Palladium-catalyzed cycloisomerization of (Z)-(2-en-4-ynyl)amines: A new synthesis of substituted pyrroles

Article abstract of DOI:10.1016/S0040-4039(00)02206-1

(Z)-(2-En-4-ynyl)amines 1 bearing an internal triple bond undergo smooth cycloisomerization into pyrroles 2 in the presence of catalytic amounts of PdCl₂ in conjunction with KCl at 25-100°C in anhydrous N,N-dimethylacetamide. When the triple bo

Full text of DOI:10.1016/S0040-4039(00)02206-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1339–1341
Palladium-catalyzed cycloisomerization of
(Z)-(2-en-4-ynyl)amines: a new synthesis of substituted pyrroles
Bartolo Gabriele,* Giuseppe Salerno,* Alessia Fazio and Maria R. Bossio
Dipartimento di Chimica, Universita` della Calabria, I-87030 Arcavacata di Rende, Cosenza, Italy
Received 11 October 2000; revised 24 November 2000; accepted 29 November 2000
Abstract—(Z)-(2-En-4-ynyl)amines 1 bearing an internal triple bond undergo smooth cycloisomerization into pyrroles 2 in the
presence of catalytic amounts of PdCl2 in conjunction with KCl at 25–100°C in anhydrous N,N-dimethylacetamide. When the
triple bond is terminal, spontaneous uncatalyzed cyclization to the corresponding pyrroles takes place. © 2001 Elsevier Science
Ltd. All rights reserved.
R2
R3
R2
R3
We recently described a new approach to the construc-
tion of the furan or thiophene ring via Pd(II)-catalyzed
cycloisomerization of (Z)-en-4-yn-1-ols1 or (Z)-2-en-4-
yne-1-thiols,2 respectively. We now wish to report a
useful extension of this methodology to the synthesis of
substituted pyrroles3 starting from readily available†
(Z)-(2-en-4-ynyl)amines 1, according to Eq. (1).
Pd cat
R4
N
R1
DMA, 25-100 °C
NH
R1
R4
(1)
2
1
Table 1. Synthesis of pyrroles 2 by cycloisomerization of (Z)-(2-en-4-ynyl)amines 1 (1 equiv.) in anhydrous N,N-dimethyl-
acetamide (DMA) in the presence of PdCl2 (0.01 equiv.) and KCl (0.02 equiv.), substrate conc.: 2 mmol/mL DMA
Run
1
R1
R2
R3
R4
T (°C)
t (h)
Yield of 2 (%)a
1
2
3
4
1a
1b
1c
1d
Bn
H
Bn
Bu
H
H
Et
Ph
Me
Me
H
Bu
Bu
Bu
Bu
100
100
25
6
6
6
4
60 (53)
75 (69)
94 (85)
93 (86)
H
25
a GLC yield (isolated yield) based on starting 1. Substrate conversion was practically quantitative in all cases.
R2
R3
R2
R1
R3
-
- X-
X
PdX2
R4
PdX
R4
2
+
N
- PdX2
NH
H
R1
Scheme 1.
Keywords: cycloisomerization; enynamines; palladium; pyrroles.
* Corresponding authors. Fax: +39 0984 492044; e-mail: b.gabriele@unical.it; g.salerno@unical.it
†
Starting 1 (R1=alkyl) were readily prepared in 50–80% yields from the corresponding (Z)-2-en-4-yn-1-ols1 through bromination with PBr3 in
the presence of pyridine in Et2O at −20°C, followed by nucleophilic substitution with a primary amine in DMF–EtOH at −15 to −10°C under
the conditions described in Ref. 4. Substrates with R1=H were prepared from the corresponding (Z)-2-en-4-yn-1-ols1 by reaction with
phthalimide via a Mitsunobu reaction5 in THF at 25°C, followed by cleavage with hydrazine in refluxing methanol under the conditions
described in Ref. 6.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02206-1

1340
B. Gabriele et al. / Tetrahedron Letters 42 (2001) 1339–1341
1) PBr3, Py, Et2O, - 20°C
2) BnNH2, DMF-EtOH, - 10°C
(49%)
N
NH
Bn
OH
Bn
2e
Scheme 2.
Representative results for enynamines bearing an inter-
nal triple bond are collected in Table 1. In a typical
experiment, PdCl2 (11 mg, 0.06 mmol) and KCl (9 mg,
0.12 mmol) were added under nitrogen to a solution of
1 (6 mmol) in anhydrous N,N-dimethylacetamide
(DMA)‡ (3 mL) in a Schlenk flask. The resulting mix-
ture was stirred under nitrogen for the time required to
obtain a satisfactory conversion, as shown by GLC
and/or TLC analysis (Table 1). After addition of Et2O,
the mixture was filtered from the catalyst, washed with
water and dried over Na2SO4. The solvent was removed
in vacuo, and products were purified by column chro-
matography (SiO2 or neutral Al2O3) using appropriate
hexane–ethyl acetate mixtures as eluent.
1-benzyl-2,3-dimethylpyrrole 2e in 49% isolated yield
based on the starting enynol (Scheme 2).§
The reaction reported here is the first example of the
synthesis of pyrroles by a Pd-catalyzed cycloisomeriza-
tion of (Z)-(2-en-4ynyl)-1-amines. Pyrroles are a very
important class of heterocyclic compounds which are
widespread in Nature and find various significant appli-
cations.8
§ 1-Benzyl-2,3-dimethylpyrrole 2e was characterized by comparison
with literature data.7 All new pyrroles were fully characterized by
IR, 1H and 13C NMR spectroscopy, mass spectrometry, and ele-
mental analysis. Spectroscopic and MS data of new compounds:
Compound 2a, yellow oil: IR (neat) 2954 (s), 2927 (s), 2857 (m),
1490 (m), 1453 (m), 1382 (w), 1354 (w), 1333 (m), 726 (m), 698 (s)
The cycloisomerization process of 1a–d did not occur in
the absence of catalyst, as shown by blank experiments.
The use of PdI2+2KI led to comparable results with
respect to PdCl2+2KCl, in terms of reaction times as
well as product yields. This is in contrast to that
previously observed in the cycloisomerization of (Z)-2-
en-4-yn-1-ols and (Z)-2-en-4-yne-1-thiols to furans1 and
thiophenes,2 for which PdI2+2KI proved to be a more
active catalyst.
cm−1 1H NMR (300 MHz, CDCl3) l 7.30–7.17 (m, 3H on phenyl
;
ring), 7.01–6.95 (m, 2H on phenyl ring), 6.49 (d, J=2.9, 1H, H-5),
5.98 (d, J=2.9, 1H, H-4), 4.97 (s, 2H, NCH2), 2.43 (t, J=7.6, 2H,
ꢀCCH2CH2), 2.05 (s, 3H, ꢀCCH3), 1.39–1.17 (m, 6H,
CH2CH2CH2CH3), 0.85–0.79 (m, 3H, CH2CH3); 13C NMR (75
MHz, CDCl3) l 139.10, 129.76, 128.61, 127.24, 126.45, 119.45,
115.23, 108.80, 50.53, 31.64, 29.86, 24.34, 22.44, 13.95, 11.59; MS
m/e 241 (M+, 23), 185 (17), 184 (100), 92 (7), 91 (70), 65 (10).
Compound 2b, yellow oil: IR (neat) 3383 (s), 2955 (m), 2927 (m),
2856 (m), 1463 (w), 713 (m) cm−1 1H NMR (300 MHz, CDCl3) l
;
From the data reported in Table 1 it is evident that
(Z)-(2-en-4-ynyl)amines substituted at C-2 and unsub-
stituted at C-3 (entries 3–4) are considerably more
reactive than the analogous ones substituted at C-3
(entries 1–2). This result suggests that the triple bond
coordinates to Pd(II) from the opposite side with
respect to the -CH2NHR1 moiety; in fact, such a coor-
dination is expected to be more favored in the absence
of a substituent at C-3 for steric reasons. The activated
triple bond then undergoes intramolecular 5-exo-dig
nucleophilic attack by the nitrogen, the catalytic cycle
being completed by protonolysis and aromatization or
vice versa (Scheme 1, X=Cl, I; anionic halide ligands
are omitted for clarity).
7.59 (br s, 1H, NH), 6.52–6.48 (m, 1H, H-5), 5.99–5.94 (m, 1H,
H-4), 2.48 (t, J=7.6, 2H, ꢀCCH2), 2.02 (s, 3H, ꢀCCH3), 1.58–1.44
(m, 2H, ꢀCCH2CH2CH2), 1.39–1.20 (m, 4H, CH2CH2CH3), 0.89 (t,
J=6.9, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) l 128.40,
114.70, 113.54, 109.82, 31.50, 29.81, 25.72, 22.39, 13.87, 10.74; MS
m/e 151 (M+, 17), 95 (7), 94 (100). Compound 2c, yellow oil: IR
(neat) 2958 (s), 2929 (s), 2869 (m), 1454 (m), 1354 (w), cm−1 1H
;
NMR l 7.29–7.14 (m, 3H on phenyl ring), 7.00–6.93 (m, 2H on
phenyl ring), 6.36–6.33 (m, 1H, H-5), 5.85–5.81 (m, 1H, H-3), 4.91
(s, 2H, CH2Ph), 2.52–2.43, (m, 2H, ꢀCCH2CH3), 2.42–2.35 (m, 2H,
ꢀCCH2CH2), 1.61–1.48 (m, 2H, ꢀCCH2CH2), 1.34–1.23 (m, 4H,
CH2CH2CH3), 1.80 (t, J=7.5, 3H, ꢀCCH2CH3), 0.89–0.82 (m, 3H,
CH2CH2CH3); 13C NMR l 139.87, 133.40, 128.50, 127.06, 126.33,
125.10, 117.21, 105.85, 49.92, 31.61, 28.53, 26.04, 22.38, 20.16,
15.17, 13.85; MS m/e 255 (M+, 22), 199 (20), 198 (69), 92 (9), 91
(100), 65 (11). Compound 2d, yellow oil: IR (neat) 2956 (s), 2929
(s), 2869 (m), 1604 (m), 1521 (m), 1455 (m), 1367 (m), 1206 (m), 757
(m), 694 (w) cm−1; 1H NMR (300 MHz, CDCl3) l 7.50–7.45 (m, 2H
on phenyl ring), 7.32–7.25 (m, 2H on phenyl ring), 7.14–7.07 (m, 1H
on phenyl ring), 6.87 (d, J=2.0, 1H, H-5), 6.19 (dt, J=2.0, 1.0, 1H,
H-3), 3.79 (t, J=7.3, 2H, NCH2), 2.53 (td, J=7.8, 1.0, 2H, ꢀCCH2),
1.78–1.63 (m, 4H, NCH2CH2+ꢀCCH2CH2), 1.47–1.30 (m, 6H,
NCH2CH2CH2CH3+CH2CH2CH2CH2CH3), 0.95 (t, J=7.3, 3H,
CH3), 0.95–0.89 (m, 3H, CH3); 13C NMR (75 MHz, CDCl3) l
136.38, 134.35, 128.49, 124.91, 124.81, 123.27, 116.48, 103.60, 46.34,
33.56, 31.80, 28.71, 26.28, 22.58, 20.08, 14.03, 13.75; MS m/e 269
(M+, 65), 227 (7), 226 (28), 213 (29), 212 (100), 198 (30), 185 (7), 184
(26), 182 (9), 171 (36), 170 (61), 169 (8), 168 (7), 157 (13), 156 (33),
129 (11), 128 (25), 127 (11), 115 (12). Elemental analyses were
satisfactory for all compounds.
(Z)-(En-4-ynyl)amines bearing a terminal triple bond
turned out to be unstable and spontaneously underwent
cycloisomerization to the corresponding pyrroles. Thus,
bromination of (Z)-3-methylpent-2-en-4-yn-1-ol fol-
lowed by reaction with benzylamine directly afforded
‡
,
DMA was dried over 4 A molecular sieves and distilled under
nitrogen before use.

B. Gabriele et al. / Tetrahedron Letters 42 (2001) 1339–1341
1341
Acknowledgements
3. For recent reviews on synthesis of aromatic heterocycles,
see: Collins, I. J. Chem. Soc., Perkin Trans. 1 2000,
2845–2861; Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
1999, 2849–2866; Gilchrist, T. L. J. Chem. Soc., Perkin
Trans. 1 1998, 615–628.
Financial support from the Ministero dell’Universita` e
della Ricerca Scientifica e Tecnologica is gratefully
acknowledged.
4. Nussbaumer, P.; Petranyi, G.; Stu¨tz, A. J. Med. Chem.
1991, 34, 65–73.
5. Mitsunobu, O. Synthesis 1981, 1–28.
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