Condensation reactions of a nitrodienamine with organocopper and alkyllithium reagents prepared from pyrrole derivatives

Article abstract of DOI:10.3987/COM-00-8859

Condensation reactions of a nitrodienamine (1) with Grignard, organocopper and alkyllithium reagents prepared from pyrrole derivatives were investigated.

Full text of DOI:10.3987/COM-00-8859

HETEROCYCLES, Vol. 53, No. 6, 2000, pp. 1351 - 1359, Received, 28th January, 2000
CONDENSATION REACTIONS OF A NITRODIENAMINE WITH
ORGANOCOPPER AND ALKYLLITHIUM REAGENTS PREPARED
FROM PYRROLE DERIVATIVES
Takeshi Koike,* Yoshifumi Shinohara, Takeshi Nishimura, Masanori Hagiwara,
Seisho Tobinaga, and Naoki Takeuchi
Showa Pharmaceutical University, Higashitamagawagakuen 3-3165, Machida,
Tokyo 194-8543, Japan
Abstract - Condensation reactions of a nitrodienamine (1) with Grignard,
organocopper and alkyllithium reagents prepared from pyrrole derivatives were
investigated.
1
Enamine chemistry has been considerably important to the progress of organic chemistry. The
nitrodienamines have the electronic “ push-pull” character such as aminodienyl esters and aminoacrylates,
1-4
5
In our previous study, we reported the synthesis
which can lead to interesting cycloaddition reactions.
of a nitrodienamine, 1-(N ,N-dimethylamino)-4-nitro-1,3-butadiene (1), some cycloadditions of 1 with
α,β-unsaturated carbonyl compounds and quinones, and condensation reactions of 1 with Grignard and
organocopper reagents prepared from indole derivatives (A) using methylmagnesium bromide and
dimethylcopperlithium, respectively, as shown in Scheme 1. We studied the condensation reactions of 1
with Grignard, organocopper and lithium reagents prepared from pyrrole derivatives. The pyrrole
3a
derivatives having a 1,3-butadiene group would be interesting compounds in pyrrole organic chemistry.
Although the condensation reaction of a nitrodienamine (1) with pyrrole (2a) under CF CO H or
3
2
CH CO H condition was unsuccessful, the reaction of 1 with pyrrole (2a) using methylmagnesium iodide
3
2
in ether-benzene afforded 2-(4-nitro-1,3-butadienyl)pyrrole (3a) in 12.2% yield as shown in Table 1. The
structure of 3a was confirmed by the following spectral data. The IR spectrum of 3a shows absorption
1
bands at 3380 and 1530 cm-1 due to an amino group and a nitro group, respectively. The H-NMR

spectrum of 3a depicts the presence of four protons at the 1-, 3-, 4- and 5- positions of the pyrrole ring.
On the other hand, reactions of 1 with pyrroles (2b) and (2c) under the same conditions were
unsuccessful (Entries 2 and 3).
3
3
3
R
R
R
2
2
1
1) MeMgBr or Me CuLi
2
R
4
5
4
5
R
R
NO
2
4
5
R
R
NO
+
2
2)
Me N
2
N
H
1
N
1
R
R
R
N
H
R
R
R
1
1
2
R =H or Me; R =H or Me;
3
A
4
R =H or Br; R =H or Br
5
NO
2
or NO ; R =H or Br
2
Scheme 1
Next, based on the consideration of reactivity and stability of nitrodienamine (1), we investigated the
condensation reactions of 1 with pyrrolyl organocopper reagents prepared from pyrrole derivatives using
dimethylcopperlithium. Pyrrolyl copperlithium reagents are considerably less basic and less nucleophilic
than the corresponding alkyllithiums. The condensation reaction of 1 with pyrrole (2a) using
dimethylcopperlithium in ether-benzene gave two condensation products, 3a (11.0% yield) and 1-(4-nitro-
1,3-butadienyl)pyrrole (5a) (29.9% yield, Entry 4). The IR spectrum of 5a does not have absorption band
by an NH group, and shows an absorption band at 1530 cm-1 due to a nitro group. The 1H-NMR spectrum
of 5a indicates the presence of four protons and the absence of a proton on nitrogen in the pyrrole ring.
Grignard and organocopper reagents have divergent behavior toward 1,3-butadiene group, depending on
the reaction conditions.
Similarly, we studied the reactivity of 1 with pyrrolyl organocopper reagents prepared from 2,5-
6
dimethylpyrrole (2b) and 3,4-dimethylpyrrole (2c). Lithium 2,5-dimethylpyrrolylcuprate (I) reacted with
1 to give 2,5-dimethyl-3-(4-nitro-1,3-butadienyl)pyrrole (4b) (36.9% yield, Entry 5). The compound (4b)
1
contains amino (3328 cm-1 ) and nitro (1530 cm-1 ) IR absorption bands, respectively. The H-NMR
[δ
spectrum reveals that 4b has a singlet resonance at the 4-position 6.06], and a broad singlet resonance at
[δ
the N-1 position
10.00]. The treatment of 1 with an organocopper reagent prepared from 3,4-
dimethylpyrrole (2c) using Me2CuLi provided 3,4-dimethyl-2-(4-nitro-1,3-butadienyl)pyrrole (3c) (3.5%
yield) and 3,4-dimethyl-1-(4-nitro-1,3-butadienyl)pyrrole (5c) (4.5% yield, Entry 6). The condensation
conditions of 1 with compound (2d) using alkyllithium in THF were shown in Entries 7-9. The

7
condensation reaction of 1 with 3-bromo-1-(triisopropylsilyl)pyrrole (2d) using tert-butyllithium in THF
afforded 1-triisopropylsilyl-3-(4-nitro-1,3-butadienyl)pyrrole (4d) (74.8% yield) and a debrominated
product, 1-triisopropylsilylpyrrole (2g) (8.3% yield, Entry 9). The IR spectrum of 4d shows an
Table 1. Equivalences, bases, and yields of 2-5
4R
5R
R3
R2
NO2
Me
N
Me
Base
1
N
R1
2
R3
R2
4R
5R
R3
4R
5R
NO2
4R
5R
N
R2
N
N
NO2
+
+
R1
R1
NO2
4
5
3
Scheme 2
1
Starting
material
R1
R2
Yield (%)
R3 R4 R5
Entry
Base
equiv
1.2
1.2
1.2
2.0
10.0
2.0
2.5
2.0
4.0
-
2a
2b
2c
2a
2b
2c
2d
2d
2d
4d
2e
2f
H
H
H
H
H
H
H
MeMgI
3a (12.2)
1
2
H
H
H
H
H
Me
H
MeMgI
Complex mixture
Complex mixture
Me
H
MeMgI
3
Me Me
(29.9)
H
Me2CuLi
Me2CuLi
Me2CuLi
n-BuLi
3a (11.0)
4b (36.9)
3c (3.5)
4d (13.4)
4
H
H
H
H
H
5a
Me
H
5
Me
H
5c (4.5)
6
Me Me
2g (R3=H,78.2)
TIPS H
TIPS H
TIPS H
TIPS H
TIPS Br
7
Br
Br
Br
-
H
H
H
H
H
H
H
2g (R3=H,15.4)
tert-BuLi 4d (69.8)
8
H
(R3=H,8.3)
2g
4d (74.8)
tert-BuLi
9
H
4a (R1=H,78.0)
(R2
Bu4N+F-
AlkylLi
AlkylLi
10
11
12
H
a)
=H,73.4)
2h (R2=H,60.0)
2g
2.0
2.0
H
H
Ts
Br
H
H
a) AlkylLi: n-BuLi and/or tert-BuLi

1
absorption band ascribable to a nitro function at 1520 cm-1. The H-NMR spectrum of 4d exhibits the
presence of four olefinic protons due to the 4-nitro-1,3-butadienyl group at the 3-position. These facts
show that the nitrodienamine (1) reacts with 3-lithio intermediates by bromine-lithium interchange with the
alkyllithium reagent. The desilylation of 4d with tetrabutylammonium fluoride in THF afforded the 3-(4-
nitro-1,3-butadienyl)pyrrole (4a) in 78.0% yield (Entry 10). On the other hand, the reaction of 1 with 2-
bromo-1-(triisopropylsilyl)pyrrole (2e) using alkyllithium in THF only afforded the 1-
triisopropylsilylpyrrole (2g) in 73.4% yield (Entry 11). It seemed that the condensation reaction was
unsuccessful because the lithium intermediate was unstable.
8
Similarly, the 2-bromo-1-(p-toluenesulfonyl)pyrrole (2f) and 1-(p-toluenesulfonyl)pyrrole (2h) were
prepared to investigate the condensation reaction with 1. However, the reaction of 1 with 2f using
alkyllithium in THF only afforded the debrominated product (2h) (Entry 12), while 2h did not afford an
identifiable product.
These results illustrate a condensation reaction of 1 with organocopper and alkyllithium reagents prepared
from pyrrole derivatives.
EXPERIMENTAL
All melting points were determined on a Yanagimoto melting point apparatus and are uncorrected. IR
spectra were recorded with a JASCO FT/IR-8000, JASCO FT/IR-200 spectrophotometer, 1 H-NMR
spectra with a JEOL EX-90, JEOL JNM-GX 270, JEOL JNM-α 500 spectrometer with tetramethylsilane as
an internal standard, MS with a JEOL JMS-D 300 spectrometer. Elemental analyses were performed
with a Yanaco CHN-corder MT-3. Silica gel 60 (Cica-MERCK) and Merck Kieselgel 60 F
were used for column chromatography and TLC, respectively.
(silica gel)
254
The Reaction of the Nitrodienamine (1) with Pyrrole (2a) Using Methylmagnesium Iodide:
2-(4-Nitro-1,3-butadienyl)pyrrole (3a)
The 0.98 M MeMgI in ether solution (0.6 mL) was added to a solution of pyrrole (2a) (33.5 mg, 0.50
mmol) in dry benzene (2 mL) with stirring at 0 °C under an argon atmosphere. The whole was stirred at 0

°C for 10 min. A solution of 1 (85 mg, 0.60 mmol) in dry benzene (4 mL) was added to the reaction
mixture and the whole was stirred at 0 °C for 30 min. The reaction mixture was poured into 10% NH Cl,
4
and then extracted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO
4
and evaporated under reduced pressure. The residue was subjected to silica gel chromatography. The eluate
with 10% ethyl acetate in chloroform gave 10.0 mg (12.2%) of 3a as dark red prisms (ether-hexane), mp
1
126-128 °C. IR (KBr) cm- 1: 3380, 1620, 1600, 1530, 1478. H-NMR (acetone-d ) δ: 6.25 (1H, m,
6
aromatic H), 6.60 (1H, m, aromatic H), 6.76 (1H, dd, J = 14.4, 13.7 Hz, olefinic H), 7.07 (1H, m,
aromatic H), 7.27 (1H, d, J = 13.7 Hz, olefinic H), 7.31 (1H, d, J = 13.1 Hz, olefinic H), 7.83 (1H, dd,
J = 14.4, 13.1 Hz, olefinic H), 10.85 (1H, br s, NH). High resolution MS m/z: Calcd for C H N O
8 8 2 2
+
(M ): 164.0586. Found: 164.0617.
General Procedure for Reactions of the Nitrodienamine (1) with Pyrroles (2a-c) Using
Dimethylcopperlithium:
The 1.06 M MeLi (0.7-1.5 mL) in ether solution was added to a suspension of CuI (75-380 mg, 0.4-2.0
mmol) in anhydrous ether (4 mL) with stirring at 0°C under an argon atmosphere. A solution of pyrrole
(2a-c) (0.2 mmol) in dry benzene (2 mL) was added to the mixture and the whole was stirred at 0 °C for
10 min under the same conditions. To the resultant solution, a solution of 1(56-284 mg, 0.4-2.0 mmol) in
dry benzene (26 mL) was added at 0 °C and then the reaction mixture was stirred at rt for 3 h. The reaction
mixture was poured into 10% NH Cl and extracted with ethyl acetate. The organic layer was washed with
4
brine, then dried over MgSO and evaporated under reduced pressure. The residue was subjected to silica
4
gel chromatography with appropriate solvents. The isolated yields of 3, 4 and 5 were based on the
corresponding starting pyrroles.
2-(4-Nitro-1,3-butadienyl)pyrrole (3a) and 1-(4-Nitro-1,3-butadienyl)pyrrole (5a)
Substrate: pyrrole (2a), 13.4 mg, 0.2 mmol. 1.06 M MeLi in ether solution: 1.5 mL. CuI: 152 mg, 0.8
mmol. 1: 56.8 mg, 0.4 mmol. Solvent for chromatography: chloroform. First eluate product: 9.8 mg
(29.9%) of 5a as yellow needles (ether-hexane), mp 125-127 °C. IR (KBr) cm-1: 1638, 1613, 1530, 1510,
1
1480. H-NMR (acetone-d ) : 6.19 (2H, t, J = 2.2 Hz, aromatic H), 6.58 (1H, dd, J = 14.0, 11.0 Hz,
δ
6
olefinic H), 7.07 (2H, t, J = 2.2 Hz, aromatic H), 7.24 (1H, d, J = 13.1 Hz, olefinic H), 7.70 (1H, d, J =

14.0 Hz, olefinic H), 7.75 (1H, dd, J = 13.1, 11.0 Hz, olefinic H). High resolution MS m/z: Calcd for
+
C H N O (M ): 164.0586. Found: 164.0584. Second eluate product: 1.8 mg (11.0%) of the 3a as dark
8 8 2 2
red prisms (ether-hexane), mp 126-128 °C. This compound was identical with 3a previously obtained.
2,5-Dimethyl-3-(4-nitro-1,3-butadienyl)pyrrole (4b)
6
Substrate: 2,5-dimethylpyrrole (2b) , 19.0 mg, 0.2 mmol. 1.06 M MeLi in ether solution: 3.8 mL. CuI:
380 mg, 2.0 mmol. 1: 284 mg, 2.0 mmol. Solvent for chromatography: chloroform. Product: 14.2 mg
(36.9%) of 4b as dark red prisms (ether-hexane), mp 187-188 °C. IR (KBr) cm-1 : 3328, 1593, 1530,
1
1480. H-NMR (acetone-d ) δ: 2.17 (3H, s, -Me), 2.31 (3H, s, -Me), 6.06 (1H, s, aromatic H), 6.52
6
(1H, dd, J = 14.9, 11.7 Hz, olefinic H), 7.26 (1H, d, J = 13.0 Hz, olefinic H), 7.34 (1H, d, J = 14.9 Hz,
olefinic H), 7.86 (1H, dd, J = 13.0, 11.7 Hz, olefinic H), 10.00 (1H, br s, NH). High resolution MS
+
m/z: Calcd for C H N O (M ): 192.0899. Found: 192.0925.
10 12 2 2
3,4-Dimethyl-2-(4-nitro-1,3-butadienyl)pyrrole
(3c)
and
3,4-Dimethyl-1-(4-nitro-1,3-
butadienyl)pyrrole (5c)
6
Substrate: 3,4-dimethylpyrrole (2c) , 19.0 mg, 0.2 mmol. 1.06 M MeLi in ether solution: 0.7 mL. CuI:
75 mg, 0.4 mmol. 1: 56.1 mg, 0.4 mmol. Solvent for chromatography: chloroform. First eluate product:
1.7 mg (4.5%) of 5c as yellow needles (ether-hexane), mp 121-123 °C. IR (KBr) cm-1: 1636, 1607, 1585,
1
1535, 1483. H-NMR (acetone-d ) δ: 1.98 (6H, s, -Me), 6.19 (2H, s, aromatic H), 6.52 (1H, dd, J =
6
13.4, 11.9 Hz, olefinic H), 7.33 (1H, d, J = 12.8 Hz, olefinic H), 7.66 (1H, d, J = 13.4 Hz, olefinic H),
+
7.85 (1H, dd, J = 11.9, 12.8 Hz, olefinic H). High resolution MS m/z: Calcd for C H N O (M ):
10 12 2 2
192.0897. Found: 192.0892. Second eluate product: 1.3 mg (3.5%) of 3c as dark red prisms (ethyl
acetate-hexane), mp 119-121 °C. IR (KBr) cm-1: 3335, 1615, 1586, 1557, 1499. 1H-NMR (acetone-d ) δ:
6
1.98 (3H, s, -Me), 2.12 (3H, s, -Me), 6.63 (1H, dd, J = 15.3, 12.5 Hz, olefinic H), 6.88 (1H, s,
aromatic H), 7.25 (1H, d, J = 12.5 Hz, olefinic H), 7.33 (1H, d, J = 15.3 Hz, olefinic H), 7.89 (1H, t, J
+
= 12.5 Hz, olefinic H). High resolution MS m/z: Calcd for C H N O (M ): 192.0899. Found:
10 12 2 2
192.0909.

The Reaction of 1 with 1-Protected Pyrroles (2d-f) Using Alkyllithium:
1- Triisopropylsilylpyrrole (2g) and 1-Triisopropylsilyl-3-(4-nitro-1,3-butadienyl)pyrrole
(4d)
The 1.7 M tert-BuLi in pentane solution (85.1 mL) was added to a solution of 3-bromo-1-
7
triisopropylsilylpyrrole (2d) (21.2 mg, 0.07 mmol) in dry THF (3 mL) with stirring at -78 °C under an
argon atmosphere and the whole was stirred at -78 °C for 20 min. To resultant solution, a solution of 1
(39.9 mg, 0.28 mmol) in dry THF (3 mL) was added at -78 °C. The reaction temperature was gradually
raised to rt and the reaction mixture was poured into water and extracted with ethyl acetate. The organic
layer was washed with brine, then dried over MgSO and evaporated under reduced pressure. The residue
4
was subjected to silica gel chromatography. The first eluate with 5% chloroform in hexane gave 1.3 mg
(8.3%) of 2g as colorless oil. This compound was identical with 2g previously reported on the basis of IR,
7
MS and NMR spectral comparisons. Second eluate gave 16.8 mg (74.8%) of 4d as dark red oil. IR
(neat) cm- 1: 1615, 1520, 1500, 1490. 1 H-NMR (CDCl ) δ: 1.10 (18H, d, J = 7.6 Hz, Me), 1.46 (3H,
3
sept, J = 7.6 Hz, methine H), 6.53 (1H, dd, J = 15.2, 12.0 Hz, olefinic H), 6.55 (1H, dd, J = 2.7, 1.5
Hz, aromatic H), 6.78 (1H, t, J = 2.7 Hz, aromatic H), 7.00 (1H, t, J = 1.5 Hz, aromatic H), 7.14 (1H, d,
J = 15.2 Hz, olefinic H), 7.15 (1H, d, J = 12.0 Hz, olefinic H), 7.78 (1H, t, J = 12.0 Hz, olefinic H).
13C-NMR (CDCl ) δ: 11.55, 17.69, 17.69, 108.32, 116.60, 124.48, 126.80, 128.44, 135.51, 141.32,
3
+
141.37. High resolution MS m/z: Calcd for C H N O Si (M ): 320.1920. Found: 320.1946.
17 28 2 2
3-(4-Nitro-1,3-butadienyl)pyrrole (4a)
The 1.0 M tetrabutylammonium fluoride in THF solution (56.7 mL) was added to a solution of 4d (60.5
mg, 0.19 mmol) in dry THF (5 mL) with stirring at -10 °C under an argon atmosphere and the whole was
stirred at -10 °C for 10 min. The reaction mixture was poured into water and extracted with ethyl acetate.
The organic layer was washed with brine, then dried over MgSO and evaporated under reduced pressure.
4
The residue was subjected to silica gel chromatography. The eluate with 25% ethyl acetate in hexane gave
24.2 mg (78.0%) of 4a as orange prisms (methanol), mp 171-172 °C. IR (KBr) cm-1: 3290, 1610, 1600,
1
1540, 1500. H-NMR (CDCl ) δ: 6.36 (1H, dd, J = 4.4, 2.2 Hz, aromatic H), 6.60 (1H, dd, J = 15.1,
3
12.2 Hz, olefinic H), 6.76 (1H, dd, J = 4.4, 2.2 Hz, aromatic H), 7.10 (1H, m, aromatic H), 7.20 (1H, d,

J = 12.2 Hz, olefinic H), 7.21 (1H, d, J = 15.1 Hz, olefinic H), 7.69 (1H, t, J = 12.2 Hz, olefinic H).
13 C-NMR (CDCl ) δ: 106.77, 116.91, 121.45, 123.05, 123.37, 136.27, 142.27, 142.96. High
3
+
resolution MS m/z: Calcd for C H N O (M ): 164.0586. Found: 164.0606. Anal. Calcd for
8 8 2 2
C H N O : C, 58.53; H, 4.91; N, 17.07. Found: C, 58.48; H, 4.97; N, 17.48.
8 8 2 2
2-Bromo-1-(p-toluenesulfonyl)pyrrole (2f)
N-Bromosuccinimide (2.9 g, 16.3 mmol) was added to a solution of pyrrole (2a) (1.0 g, 14.9 mmol) in
dry THF (60 mL) with stirring at -78 °C under an argon atmosphere and the whole was allowed to stand at
- 15 °C for 15 h. 60% NaH (1.26 g, 31.5 mmol) and dry DMF (18 mL) were added to a solution of the
reaction mixture at -20 °C and the whole was stirred at the same conditions for 3 h. A solution of p-
toluenesulfonyl chloride (3.0 g, 15.7 mmol) in dry THF (15 mL) was added to the reaction mixture at -20
°C and the whole was stirred at the same conditions for 1 h. The reaction mixture was concentrated, and the
residue was poured into water and extracted with ethyl acetate. The organic layer was washed with brine,
then dried over MgSO and evaporated under reduced pressure. The residue was subjected to silica gel
4
chromatography. The eluate with 25% chloroform in hexane gave 2.3 g (51.4%) of 2f as colorless needles
1
(ethanol), mp 122-123 °C. IR (KBr) cm-1: 1670, 1595, 1535, 1465. H-NMR (CDCl ) δ: 2.43 (3H, s,
3
Me), 6.24 (1H, t, J = 3.6 Hz, aromatic H), 6.27 (1H, dd, J = 3.6, 1.9 Hz, aromatic H), 7.32 (2H, d, J =
8.3 Hz, aromatic H), 7.46 (1H, dd, J = 3.6, 1.9 Hz, aromatic H), 7.81 (2H, d, J = 8.3 Hz, aromatic H).
+
79
High resolution MS m/z: Calcd for C H NO BrS (M for Br): 298.9613. Found: 298.9623.
11 10
2
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