A heterotrimetallic Pd-Sm-Pd complex for asymmetric Friedel-Crafts alkylations of pyrroles with nitroalkenes

Article abstract of DOI:10.1039/c2ob25074h

Catalytic asymmetric Friedel-Crafts alkylations of pyrroles and nitroalkenes were carried out by using a novel heterotrimetallic Pd-Sm-Pd catalyst based on a simple chiral ligand 1, to give the adducts with high yields and up to 93% ee. The Royal Society

Full text of DOI:10.1039/c2ob25074h

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A heterotrimetallic Pd–Sm–Pd complex for asymmetric Friedel–Crafts
alkylations of pyrroles with nitroalkenes†
Guoqi Zhang‡*
Received 11th January 2012, Accepted 2nd February 2012
DOI: 10.1039/c2ob25074h
systems involving ligands 1–3 as catalysts for asymmetric
Friedel–Crafts alkylation of pyrrole 4a with nitrostyrene 5a
(Table 2). The initial catalyst screening was performed in THF at
room temperature using the combination of reduced Schiff base
1, Cu(OAc)2 and Eu(OTf)3 in a 2 : 2 : 1 ratio (entry 1, Table 1).†
To our delight, good enantioselectivity was observed for the
product 6aa (70% ee) with the presence of only 2.5 mol% of cat-
alyst, while the yield was moderate. The ee was slightly
increased by replacing Eu(OTf)3 with Sm(OTf)3, with almost no
change in yield (entry 2, Table 1). However, the replacement of
other rare earth salts gave much inferior results (entries 3 and 4,
Table 1). Next changing the transition metals into NiII, ZnII,
MnII or PdII which are well suited for the inner N2O2 cavity of 1
was studied (entries 5–8, Table 1).10 Interestingly, the choice of
Pd(OAc)2 resulted in a remarkable improvement in terms of
yield and ee value (86% yield and 85% ee). Further trials in
other solvent conditions gave much lower enantioselectivity,
although the yield was very high using toluene as a solvent
(entries 9–11, Table 1). It was assumed that a cooperative trime-
tallic complex species was responsible for the reactivity observed
above, on the basis of our further catalysts screening, as no reac-
tion happened at all while using Pd(OAc)2 or Sm(OTf)3 alone as
Catalytic asymmetric Friedel–Crafts alkylations of pyrroles
and nitroalkenes were carried out by using a novel heterotri-
metallic Pd–Sm–Pd catalyst based on a simple chiral ligand
1, to give the adducts with high yields and up to 93% ee.
In synthetic chemistry, the Friedel–Crafts alkylation is one of the
most important C–C bond formation reactions.1 Studies on cata-
lytic asymmetric Friedel–Crafts reactions are a focus of current
research, and great progress has been witnessed in the recent
decade.2,3 Pyrroles are important structural units or building
blocks of natural products and pharmaceuticals.4 However, the
asymmetric Friedel–Crafts alkylations using pyrroles, especially
unprotected pyrroles are less explored,5 due to the relative
instability of pyrroles towards acidic environments.6 The asym-
metric Friedel–Crafts reactions between pyrroles and nitroalk-
enes are very useful and highly desirable in organic synthesis.
Surprisingly, efficient catalytic versions for these reactions
remain extremely rare.6,7 Among these, there are three examples
concerning mono- or dinuclear zinc complexes,6,7a,b one of a
Schiff base-Cu complex7c and an organocatalytic version dealing
with chiral phosphoric acids as catalysts.7d Constable and co-
workers have recently reported on the catalytic asymmetric
Henry reaction using bimetallic complexes of salen or reduced
salen ligands 1–3 (Scheme 1), and have found that both yields
and enantioselectivities could be improved significantly in the
presence of a second metal center.8 We report here the asym-
metric Friedel–Crafts alkylations of unprotected pyrroles with
nitroolefins catalyzed by a novel heterotrinuclear Pd–Sm–Pd
complex of 1.
Salen-type Schiff base ligands with a pendant O4 cavity have
been extensively applied as bimetallic catalysts for a range of
asymmetric reactions by Shibasaki and coworkers.9 It has been
recently observed that Schiff base 2 could be an ideal building
block for construction of ionic di- or tri-metallic complexes.10
Therefore, it was of interest to investigate the multimetallic
Department of Chemistry, University of Basel, Spitalstrasse 51,
CH-4056 Basel, Switzerland. E-mail: gqzhang79@gmail.com
†Electronic supplementary information (ESI) available: Experimental
procedures and characterization data of new compounds, chiral HPLC
profiles. CCDC reference number 842060. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2ob25074h
‡Present address: Chemistry Division, Los Alamos National Laboratory,
NM, 87544, United States.
Scheme 1 Structures of chiral ligands 1–3 and proposed structure of
ionic heterotrimetallic Pd–Sm–Pd complex.
2534 | Org. Biomol. Chem., 2012, 10, 2534–2536
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Table 1 Optimization of reaction conditions of heterotrimetallic
complexes catalyzed Friedel–Crafts reaction of pyrrole and
β-nitrostyrenea
Metal sources
Entry
Mb
Rec
Solvent
Yield (%)d
ee (%)e
Fig. 1 X-ray structure of the cationic heterotrimetallic Pd–Sm–Pd
complex with 1. Three triflate counterions and solvent molecules were
omitted for clarity.
1
2
3
4
5
6
7
8
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Ni(II)
Zn(II)
Mn(II)
Pd(II)
Pd(II)
Pd(II)
Pd(II)
Pd(II)
—
Eu
Sm
La
THF
THF
THF
THF
THF
THF
THF
THF
EtOH
CH2Cl2
Toluene
THF
THF
THF
THF
THF
THF
THF
52
54
40
0
70
72
34
—
—
12
—
85
8
60
67
—
—
85
83
19
14
—
Yb
Sm
Sm
Sm
Sm
Sm
Sm
Sm
—
Sm
Sm
Sm
Sm
Sm
Sm
0
of 1, Pd(OAc)2 and Sm(OTf)3 did not improve the result signifi-
cantly (entries 14–16, Table 1). The use of ligands 2 and 3
resulted in much lower ee value or even no reactivity (entries 17
and 18, Table 1). These results indicated that the 1/Pd(OAc)2/Sm
(OTf)3 (2 : 2 : 1) combination as well as THF as a solvent were
essential to obtain both high reactivity and enantioselectivity in
the present reaction.
14
<5
86
62
92
95
0
9
10
11
12
13
14f
15g
16h
17i
18j
0
Pd(II)
Pd(II)
Pd(II)
Pd(II)
Pd(II)
38
88
71
50
<5
The substrate scope of the reaction under optimized reaction
conditions was investigated as summarized in Table 2. Several
substituted nitroalkenes 5b–e, containing both electron-donating
and electron-withdrawing groups were tested, and excellent
yields and high enantioselectivities were observed for the result-
ing adducts with 4a (entries 2–5, Table 2). Heteroaryl-substituted
nitroalkenes 5f and 5g were well tolerated for the reaction under
the optimized conditions, and the thiophene-derived substrate
gave the highest ee value (93% ee, entry 7, Table 2). In contrast,
the alkyl-substituted nitroalkene 5h gave much lower yield and
selectivity (entry 8, Table 2). Substituted pyrroles were also
tested. The pyrrole bearing an ethyl substituent at the 2-position
was applicable for the Friedel–Crafts reactions (entries 9–12,
Table 2), although in some cases only inferior enantioselectiv-
ities were obtained (entries 9 and 10, Table 2). Nevertheless, the
observed catalyst system is suitable for a wide range of substrates
for both substituted pyrroles and nitroalkenes as presented
above, and the results here are well comparable to other reported
results.6,7
a Reactions performed with pyrrole 4a (3 equiv.) and nitrostyrene 5a (1
equiv.) in the air. b M(OAc)2 was used. c Re(OTf)3 was used, where Re
represents rare earth. d Yields of isolated 6aa by column
chromatography. e Enantiomeric excess (ee) was determined by HPLC
using a Chiralcel OD-H column. f The reaction was performed at 0 °C.
g With 5 mol% catalyst. h 1/M/Re = 1 : 1 : 1 and with 5 mol% catalyst.
i Ligand 2 was used. j Ligand 3 was used.
Table 2 Catalytic asymmetric Friedel–Crafts reaction of various
pyrroles and nitroalkenesa
Product Yield (%)b ee (%)c
The absolute stereochemistry of the products was determined
by comparison of the optical rotations with those reported by
You and Du et al. in the literature.7 The absolute configuration
of the products was determined to be R.
Entry Pyrrole Nitroalkene (R′)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
C6H5– (5a)
6aa
6ab
6ac
6ad
86
92
94
93
92
95
86
55
86
90
92
94
85
91
71
80
89
85
93
59
66
50
85
87
4-F–C6H5– (5b)
4-Cl–C6H5– (5c)
4-Br–C6H5– (5d)
4-MeO–C6H5– (5e) 6ae
2-Furyl– (5f) 6af
2-Thiophenyl– (5g) 6ag
n-Butyl– (5h)
C6H5– (5a)
4-Br–C6H5– (5d)
2-Furyl– (5f)
To ascertain the structure of the catalytic species in the reac-
tions, 1, Pd(OAc)2 and Sm(OTf)3 were combined in a 2 : 2 : 1
ratio in THF, after stirring and removal of the solvent, the result-
ing solid was recrystallized by slow diffusion of diethyl ether
into a chloroform–toluene solution of 1a, yellow crystals were
obtained within two weeks (see ESI†). The main structure of the
complex was unambiguously elucidated by single crystal X-ray
crystallography, though the crystal quality was not perfect.
Indeed, a heterotrinuclear complex was observed in the crystal
structure (see Fig. 1 and Fig. S1†), which is consistent with the
optimized catalyst system utilized for the asymmetric Friedel–
Crafts alkylation. The samarium ion was bound between two
[Pd-1] coordination domains with the outer O4 cavities and one
water molecule saturated the nine-coordinate sphere of SmIII. We
proposed that during the catalytic reaction, this trinuclear
6ah
6ba
6bd
6bf
9
10
11
12
2-Thiophenyl– (5g) 6bg
a The reactions were performed using 2.5 mol% 1–Pd(OAc)2–Sm(OTf)3
(2 : 2 : 1). b Yields of isolated
6
by column chromatography.
c Enantiomeric excess (ee) was determined by HPLC using Chiralcel
OD-H or AD-H columns.
metal salts (entries 12 and 13, Table 1). Lowering the reaction
temperature, increasing the catalyst loading or changing the ratio
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4 For selected examples: (a) A. Fürstner, K. Radkowski and H. Peters,
Angew. Chem., Int. Ed., 2005, 44, 2777; (b) A. Fürstner, Angew. Chem.,
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Chem. Soc., 2002, 124, 6900; (d) H. Hoffmann and T. Lindel, Synthesis,
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S. Baran, J. M. Richter and D. W. Lin, Angew. Chem., Int. Ed., 2005, 44,
609.
5 (a) G. Blay, I. Fernández, J. R. Pedro and C. Vila, Org. Lett., 2007, 9,
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complex behaved as a bifunctional catalyst to activate both sub-
strates with PdII and SmIII active sites,11 similar to the reported
working model with a dinuclear ZnII catalyst.6
In summary, the enantioselective Friedel–Crafts reactions
of unprotected pyrroles with nitroalkenes catalyzed by a novel
Pd–Sm–Pd heterotrimetallic complex based on a simple reduced
Schiff base ligand. The catalyst can be readily prepared in situ
and was structurally characterized by X-ray crystallography, and
the reactions were usually performed under mild reaction con-
ditions without protection. This protocol provides a facile access
to highly enantioenriched 2-substituted and 2,5-disubstituted
pyrroles. Further investigations concerning other applications of
similar trimetallic complexes are under way.
Acknowledgements
6 B. M. Trost and C. Müller, J. Am. Chem. Soc., 2008, 130, 2438.
7 (a) H. Liu, S.-F. Lu, J.-X. Xu and D.-M. Du, Chem.–Asian J., 2008, 3,
1111; (b) N. Yokoyama and T. Arai, Chem. Commun., 2009, 3285;
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Chem.–Eur. J., 2011, 17, 11127; (d) Y.-F. Sheng, Q. Gu, A.-J. Zhang and
S.-L. You, J. Org. Chem., 2009, 74, 6899.
The author thanks the generous support from Prof. Wolf-D.
Woggon (University of Basel) for this work, and the Novartis
Foundation, formerly the Ciba-Geigy Jubilee Foundation, for
financial support.
8 (a) E. C. Constable, G. Zhang, C. E. Housecroft, M. Neuburger,
S. Schaffner and W.-D. Woggon, New J. Chem., 2009, 33, 1064;
(b) E. C. Constable, G. Zhang, C. E. Housecroft, M. Neuburger,
S. Schaffner, W.-D. Woggon and J. A. Zampese, New J. Chem., 2009, 33,
2166.
Notes and references
1 For reviews of Friedel–Crafts alkylation reactions, see: (a) G. A. Olah,
Friedel–Crafts and Related Reactions, Wiley-Interscience, New York,
1964, vol. II, Part 1; (b) R. M. Roberts and A. A. Khalaf, Friedel–Crafts
Alkylation Chemistry A Century of Discovery; Dekker, New York, 1984;
(c) G. A. Olah, R. Krishnamurit, G. K. S. Prakash, Friedel–Crafts Alky-
lations in Comprehensive Organic Synthesis; Pergamon Press, Oxford,
1991.
2 For recent reviews, see: (a) M. Bandini, E. Emer, S. Tommasi and
A. Umani-Ronchi, Eur. J. Org. Chem., 2006, 3527; (b) M. Bandini,
A. Melloni, S. Tommasi and A. Umani-Ronchi, Synlett, 2005, 1199–
1222; (c) M. Bandini, A. Melloni and A. Umani-Ronchi, Angew. Chem.,
Int. Ed., 2004, 43, 550–556; (d) K. A. E. Jørgensen, Synthesis, 2003,
1117.
3 For recent examples, see: (a) Y. X. Jia, S. F. Zhu, Y. Yang and
Q. L. Zhou, J. Org. Chem., 2006, 71, 75; (b) H. M. Li, Y. Q. Wang and
L. Deng, Org. Lett., 2006, 8, 4063; (c) R. P. Herrera, V. Sgarzani,
L. Bernardi and A. Ricci, Angew. Chem., Int. Ed., 2005, 44, 6576;
(d) T. Poulsen and K. A. Jørgensen, Chem. Rev., 2008, 108, 2903;
(e) S.-L. You, Q. Cai and M. Zeng, Chem. Soc. Rev., 2009, 38, 2190.
9 (a) Z. Chen, H. Morimoto, S. Matsunga and M. Shibasaki, J. Am. Chem.
Soc., 2008, 130, 2170; (b) Z. Chen, K. Yakura, S. Matsunga and
M. Shibasaki, Org. Lett., 2008, 10, 3239; (c) S. Handa, V. Gnanadesikan,
S. Matsunga and M. Shibasaki, J. Am. Chem. Soc., 2007, 129, 4900;
(d) N. E. Shepherd, H. Tanabe, Y. Xu, S. Matsunaga and M. Shibasaki, J.
Am. Chem. Soc., 2010, 132, 3666; (e) S. Handa, V. Gnanadesikan,
S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 4925;
(f) I. Fujimori, T. Mita, K. Maki, M. Shiro, A. Sato, S. Furusho,
M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2006, 128, 16438.
10 (a) E. C. Constable, G. Zhang, C. E. Housecroft, M. Neuburger and
J. A. Zampese, CrystEngComm, 2010, 12, 1764 and references therein;
(b) E. C. Constable, G. Zhang, C. E. Housecroft, M. Neuburger and
J. A. Zampese, Inorg. Chim. Acta, 2010, 363, 4207.
11 We assumed that water molecule bound to the SmIII center was readily
removed in the presence of relatively strong coordinated substrates
(bearing pyrrole–NH or nitro–O), thus the SmIII ion of the complex acti-
vated one substrate and the PdII ion activated the other one.
2536 | Org. Biomol. Chem., 2012, 10, 2534–2536
This journal is © The Royal Society of Chemistry 2012