Reactions of a nitrodienamine with 1-protected indolyllithium

Article abstract of DOI:10.3987/COM-00-9035

Reactions of a nitrodienamine (1) with indolyllithiums prepared from 1-protected indole derivatives were investigated.

Full text of DOI:10.3987/COM-00-9035

HETEROCYCLES, Vol. 53, No. 12, 2000, pp. 2701-2708, Received, 8th August, 2000
REACTIONS OF A NITRODIENAMINE WITH 1-PROTECTED
INDOLYLLITHIUM
Takeshi Koike*, Yoshifumi Shinohara, Seisho Tobinaga, and Naoki Takeuchi
Showa Pharmaceutical University, Higashitamagawagakuen 3-3165, Machida,
Tokyo 194-8543, Japan
Abstract - Reactions of a nitrodienamine (1) with indolyllithiums prepared from
1-protected indole derivatives were investigated.
The chemistry of enamine and nitroolefin has been considerably important to the progress of organic
chemistry.1 The nitrodienamines have an electronic “push-pull” character as observed in aminodienyl
esters and aminoacrylates, which can lead to interesting cycloaddition reactions.1-4 In our previous
studies,5 we reported the synthesis of a nitrodienamine, 1-(N,N-dimethylamino)-4-nitro-1,3-butadiene (1),
some cycloadditions of 1 with a,b -unsaturated carbonyl compounds and quinones, and condensation
reactions of 1 with indolyl metal reagents (indolyl Grignard and organocopper reagents) which afforded
two products of 1- and 3-(4-nitro-1,3-butadienyl)indole derivatives. Further, we found that the 1-(4-nitro-
1,3-butadienyl)indole was not useful derivative of the cycloaddition reaction, but the 3-(4-nitro-1,3-
butadienyl)indole (2) could yield the cyclization product, carbazole (3) as shown in Scheme 1. Therefore,
we investigated the synthesis of 3-substituted indoles (6) from 1-protected indoles (5). We also studied
Me
NO2
N
Me
NO2
1
N
H
N
N
H
MgBr
2
3
Scheme 1

R3
R2
R4
R5
R3
R2
R4
R5
R3
R4
R4
NO2
+
1) Me2CuLi or BuLi
+
Me
NO2
R5 N
R5 N
R2
2)
N
N
N
NO2
R1
R1
R1
Me
1
R1=H or TIPS; R2=H or Me or Br;
R3=H or Me or Br; R4=H or Me; R5=H or Me
4
NO2
Scheme 2
the condensation reactions of 1 with lithium reagents prepared from 1-protected pyrrole derivatives as
shown in Scheme 2.
In this paper, we report reactions of 1 with 1-protected indoles (5a-c) using alkyllithium as shown in
Scheme 3. The conditions of 1 with 3-bromo-1-tert-butyldimethylsilylindole (5a)6 using alkyllithium in
THF were shown in Entries 1-7 in Table 1. Typical example is the reaction of 1 with compound (5a) using
tert-butyllithium7 in THF affording three products, namely, 1-tert-butyldimethylsilyl-3-(4-nitro-1,3-
butadienyl)indole (6a) (17.7%), the desilylated product, 3-(4-nitro-1,3-butadienyl)indole (2) (52.2%), and
the debrominated product, 1-tert-butyldimethylsilylindole (8a) (21.8%) (Entry 6).
The structures of 6a and 2 were identified by the following spectral data. The IR spectrum of 6a shows an
absorption band at 1515 cm-1 due to a nitro group. The 1H-NMR spectrum indicates the presence of four
olefinic protons at d 6.88 (1H, dd, J = 15.6, 12.2 Hz), 7.23 (1H, d, J = 12.2 Hz), 7.36 (1H, d, J = 15.6
Hz), 7.84 (1H, t, J = 12.2 Hz) due to 4-nitro-1,3-butadienyl group at the 3-position and exhibits a singlet
at d 7.89 due to a proton at the 2-position of the indole ring. The compound (2) contains amino (3300 cm
-1) and nitro (1512 cm-1) IR absorption bands, respectively. The 1H-NMR spectrum reveals that 2 has a
singlet ascribed to the 2-position [d 7.86], and a broad singlet ascribed to the N-1 position [d 10.95]. These
facts depict that the nitrodienamine (1) reacts with 3-lithio intermediates generated by bromine-lithium
interchange with the alkyllithium reagent. The desilylation of 6a with tetrabutylammonium fluoride in THF
furnished 2 in 74.9% yield (Entry 8).
Similarly, the reaction of 1 with 3-bromo-1-triisopropylsilylindole (5b)8 using tert-butyllithium in THF
gave the condensation product, 1-triisopropylsilyl-3-(4-nitro-1,3-butadienyl)indole (6b) (95.0%) and the

debrominated product, 1-triisopropylsilylindole (8b)9 (3.2%) (Entry 10).
On the other hand, the 1-p-toluenesulfonylindole (5c)10 was prepared to investigate the reaction of a
nitrodienamine (1). The reaction of 1 with compound (5c) using lithium diisopropylamide (LDA)11 in
Table 1. Bases and yields of 2,6-8
NO2
Me
R3
N
Me
Base
1
N
R1
5
R3
NO2
H
H
H
+
N
R1
N
R1
+
N
R1
NO2
8
6
7
2(R1=H)
Scheme 3
1
Base
Starting
material
R1
Entry
R3
Yield (%)
(equiv)
(equiv)
1.1
2.5
6.0
6.0
10.0
4.0
6.0
-
5a
5a
5a
5a
5a
5a
5a
6a
5b
5b
6b
5c
Br
Br
Br
Br
Br
Br
Br
-
n-BuLi(1.1)
n-BuLi(2.2)
n-BuLi(2.0)
n-BuLi(5.0)
n-BuLi(9.0)
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TIPS
1
2
6a(24.2) 2(10.8) 8a(58.3)
6a(43.1) 2(20.5) 8a(28.1)
6a(37.8) 2(28.1) 8a(32.9)
6a(48.2) 2(16.8) 8a(30.1)
6a(20.8) 2(20.3) 8a(56.3)
6a(17.7) 2(52.2) 8a(21.8)
3
4
5
tert-BuLi(1.0)
6
tert-BuLi(5.0)
7
6a(3.0)
2(74.9)
2(9.4)
8a(81.5)
Bu4N+F-(0.3)
8
2.5
4.0
-
Br
Br
-
n-BuLi(2.2)
9
6b(44.6) 8b(40.9)
6b(95.0) 8b(3.2)
2(68.8)
tert-BuLi(2.1)
TIPS
10
11
12
Bu4N+F-(0.3)
TIPS
4.0
H
LDA(1.1)
Ts
7c(7.4)
5c(66.0)

THF provided the condensation product at the 2-position, 2-(4-nitro-1,3-butadienyl)-1-p-
toluenesulfonylindole (7c) in 7.4% yield (Entry 12). 7
In this time, the reactions of 1 with 1-protected indolyllithium reagents prepared from 1-silylated 3-
bromoindoles (5) using alkyllithiums afforded 3-substituted indoles (2 and 6) without giving N-substituted
product, followed by 1-deprotection of the silyl group in 6 could provide 3-substituted indole (2).
These results illustrate that alkyllithium reagents have divergent behavior toward 1,3-butadiene group,
depending on the reaction conditions.
EXPERIMENTAL
All melting points were determined on a Yanagimoto melting point apparatus and are uncorrected. IR
1
spectra were recorded with a JASCO FT/IR-8000, JASCO FT/IR-200 spectrophotometer, H-NMR
spectra with a JEOL EX-90, JEOL JNM-GX 270, JEOL JNM-a 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 F254 (silica gel)
were used for column chromatography and TLC, respectively.
The Reaction of the Nitrodienamine (1) with 1-Protected Indoles (5a-c) Using
Alkyllithium:
1-tert-Butyldimethylsilyl-3-(4-nitro-1,3-butadienyl)indole (6a) and 3-(4-Nitro-1,3-
butadienyl)indole (2) and 1-tert-Butyldimethylsilylindole (8a)
The 1.7 M tert-BuLi in hexane solution (75.9 mL, 0.13 mmol) was added to a solution of 3-bromo-1-tert-
butyldimethylsilylindole (5a)6 (40 mg, 0.13 mmol) in dry THF (3 mL) with stirring at -78 °C under a
nitrogen atmosphere and the whole was stirred at -78 °C for 15 min. To resultant solution, a solution of 1
(73.3 mg, 0.52 mmol) in dry THF (4 mL) was added at -78 °C and then the whole was stirred for 1 h
under the same conditions. 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 MgSO4 and concentrated. The residue was subjected to silica gel chromatography. The first eluate

with 5% ethyl acetate in hexane gave 6.5 mg (21.8%) of 8a as colorless needles (ether-hexane), mp 39-40
°C (lit.,7 mp 38-39 °C). This compound was identical with 8a previously reported on the basis of IR, MS
and NMR spectral comparisons.7 Second eluate gave 7.5 mg (17.7%) of 6a as orange plates (hexane-
chloroform), mp 136-137 °C. IR (KBr) cm-1: 1620, 1515, 1490. 1H-NMR (CDCl3) d: 0.64 (6H, s, Me),
0.95 (9H, s, Me), 6.88 (1H, dd, J = 15.6, 12.2 Hz, olefinic H), 7.23 (1H, d, J = 12.2 Hz, olefinic H),
7.26-7.29 (2H, m, aromatic H), 7.36 (1H, d, J = 15.6 Hz, olefinic H), 7.46 (1H, m, aromatic H), 7.51-
7.55 (1H, m, aromatic H), 7.84 (1H, t, J = 12.2 Hz, olefinic H), 7.89 (1H, s, aromatic H). 13C-NMR
(CDCl3) d: 3.97 (SiMe2), 19.26 (SiCMe3), 26.22 (SiCMe3), 114.73 (C7), 116.74 (C2'), 116.95 (C3),
120.21 (C5), 121.70 (C6), 123.12 (C4), 128.18 (C3a), 135.55 (C4'), 136.17 (C2), 140.35 (C1'),
+
141.76 (C3'), 142.48 (C7a). High resolution MS m/z: Calcd for C18H24N2O2Si (M ): 328.1606. Found:
328.1636. Anal. Calcd for C18H24N2O2Si: C, 64.52; H, 7.65; N, 8.85. Found: C, 64.82; H, 7.32; N,
8.55. Third eluate gave 14.4 mg (52.2%) of 2 as dark red prisms (ethyl acetate-hexane), mp 166-167 °C
(lit.,5c mp 175.5-177.5 °C). IR (KBr) cm-1: 3300, 1599, 1574, 1512. 1H-NMR (acetone-d6) d: 6.98-8.07
(9H, m, aromatic and olefinic H), 7.89 (1H, br s, NH). High resolution MS m/z: Calcd for C12H10N2O2
+
(M ): 214.0740. Found: 214.0738. Anal. Calcd for C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found:
C, 67.05; H, 4.80; N, 12.73.
3-(4-Nitro-1,3-butadienyl)indole (2) from 6a
The 1.0 M tetrabutylammonium fluoride in THF solution (27.9 mL, 0.03 mmol) was added to a solution of
6a (30.5 mg, 0.09 mmol) in dry THF (2 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 MgSO4 and concentrated. The
residue was subjected to silica gel chromatography. The eluate with 50% ethyl acetate in hexane gave 14.9
mg (74.9%) of 2 as dark red prisms (ethyl acetate-hexane), mp 165-167 °C (lit.,5c mp 175.5-177.5 °C).
This compound was identical with 2 previously obtained.
3-Bromo-1-triisopropylsilylindole (5b)
The N-bromosuccinimide (NBS) (1.4 g, 7.87 mmol) was added to a solution of 1-triisopropylsilylindole
(8b)9 (2.11 g, 7.73 mmol) in dry THF (40 mL) with stirring at -10 °C under an argon atmosphere and the

whole was gradually raised to rt and was stirred at the rt for 30 min. Pyridine (0.25 mL) and hexane (25
mL) was added to the reaction mixture, then the whole was filtered by Celite. The filtrate was evaporated.
The residue was subjected to Al2O3 chromatography. The eluate with hexane gave 1.74 g (63.9%) of 5b
as colorless prisms (ethyl acetate-hexane), mp 63-64 °C (lit.,8 mp 62-64 °C). This compound was identical
with 5b previously reported on the basis of IR, MS and NMR spectral comparisons.8
1-Triisopropylsilyl-3-(4-nitro-1,3-butadienyl)indole
(8b)
(6b)
and
1-Triisopropylsilylindole
The 1.7 M tert-BuLi in pentane solution (72.8 µL, 0.12 mmol) was added to a solution of 5b (20.5 mg,
0.06 mmol) in dry THF (1 mL) with stirring at -78 °C under a nitrogen atmosphere and the whole was
stirred at -78 °C for 20 min. To resultant solution, a solution of 1 (33.1 mg, 0.23 mmol) in dry THF (2
mL) was added at -78 °C and then the whole was gradually raised to rt. The reaction mixture was poured
into water and extracted with ethyl acetate. The organic layer was washed with brine, then dried over
MgSO4 and concentrated. The residue was subjected to silica gel chromatography. The first eluate with
30% hexane in chloroform gave 0.5 mg (3.2%) of 8b as colorless oil. This compound was identical with
8b previously reported on the basis of IR, MS and NMR spectral comparisons.9 Second eluate gave 20.4
mg (95.0%) of 6b as dark red oil. IR (neat) cm-1: 1615, 1520. 1H-NMR (CDCl3) δ: 1.16 (18H, d, J = 7.3
Hz, Me), 1.72 (3H, sept, J = 7.3 Hz, methine H), 6.89 (1H, dd, J = 15.4, 12.0 Hz, olefinic H), 7.24 (1H,
d, J = 12.0 Hz, olefinic H), 7.27-7.28 (2H, m, aromatic H), 7.38 (1H, d, J = 15.4 Hz, olefinic H), 7.53
(1H, s, aromatic H), 7.54-7.55 (1H, m, aromatic H), 7.86 (1H, t, J = 12.0 Hz, olefinic H), 7.88-7.90
(1H, m, aromatic H). 13C-NMR (CDCl3) δ: 12.71 (SiCHMe2), 18.01 (SiCHMe2), 114.64 (C7), 116.53
(C2'), 116.95 (C3), 120.19 (C6), 121.73 (C5), 123.15 (C3a), 128.18 (C4), 135.43 (C4'), 136.52 (C2),
+
140.54 (C1'), 141.85 (C3'), 142.32 (C7a). High resolution MS m/z: Calcd for C21H30N2O2Si (M ):
370.2076. Found: 370.2075.
3-(4-Nitro-1,3-butadienyl)indole (2) from 6b
The 1.0 M tetrabutylammonium fluoride in THF solution (39.4 µL, 0.04 mmol) was added to a solution of
6b (48.6 mg, 0.15 mmol) in dry THF (1 mL) with stirring at -10 °C under an argon atmosphere and the
whole was stirred at rt for 15 min. The reaction mixture was poured into water and extracted with ethyl

acetate. The organic layer was washed with brine, then dried over MgSO4 and concentrated. The residue
was subjected to silica gel chromatography. The eluate with 50% ethyl acetate in hexane gave 21.8 mg
(68.8%) of 2 as dark red prisms (ethyl acetate-hexane), mp 165-167 °C. This compound was identical with
2 previously obtained.
2-(4-Nitro-1,3-butadienyl)-1-p-toluenesulfonylindole (7c)
The 1.5 M BuLi in hexane solution (82.5 µL, 0.12 mmol) was added to a solution of diisopropylamine
(18.6 µL, 0.13 mmol) in dry THF (1 mL) with stirring at -78 °C under a nitrogen atmosphere and the
whole was stirred at 0 °C for 30 min. To resultant solution, a solution of 1-p-toluenesulfonylindole (5c)10
(30.0 mg, 0.11 mmol) in dry THF (1 mL) was added at -78 °C and then the whole was stirred at -78 °C for
1 h and then at 0 °C for 1 h. A solution of 1 (62.9 mg, 0.44 mmol) in dry THF (1 mL) was added to the
reaction mixture at -78 °C and the whole was stirred at -78 °C for 2 h. The reaction mixture was poured into
water and extracted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO4
and concentrated. The residue was subjected to silica gel chromatography. The first eluate with 50%
chloroform in hexane gave 19.8 mg (66.0%) of 5c as colorless prisms (ether-hexane), mp 85 °C (lit.,10
mp 85 °C). This compound was identical with 5c previously reported on the basis of IR, MS and NMR
spectral comparisons.10 Second eluate gave 3.0 mg (7.4%) of 7c as dark red prisms (methanol), mp 205
1
°C (decomp). IR (KBr) cm-1: 1610, 1500. H-NMR (CDCl3) δ: 2.32 (3H, s, Me), 6.82 (1H, dd, J = 15.1,
12.3 Hz, olefinic H), 7.03 (1H, s, aromatic H), 7.24 (1H, d, J = 12.3 Hz, olefinic H), 7.18 (2H, d, J =
8.6 Hz, aromatic H), 7.27 (1H, t, J = 7.6 Hz, aromatic H), 7.39 (1H, t, J = 7.6 Hz, aromatic H), 7.50
(1H, d, J = 7.6 Hz, aromatic H), 7.60 (2H, d, J = 8.6 Hz, aromatic H), 7.85 (1H, t, J = 12.3 Hz, olefinic
H), 7.96 (1H, d, J = 15.1 Hz, olefinic H), 8.22 (1H, d, J = 7.6 Hz, aromatic H). 13C-NMR (CDCl3) δ:
21.60 (-Me), 112.17 (C3), 115.37 (C2'), 121.52 (C3), 123.18 (C5), 124.52 (C6), 126.51 (C3",5"),
126.57 (C4), 129.37 (C3a), 129.89 (C2",6"), 134.53 (C4'), 135.10 (C4"), 137.05 (C2), 138.08 (C7a),
+
138.51 (C1'), 139.19 (C3'), 145.31 (C1"). High resolution MS m/z: Calcd for C19H16N2O4S (M ):
368.0828. Found: 368.0802.
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