Synthesis of pyridinylpyrrole derivatives via the palladium-catalyzed reaction of acetylpyridines with methyleneaziridines

Article abstract of DOI:10.1021/ja0455401

The reaction of methyleneaziridines with o-, m-, and p-acetylpyridines proceeds very smoothly in the presence of a palladium catalyst, affording the biologically very important o-, m-, and p-pyridinylpyrrole derivatives in good to high yields. Not only ortho, meta, and para, but also related substrates, such as acetyl aromatics and hetarenes, can be used as the starting acetyl derivatives to synthesize related compounds to pyridinylpyrrole derivatives. Copyright

Full text of DOI:10.1021/ja0455401

Published on Web 10/09/2004
Synthesis of Pyridinylpyrrole Derivatives via the Palladium-Catalyzed
Reaction of Acetylpyridines with Methyleneaziridines
Amal I. Siriwardana, Kalum K. A. D. S. Kathriarachchi, Itaru Nakamura, Ilya D. Gridnev, and
Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received July 25, 2004; E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
Table 1. Palladium-Catalyzed Reactions of o-Acetylpyridine 4a
R-Pyridinylpyrroles 1 and their reduced derivatives, pyrrolidines
with the Methyleneaziridines 3a
2, have attracted considerable interest from pharmaceutical and
medicinal chemists due to their biological activities.1 The synthetic
entry
3
product 1
yield of 1/%b
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
1a
1b
1c
1d
1e
1f
69
75
74
87
43
78
74
3g
1g
a The reaction of 3 (0.3 mmol) with 4a (0.6 mmol) was carried out in
the presence of 30 mol % Pd(PPh3)4 without solvent at 120 °C for 3 days
in a pressure vial under Ar atmosphere. b Isolated yield based on 3.
methodologies for these pyrroles are divided into two major
categories: (1) pyridine derivatives, having an alkyl chain with a
1,4-diketone functional group at the ortho, meta, or para position,
are synthesized first, and then they are converted to the corre-
sponding pyrroles through the standard procedures;2 (2) the coupling
reaction between R-metallopyrroles and halopyridines (or vice
versa) under the Kumada, Negishi, and other conditions gives the
desired products 1.3 Catalytic hydrogenation of 1 gives pyrrolidine
derivatives 2.4
Scheme 1
We report herein an entirely new approach for the synthesis of
1 (eq 1). The palladium-catalyzed reaction of the methyleneaziri-
dines 3 with o-acetylpyridine 4a gave the o-pyridinylpyrroles 1 in
good to high yields. Not only o- but also m- and p-acetylpyridines
and related substrates can be used as the starting acetyl derivatives.
The results of the reaction of 4a with 3, having various R
substituents, are summarized in Table 1.
Table 2. Palladium-Catalyzed Reactions of Various
Acetylpyridines 4b-d and Acetylpyrazine 4e with 3ba
entry
4
product 1
yield of 1/%b
1
2
3
4
4b
4c
4d
4e
1h
1i
1j
72
88
72
96
1k
a The reaction of 3b (0.3 mmol) with 4 (0.6 mmol) was carried out in
the presence of 30 mol % Pd(PPh3)4 without solvent at 120 °C for 3 days.
b Isolated yield based on 3b.
reaction of 3e bearing an electron-withdrawing functional group
gave 1e in a moderate yield (entry 5). Furthermore, the reactions
of 3f and 3g proceeded smoothly, producing 1f and 1g in 78% and
74% yields, respectively (entries 6 and 7).
We extended the new methodology to synthesize the m- and
p-pyridinylpyrroles and related compounds 1h-k (Scheme 1, Table
2). The reaction of 3b with the m- and p-pyridine derivatives, 4b
and 4c, afforded 1h and 1i in 72% and 88% yield, respectively
(entries 1 and 2). Similarly, 4d and 4e gave the corresponding
pyrroles 1j and 1k, respectively, in good to high yields (entries 3
and 4).
A plausible mechanism is shown in Scheme 2. The oxidative
insertion of Pd(0) into an R-carbon-hydrogen bond of o-acetyl-
pyridine 4a produces the hydridopalladium species 55 (or its oxa-
π-allyl structure 5′), and then the hydropalladation of 3 with 5 takes
place as shown in 6. Reductive elimination of palladium may then
The reaction of 1-benzyl-2-methyleneaziridine (3a, 0.3 mmol)
with o-acetylpyridine (4a, 0.6 mmol) in the presence of 30 mol %
of Pd(PPh3)4 proceeded smoothly at 120 °C without solvent to give
the corresponding o-pyridinylpyrrole 1a in 69% yield (entry 1).
Other catalysts, such as Pd2(dba)3‚CHCl3, Pd(OAc)2, and Pt(PPh3)4,
did not promote the reaction at all. In the absence of the palladium
catalyst, the reaction did not proceed at all, indicating that the
palladium catalyst is essential to make the above transformation
feasible. In the presence of additional phosphine ligands, such as
dppe, dppb, P(OBu)3, and extra PPh3, unsatisfactory results were
obtained. Normally, 2 equiv of o-acetylpyridine was used. When 1
equiv of 4a was used, the yield of 1a decreased to 55%. Likewise,
the reactions of 3b, 3c, and 3d proceeded smoothly to afford 1b,
1c, and 1d, respectively, in good to high yields (entries 2-4). The
9
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10.1021/ja0455401 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
palladation to the CdC double bond of 3 is proposed (eq 5).9 The
presence of a ketone group in the pertinent position of 6 would
make it possible to lead to the ring-closing reaction (7 f 8).
Scheme 2. Plausible Mechanism for the Formation of
o-Pyridinylpyrrole 1
We have developed a simple and efficient method for the
synthesis of various pyridinylpyrroles using palladium catalyst.
Moderate to good yields of the products are obtained in all cases,
and a wide range of acetyl aromatics and hetarenes can be used as
a starting material, which makes it feasible to synthesize biologically
very important pyridinylpyrrole derivatives and related compounds.
occur to afford the intermediate 7 and Pd(0) species. Subsequent
cyclization affords the intermediate 8, and elimination of H2O
produces 1 (see also the Supporting Information and ref 6).
The fact that not only the o- but also the m- and p-acetylpyridines
undergo rather facile pyrrole formation strongly suggests that a
chelation effect of the nitrogen of pyridine ring on the Pd(0)
insertion step is not essential but the acidity of R-C-H group is a
key for the present interesting transformation.
The reaction of 3a with acetophenone 9 under the same
conditions as above gave 10 in 95% yield (eq 2), indicating that
the chelation effect of nitrogen of pyridine is not operative. The
structure of 10 was confirmed unambiguously by synthesizing its
authentic sample through the reported procedure.7 To confirm the
proposed mechanism, the reaction of deuterated acetophenone 9-d3
with 3a was carried out under the same reaction conditions as shown
in eq 2, giving the deuterated product 11 (d content at C-3 and
CH3 was about 70%) in 82% isolated yield, together with recovered
9-d3 (d content at CH3 group was 55%, eq 3, see also Supporting
Information). Two deuteriums were labeled at CH3 of 11, probably
because the equilibration occurs via reversible â-H (or â-D)
elimination of 13. A strong support for the hydropalladation
mechanism was obtained by the fact that the deuterium labeling
occurred at C-3 of 11.
Supporting Information Available: Experimental procedures and
spectral data for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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