6 H, OCH3),
4.16 (s, 2 H, CH2), 5.15 (s, 1 H, CH) ppm. NOE observed between
1.74 (CH3) and 4.16 (CH2) ppm in (Z) isomer. 13C NMR [75 MHz,
CDCl3, (Z) isomer]: δ = 12.17 (CH3), 51.75 (CH2), 55.38 (OCH3),
105.3 (CH), 112.5 (=C-CN), 117.0 (CN), 151.8 (CH3-C=), 170.8
(-C=N) ppm. IR: ν = 2934, 2215, 1736, 1623, 1576, 1445, 1209,
˜
1102, 1066 cm–1.
Mixture of (2E)- and (2Z)-[15N]-2-{[(Diphenylmethylene)amino]-
methyl}-4,4-dimethoxy-3-methylbut-2-enenitrile (6a): Similarly,
[15N]-5a (3.51 g, 15 mmol) yielded 6a (4.35 g, 87%) as a mixture of
(E/Z) isomers in a 3:2 ratio as a light-yellow oil. 1H NMR
[300 MHz, CDCl3, (Z/E) isomers]: δ = 4.16 (m, CH2), 4.20 (m,
CH2) ppm. 13C NMR [75 MHz, CDCl3, (Z/E) isomers]: δ = 51.75
(2ϫC H ), 170.8 (C=N) ppm. IR: ν = 2247, 1622, 1595, 1575,
˜
6
5
1490, 1445, 1408, 1315, 1286 cm–1.
1
1
[3-15N]-[(Diphenylmethylene)amino]propionitrile (5a): Similarly, β-
[15N]-phthalimidopropionitrile (4a) was treated with hydrazine hy-
drate. The ethanol solution of 3-aminopropionitrile and fumaric
(d, JC,15 = 1.6 Hz, CH2), 51.14 (d, JC,15 = 1.6 Hz, CH2) ppm.
N
N
15N NMR [30 MHz, CDCl3, (Z/E) isomers]: δ = 313.1, 314.7 ppm.
3-Cyano-4-methyl-1H-pyrrole (1)
acid yielded [3-15N]-aminopropionitrile fumarate (2.30 g,
3
18 mmol).1H NMR (300 MHz, CDCl3): δ = 2.64 (td, JH,H
=
Method A: HCl (2.5 , 50 mL) was added to (E/Z)-6 (4.35 g,
13 mmol), and the mixture was stirred for 1 h at room temperature.
The mixture was extracted with CH2Cl2 (2ϫ100 mL), washed with
10% NaHCO3, dried with MgSO4, and filtered. The solvent was
evaporated under reduced pressure. The product was separated
from benzophenone by column chromatography (silica gel 60; ethyl
acetate/n-hexane, 1:3) to yield 1 (0.89 g, 65%) as a light-yellow so-
lid. Rf = 0.22 (ethyl acetate/n-hexane, 1:3). 1H NMR (600 MHz,
2
3
6.8 Hz, JH,15 = 1.9 Hz, 2 H, CH2), 2.88 (t, JH,H = 6.9 Hz, 2 H,
N
CH2), 6.42 (s, 2 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ =
1
18.47 (CH2), 36.42 (d, JC,15 = 5.1 Hz, CH2), 119.2 (CN), 135.1
N
(2ϫCH), 168.0 (C=O) ppm. 15N NMR (30 MHz, CDCl3): δ =
29.30 ppm. IR: ν = 2736 (br.), 2258, 1645, 1520, 1506, 1472, 1358,
˜
1232 cm–1.
[3-15N]-[(diphenylmethylene)amino]propionitrile
5a
4
Similarly,
CDCl3): δ = 2.19 (d, JH,H = 1.2 Hz, 3 H, CH3), 6.57 (m, 1 H, 5-
(3.51 g, 83%) was obtained from [3-15N]-aminopropionitrile fumar-
ate (2.30 g, 18 mmol) and benzophenone imine (3.27 g, 18 mmol)
3
4
CH), 7.27 (dd, JH,H = 3.0 Hz, JH,H = 2.4 Hz, 1 H, 2-CH), 8.92
(br., 1 H, NH) ppm. 13C NMR (150 MHz, CDCl3): δ = 10.29
(CH3), 93.82 (3-C), 116.7 (5-CH), 116.8 (CN), 122.0 (4-C), 125.3
1
as a light-yellow crystalline solid. H NMR (300 MHz, CDCl3): δ
3
2
= 2.72 (td, JH,H = 6.7 Hz, JH,15 = 2.8 Hz, 2 H, CH2), 3.58 (td,
N
(2-CH) ppm. IR: ν = 3270, 2230, 1560, 1524, 1449, 1239, 1175,
˜
3JH,H = 6.7 Hz, JH,15 = 1.0 Hz, 2 H, CH2), 7.16–7.64 (m, 10 H,
3
N
1102, 1069 cm–1. MS (EI): m/z (%) = 105 (100), 106 (82), 107 (11),
2ϫC6H5) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.83 (d, JC,15
1
N
78 (20).
= 5.1 Hz, CH2), 48.92 (CH2), 118.7 (CN), 127.5–139.0 (2ϫC6H5),
Method B: To a solution of (E/Z)-6 (4.35 g, 13 mmol) in ethyl ace-
tate (50 mL) was added 10% aqueous solution of oxalic acid
(50 mL), and the mixture was heated at reflux for 30 min. The reac-
tion mixture was extracted with CH2Cl2 (3ϫ200 mL), washed with
10% NaHCO3 (100 mL), and dried with MgSO4. The solvent was
removed under reduced pressure to yield a light-yellow oil. Product
1 (Rf = 0.22) was separated from benzophenone (Rf = 0.45) by
column chromatography (silica gel 60; ethyl acetate/n-hexane, 1:3)
to yield light-yellow solid 1 (0.8 g, 58%).
1
170.6 (d, JC,15 = 5.6 Hz, C=N) ppm. 15N NMR (30 MHz,
N
CDCl ): δ = 315.4 ppm. IR: ν = 2246, 1660, 1608, 1592, 1568, 1489,
˜
3
1445, 14408, 1316, 1276 cm–1. MS (EI+): m/z = 235, 195, 105, 91.
HRMS: calcd. for
C
16
1H1414N15N 235.11569; found 235.1134.
12
Mixture of (2E)- and (2Z)-2-{[(Diphenylmethylene)amino]methyl}-
4,4-dimethoxy-3-methylbut-2-enenitrile (6): A solution of LDA
(45 mmol) was prepared by the addition of nBuLi (1.6  in hexanes,
28 mL, 45 mmol) to a solution of diisopropylamine (4.60 g,
45 mmol) in THF (150 mL) at –70 °C. Compound 5 (3.51 g,
15 mmol) in THF (25 mL) was added dropwise to this solution.
The reaction mixture was stirred 15 min at –70 °C, followed by the
addition of a solution of diethyl chlorophosphate (2.58 g, 15 mmol)
in THF (25 mL). After 30 min, a solution of 1,1-dimethoxyacetone
(1.90 g, 16 mmol) in THF (25 mL) was added dropwise. The reac-
tion mixture was warmed to room temperature over approximately
2 h and further stirred 2 h at room temperature. Work up was ac-
complished by adding saturated NH4Cl (100 mL) and saturated
NaCl (100 mL). The mixture was extracted with diethyl ether
(3ϫ200 mL), dried with MgSO4, filtered, and concentrated in
vacuo to give a yellow oil. The product was purified by column
chromatography (silica gel 60; ethyl acetate/n-hexane, 1:3) to afford
6 (4.35 g, 87%) as a mixture of (E/Z) isomers in a 3:2 ratio as a
light-yellow oil. Rf = 0.40 (ethyl acetate/n-hexane, 1:3). 1H NMR
[300 MHz, CDCl3, (E) isomer]: δ = 2.08 (s, 3 H, CH3), 3.26 (s, 6
H, OCH3), 4.21 (s, 2 H, CH2), 4.91 (s, 1 H, CH), 7.19–7.66 [m, 20
H, C6H5, (E/Z) isomers] ppm. 13C NMR [75 MHz, CDCl3, (E)
Method C: A solution of (E/Z)-6 (4.35 g, 13 mmol) in glacial acetic
acid (50 mL) was heated at reflux for 1 h. The solvent was removed
under reduced pressure to yield a light-yellow oil. The products
were separated from benzophenone by column chromatography
(silica gel 60; ethyl acetate/hexane, 1:3) to yield light-yellow solid
mixtures of 1 and 1-acetyl-3-cyano-4-methylpyrrole in a 6:4 ratio
(0.85 g). 1-Acetyl-3-cyano-4-methylpyrrole (0.34 g) (Rf = 0.42; ethyl
acetate/hexane, 1:1, 1% Et3N) was further separated from pyrrole
1 (0.4 g) by column chromatography (silica gel 60; ethyl acetate/
hexane, 1:1, 1% Et3N) as a light-yellow solid. Data for 1-acetyl-3-
1
cyano-4-methylpyrrole: H NMR (600 MHz, CDCl3): δ = 2.18 (d,
4JH,H = 1.2 Hz, 3 H, CH3), 2.54 (s, 3 H, CH3), 7.09 (s, 1 H, 5-CH),
7.70 (s, 1 H, 2-CH) ppm. 13C NMR (150 MHz, CDCl3): δ = 10.44
(CH3), 22.02 (CH3-C=O), 100.2 (3-C), 114.5 (CN), 117.4 (5-CH),
125.9 (4-C), 128.9 (2-CH), 166.6 (C=O) ppm. IR: ν = 3132, 2228,
˜
1728, 1652, 1519, 1385, 1354, 1318, 1227, 1215, 1075 cm–1.
1-Acetyl-3-cyano-4-methylpyrrole (0.34 g, 2.3 mmol) was treated
isomer]: δ = 17.33 (CH3), 51.14 (CH2), 54.15 (OCH3), 100.9 (CH), with 10% NaOH (10 mL) and stirred for 12 h at room temperature,
113.5 (=C-CN), 117.8 (CN), 125.4, 125.7, 127.4, 127.6, 127.7, neutralized with 2  HCl, and extracted with diethyl ether
128.0, 128.6, 128.7, 128.8, 130.4, 135.9, 139.0 [C6H5, (E/Z) iso-
(3ϫ50 mL). The solvent was washed with saturated NaCl, dried
Eur. J. Org. Chem. 2008, 2288–2292
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2291

P. B. S. Dawadi, J. Lugtenburg
FULL PAPER
with MgSO4, and filtered. The solvent was evaporated to get yellow
C6H5), 127.5 (2-CH), 128.3 (4Ј-CH, C6H5), 128.9 (2Ј-CH, 6Ј-CH,
solid of pyrrole 1 (0.21 g, 87%).
C H ), 136.0 (1Ј-C) ppm. IR: ν = 3124, 2209, 1525, 1495, 1358,
˜
6 5
1149 cm–1. MS (ESI): m/z = 197 [M + H]+.
[1-15N]-3-Cyano-4-methyl-1H-pyrrole (1a): Similarly, (E/Z)-6
(4.35 g, 13 mmol) in 2.5  HCl (20 mL, method A) yielded 1a
(0.81 g, 59%) as a light-yellow solid. 1H NMR (300 MHz, CDCl3):
4
Acknowledgments
δ = 2.18 (d, JH,H = 1.0 Hz, 3 H, CH3), 6.57 (m, 1 H, 5-CH), 7.21
(m, 1 H, 2-CH), 9.11 (ddd, 1JH,15 = 97.9 Hz, 3JH,H = 2.5 Hz, 3JH,H
N
= 2.5 Hz, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 10.27
This work was supported by grants from Volkswagen Stiftung
(I/79979). We are very thankful to Prof. Dr. W. Gaertner (Max
Planck-Institute for Bioinorganic Chemistry, Muelheim, Ger-
many), Prof. Dr. J. Hughes (Plant Physiology, Justus-Liebig Univer-
sity, Giessen, Germany), and Dr. J. Matysik (Leiden Institute of
Chemistry) for their valuable suggestions. The authors wish to
thank C. Erkelens and F. Lefeber for recording the NMR spectra
and J. Erkelens (Leiden Institute of Chemistry) and H. Peeters
(Free University, Amsterdam, The Netherlands) for recording the
mass spectra.
2
1
(CH3), 93.77 (d, JC,15N = 5.5 Hz, 3-C), 116.7 (d, JC,15N = 12.8 Hz,
2
5-CH), 116.8 (CN), 122.0 (d, JC,15 = 2.9 Hz, 4-C), 125.3 (d,
N
1JC,15 = 14.5 Hz, 2-CH) ppm. 15N NMR (30 MHz, CDCl3): δ =
N
153.0 ppm.[9] IR:
ν = 3290, 2219, 1560, 1516, 1443, 1309,
˜
1237 cm–1. MS (EI+): m/z (%) = 106 (100), 107 (78), 108 (37), 78
(6). HRMS: calcd. for C6H6N15N 107.05309; found 107.0505.
4-Methyl-1H-pyrrole-3-aldehyde (7): To a solution of 1 (0.76 g,
7.2 mmol) in diethyl ether (100 mL) cooled to –60 °C was added
DIBAL-H (1  in n-hexane, 10 mL, 10 mmol). The reaction mix-
ture was warmed up to –30 °C over 1 h and then stirred for 1 h at
room temperature. A homogeneous mixture of silica gel/water (8 g/
3 mL) was added to the mixture and continued to stir 1 h at 0 °C
and further 1 h at room temperature. Then, K2CO3 (12 g) and
MgSO4 (12 g) were added to the solution, and the mixture was
stirred for 1 h at room temperature. The mixture was filtered and
washed thoroughly with diethyl ether. The solvent was removed
under reduced pressure to yield yellow solid of 7 (0.64 g, 82%). Rf
[1] R. M. Acheson, An Introduction to the Chemistry of Heterocy-
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[2] G. M. Badger, The Chemistry of Heterocyclic Compounds, Aca-
demic, New York, 1961.
[3] A. H. Jackson, Comprehensive Organic Chemistry – The Syn-
thesis and Reactions of Organic Compounds Vol. 4: Pyrroles
(Eds.: D. Barton, W. D. Ollis), Pergamon, Oxford, 1979, ch.
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[4] S. Hu, A. Mukherjee, C. Piffat, R. S. W. Mak, X. Y. Li, T. G.
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1
= 0.47 (diethyl ether). H NMR (600 MHz, CDCl3): δ = 2.33 (d,
4JH,H = 1.2 Hz, 3 H, CH3), 6.58 (m, 1 H, 5-CH), 7.34 (dd, 3JH,H
=
4
3.3 Hz, JH,H = 2.4 Hz, 1 H, 2-CH), 8.57 (br., 1 H, NH), 9.87 (s, 1
H, CHO) ppm. 13C NMR (150 MHz, CDCl3): δ = 11.0 (CH3),
118.3 (5-CH), 120.2 (3-C), 125.1 (4-C), 127.9 (2-CH), 186.2 (C=O)
ppm. IR: ν = 3264, 2920, 2826, 2768, 1658, 1651, 1654, 1515 cm–1.
˜
MS (EI): m/z (%) = 109 (92), 108 (100), 80 (24), 53 (21).
1-Benzyl-3-cyano-4-methylpyrrole (8): KOtBu (0.34 g, 3 mmol) was
added to a solution of 18-crown-6 (0.13 g, 0.5 mmol) in diethyl
ether (20 mL) at room temperature. To the mixture was added 1
(0.24 g, 2.3 mmol) in diethyl ether (10 mL) and after 15 min stirring
followed by the addition of benzyl bromide (0.52 g, 3 mmol). The
reaction was stirred under a N2 atmosphere for 18 h at room tem-
perature. The reaction was quenched by the addition of water
(20 mL). Ether phase was separated and aqueous phase was ex-
tracted with diethyl ether (3ϫ50 mL). The ether phase was washed
with saturated NaCl and dried with MgSO4, and filtered, and the
solvent was evaporated under reduced pressure. Purification by col-
umn chromatography (silica gel 60; ethyl acetate/n-hexane, 1:3) af-
forded yellow solid of product 8 (0.38 g, 85%). Rf = 0.42 (ethyl
[12] a) M. J. O’Donnell, W. D. Bennett, S. Wu, J. Am. Chem. Soc.
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[13] L. Wessjohann, G. McGaffin, A. de Meijere, Synthesis 1989,
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[14] L. Kurti, B. Czako, Strategic Applications of the Named Reac-
tions, Elsevier, Oxford, 2005.
[15] J. B. Lambert, H. F. Shurvell, D. A. Lightner, R. G. Cooks, Or-
ganic Structural Spectroscopy, Prentice Hall, 1998.
Received: January 23, 2008
1
acetate/n-hexane, 1:3). H NMR (400 MHz, CDCl3): δ = 2.15 (s, 3
4
H, CH3), 4.98 (s, 2 H CH2), 6.41 (m, 1 H, 5-CH), 7.05 (d, JH,H
=
1.84 Hz, 1 H, 2-CH), 7.25–7.38 (m, 5 H, C6H5) ppm. 13C NMR
(100 MHz, CDCl3): δ = 10.51 (CH3), 53.85 (CH2), 94.03 (3-C),
116.3 (CN), 119.9 (5-CH), 123.2 (4-C), 127.2 (3Ј-CH, 5Ј-CH,
Published Online: March 20, 2008
2292
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2288–2292