Palladium-catalysed amination of 2-acyl-1-alkyl-5-bromopyrroles

Article abstract of DOI:10.1016/j.tetlet.2003.11.029

The first intermolecular C-N bond-forming reactions between substituted 2-bromopyrroles and primary and cyclic secondary amines were performed using Pd₂(dba)₃ as catalyst with BINAP as the ligand. The aminations proceeded in the presence of NaO^tBu at 80-100°C in 31-93% yields.

Full text of DOI:10.1016/j.tetlet.2003.11.029

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 769–772
Palladium-catalysed amination of 2-acyl-1-alkyl-5-bromopyrrolesq
Isabel Castellote, Juan J. Vaquero and Julio Alvarez-Builla*
ꢀ
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Universidad de Alcala, 28871-Alcalade Henares, Madrid, Spain
Received 3 October 2003; revised 4 November 2003; accepted 10 November 2003
Abstract—The first intermolecular C–N bond-forming reactions between substituted 2-bromopyrroles and primary and cyclic
secondary amines were performed using Pd2(dba)3 as catalyst with BINAP as the ligand. The aminations proceeded in the presence
of NaOtBu at 80–100 ꢀC in 31–93% yields.
ꢁ 2003 Elsevier Ltd. All rights reserved.
In conjunction with our recent work on the chemistry
R
Ph
Me
and biology of pyrrolodiazines1–4 we had to prepare a
series of dihydropyrrolo[1,2-a]pyrazine derivatives of
general structure 1 (Fig. 1). As it was envisaged that a
palladium-catalysed amination of the appropriate
haloheterocycle would provide the desired series, we
needed to investigate the palladium-catalysed amination
of the pyrrole moiety.
Br
Br
Ar
N
N
N
N
R
N
O
Me
N
1
2
3
Figure 1.
parent heterocycle and a protected model (Me, TIPS).12
Thus we selected 2-acetyl-5-bromo-1-methylpyrrole 213
as the simplest model to establish the most effective
conditions for the C–N bond formation.
Although palladium-catalysed carbon–nitrogen bond
formation using aryl halides has been extensively
investigated in recent years,5–8 allowing the coupling of a
great variety of amines with any halobenzene or halo-
azine, no broadly applicable methodology had been
developed to prepare five-membered heterocycles9;10
until very recently when Hartwig reported the successful
amination of halofurans, -thiophenes, -thiazoles,
-oxazoles, -indoles and -benzimidazoles.11 However, the
methodology was not extended to halopyrroles because
of the instability of these substrates. Herein we wish to
report our progress in the Pd-catalysed cross coupling
reaction between functionalised 2-bromopyrroles 2 and
3 and a selection of primary and secondary amines.
Initially, the reaction between 2 and morpholine was
tested using Pd2(dba)3 as catalyst in the presence of
different ligands such as dppf, BINAP, PtBu3 and
biphenyl PtBu2. Using a strong base such as NaOtBu in
THF, the dppf ligand failed to form any coupled
product whereas in toluene PtBu3 and biphenyl PtBu2
produced low or moderate yields. Racemic BINAP
appeared to be the ligand, which afforded the best yield14
in combination with NaOtBu (weaker bases such as
CsCO3 and K3PO4 were also tested) in toluene at 80 ꢀC.
Using the optimised conditions shown in Scheme 1 a
variety of cyclic secondary amines (Table 1, entries 1–6)
were successfully coupled with substrate 2 with yields
shown in Table 1. However, when the above optimised
conditions were applied to the coupling reaction of 2
and acyclic secondary amines such as di-n-butylamine,
diphenylamine and dipropenylamine, no reaction was
observed. An alternative study of the reaction condi-
tions for the coupling of di-n-butylamine and 2 using the
same ligands in combination with Pd(OAc)2 or Pd(dba)2
was also unsuccessful.
As a starting point, it is noticeable that all our attempts
to carry out the amination reaction between morpholine
and either 2- or 3-bromopyrrole failed both with the
Keywords: Palladium; Catalysed; Amination; Functionalised; 2-Halo-
pyrroles.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.11.029
* Corresponding author. Tel.: +34-1-918854606; fax: +34-1-9188546-
86; e-mail: julio.alvarez@uah.es
0040-4039/$ - see front matter ꢁ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.029

770
I. Castellote et al. / Tetrahedron Letters 45 (2004) 769–772
Pd2(dba)3 (2%)
BINAP (4%)
NaOtBu (1.4 equiv)
R
R
R
Me
Me
N
R
Br
+
H
N
N
N
O
O
°
Toluene, 80
C
Me
Me
2
4
Scheme 1.
Table 1. Palladium-catalysed amination of 2-acetyl-5-bromo-1-methylpyrrole (2)
Entry
Amine
Coupling product (4)
Yield (%)
73
Me
NH
O
1
N
N
O
O
Me
Me
NH
N
2
3
65
93
N
N
O
Me
Me
NH
Me
N
N
N
Me
O
Me
Me
Me
Me
NH
4
5
EtO2C
N
85
69
N
N
N
N
N
N
N
CO2Et
O
O
O
Me
NH
N
Ph
N
N
Ph
Me
NH
6
7
80
Ph
N
Me
Ph
Me
Me
Bu
N
N
0
NH
O
Bu
Me
Me
NH2
Me
Me
Me
8
9
82
48
MeO
N
H
N
OMe
O
O
O
Me
Me
Me
NH2
N
H
N
Me
OMe
MeO
NH2
10
11
50
45
N
H
N
Me
NH2
Me
Me
N
H
N
O
O
Me
12
31
NH2
N
H
N
Me

I. Castellote et al. / Tetrahedron Letters 45 (2004) 769–772
771
Pd2(dba)3 (2%)
BINAP (4%)
NaOtBu (1.4 equiv)
Ph
Br
+
H
N
Ph
N
N
N
°
Toluene, 100 C
N
N
5
3
Scheme 2.
Table 2. Palladium-catalysed amination of 6-bromo-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine (3)
Entry
Amine
Coupling product (5)
Yield (%)
69
1
NH
O
Ph
Ph
N
N
O
N
2
64
NH
N
N
N
NH
Ph
N
69
45
3
4
N
N
NH
Ph
N
N
Me
N
Me
Me
Ph
Me
N
NH
5
6
43
51
Ph
N
N
N
N
N
NH
Ph
N
N
Ph
In contrast with the lack of reactivity of di-n-butyl-
amine, primary amines did react with 2 under the same
conditions used for cyclic secondary amines, affording
the corresponding coupled products in good (Table 1,
entry 8) or moderate yields (Table 1, entries 9–12).15
These isolated yields were moderate at least in part
because of the difficulties of isolation of the amines 4
(Table 1, entries 9–12).
perature, with heating at 100 ꢀC (instead of 80 ꢀC used
for substrate 2) affording the best isolated yields.17
In summary, we have studied the conditions for the
amination of 6-bromo-1-phenyl-3,4-dihydro-pyrrolo-
[1,2-a]pyrazine using 2-acetyl-5-bromo-1-methyl-
pyrrole as a simple model for the palladium-catalysed
amination, which occurred in the presence of Pd2(dba)3,
BINAP and NaOtBu in toluene at 80–100 ꢀC. This pro-
cedure allowed for, the first time, the amination of
substituted 2-halopyrroles with cyclic secondary and
primary amines. Work is in progress to extend this
methodology to a variety of substituted 2- and 3-halo-
pyrroles.
The large difference in reactivity of substrate 2 with the
selection of amines tested was also found with 6-bromo-
1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine 3.16 In fact,
this substrate only reacted with cyclic secondary amines,
affording compounds 5 shown in Table 2. No acyclic
secondary or primary amine reacted under the condi-
tions employed for the successful coupling of cyclic
secondary amines or under any of the other conditions
tested [Pd(dba)2 or Pd(OAc)2 and PtBu3, ferrocenyl
di-tert-butylphosphine, biphenyl PtBu2 or dppf], with
substrate 3 being recovered unaltered or as the debro-
minated compound (Scheme 2). It is noteworthy that in
this case the yields of amination using cyclic secondary
amines were strongly dependent on the reaction tem-
Acknowledgements
ꢀ
Financial support from the Comision Interministerial de
Ciencia y Tecnologıa (CICYT, project BQU2001-1508)
ꢀ
is gratefully acknowledged.

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I. Castellote et al. / Tetrahedron Letters 45 (2004) 769–772
15. General procedure for the reaction of 2. An oven-dried
References and notes
glass vial was charged with 2 (1.0 mmol), 1.2 mmol (entries
1–8, 10) or 3.0 mmol (entries 9, 11, 12) of the amine,
NaOtBu (1.4 mmol), Pd2(dba)3 and (0.02 mmol), and
BINAP (0.04 mmol), in dry toluene (2 mL) under argon.
The flask was immersed in an oil bath heated at 80 ꢀC and
stirred overnight. The solution was then allowed to cool to
room temperature, taken up in CH2Cl2 (10 mL), filtered
over Celite and concentrated. Column chromatography of
the residue on silica gel using EtOAc as eluent gave pure
compounds 4.
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1. Mınguez, J. M.; Castellote, M. I.; Vaquero, J. J.; Garcıa
Navıo, J. L.; Alvarez-Builla, J.; Castano, O.; Andres, J. L.
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Alvarez-Builla, J. Tetrahedron Lett. 1996, 37, 4263.
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Navıo, J. L.; Alvarez-Builla, J.; Castano, O.; Andres, J. L.
Tetrahedron 1997, 53, 9341.
4. Minguez, J. M.; Vaquero, J. J.; Alvarez-Builla, J.;
16. This compound was prepared (Castellote, I. Ph.D. Thesis,
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~
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Castano, O.; Andres, J. L. J. Org. Chem. 1999, 64, 7788.
5. Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
6. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
7. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805.
University of Alcala, 2001) by bromination with NBS
(1.5 mmol, CH2Cl2) of the corresponding 1-phenyl-3,4-
dihydropyrrolo[1,2-a]pyrazine, which was obtained fol-
lowing the method described by Flament, I.; Sonney, P.;
Ohloff, G. Helv. Chim. Acta 1997, 60, 1872.
(3): Mp 84–86 ꢀC; IR (KBr) mmax (cmꢀ1): 2947, 1589, 1566,
1408, 1036. 1H NMR (300 MHz, DMSO-d6) d (ppm) 7.72–
7.69 (m, 2H); 7.43–7.40 (m, 3H); 6.37 (d, 1H, J ¼ 4:0 Hz);
6.23 (d, 1H, J ¼ 4:0 Hz); 4.04–3.92 (m, 4H). 13C NMR
(50 MHz, CDCl3) d (ppm) 159.8, 137.5, 128.4, 128.3,
125.8, 113.2, 110.8, 106.4, 48.0, 40.2; Anal. Calcd for
C13H11BrN2; C, 56.75; H, 4.03; N, 10.18. Found: C, 56.49;
H, 4.23; N, 10.11.
8. Hartwig, J. F. In Modern Amination Methods; Ricci, A.,
Ed.; Wiley-VCH: Weinheim, Germany, 2000.
9. For aminations of thiophenes, see: (a) Watanabe, M.;
Yamamoto, T.; Nishiyama, M. Chem. Commun. 2000,
133; (b) Luker, T. J.; Beaton, H. G.; Whiting, M.; Mete,
A.; Cheshire, D. R. Tetrahedron Lett. 2000, 41, 7731; (c)
Ogawa, K.; Radke, K. R.; Rothstein, S. D.; Rasmussen, S.
C. J. Org. Chem. 2001, 66, 9067.
10. For amination of thiazoles and imidazoles, see: (a) Hong, Y.;
Tanoury, G. J.; Wilkinson, S. H.; Bakale, R. P.; Wald, S. A.;
Senanayake, C. H. Tetrahedron Lett. 1997, 38, 5607; (b)
Wang, Z.; Rizzo, C. J. Org. Lett. 2001, 3, 565; (c) Schoffers,
E.; Olsen, P. D.; Means, J. C. Org. Lett. 2001, 3, 4221.
11. Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org.
Chem. 2003, 68, 2861.
12. This study was carried out before HartwigÕs work in Ref.
11 was published.
13. Kim, E.-H.; Koo, B.-S.; Song, C.-E.; Lee, K.-J. Synth.
Commun. 2001, 31, 3627.
14. Both racemic and R-(+)-BINAP give the same yields in the
amination reaction.
17. General procedure for the reaction of 3. An oven-dried
glass vial was charged with 3 (1.0 mmol), 1.2 mmol of the
amine, NaOtBu (1.4 mmol), Pd2(dba)3 and (0.02 mmol),
and BINAP (0.04 mmol) in dry toluene (2 mL) under
argon. The flask was immersed in an oil bath heated at
100 ꢀC and stirred overnight. The solution was then
allowed to cool to room temperature, diluted with water
(15 mL) and extracted with CH2Cl2 (3 · 15 mL). The
organic phase was dried (Na2SO4), concentrated in vacuo
and the residue chromtographed on silica gel. Com-
pounds 5 were isolated using CH2Cl2/MeOH (8:2) satu-
rated with ammonia as eluent.