Enantioselective nickel-catalyzed michael additions of 2-acetylazaarenes to nitroalkenes

Article abstract of DOI:10.1021/ol400578c

2-Acetylazaarenes undergo catalytic enantioselective Michael additions to nitroalkenes in the presence of a chiral Ni(II)-bis(oxazoline) complex. The process is tolerant of a range of azines or azoles in the pronucleophilic component, resulting in Michael products in moderate to high enantioselectivities.

Full text of DOI:10.1021/ol400578c

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Enantioselective Nickel-Catalyzed
Michael Additions of 2‑Acetylazaarenes
to Nitroalkenes
Alain J. Simpson and Hon Wai Lam*
EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building,
The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, United Kingdom
h.lam@ed.ac.uk
Received March 2, 2013
ABSTRACT
2-Acetylazaarenes undergo catalytic enantioselective Michael additions to nitroalkenes in the presence of a chiral Ni(II)Àbis(oxazoline) complex.
The process is tolerant of a range of azines or azoles in the pronucleophilic component, resulting in Michael products in moderate to high
enantioselectivities.
The ubiquitous occurrence of azaarenes in chiral, biolo-
gically active compounds and other functional molecules
renders the development of new catalytic enantioselective
methods to prepare chiral azaarene-containing compounds
a valuable objective. In this context, recent work from our
group has targeted the utilization of the CdN moiety
embedded within various azaarenes for the activation of
adjacent alkenyl or alkyl groups in several catalytic enantio-
selective processes.1 To increase the range of potential
transformations that may be developed, we became inter-
ested in processes in which the CdN moiety of an azaarene
could participate in other modes of substrate activation.
Recently, the use of 1,2-dicarbonyl compounds as pro-
nucleophiles in catalytic enantioselective reactions has
received increasing attention.2 We therefore questioned
whether the homology between 1,2-dicarbonyls and 2-acyl-
azaarenes could be exploited in the development of
catalytic enantioselective processes that employ the latter
compounds as pronucleophiles. In a similar manner to
1,2-dicarbonyl compounds in related processes,3 two-
point binding of a 2-acylazaarene toa chiral metal complex
would be expected to facilitate R-deprotonation with a
basic counterion to generate a chiral metal enolate that
could then participate in an enantioselective addition to
an electrophile (Scheme 1). To our knowledge, the use
of 2-acylazaarenes in this manner has not been reported
previously.4 Such a process would be attractive, as the
resulting chiral azaarene-containing products could serve
as valuable building blocks for synthesis. In this paper, we
describe the successful realization of this strategy with the
development of enantioselective nickel-catalyzed Michael
additions of 2-acetylazaarenes to nitroalkenes.5À7
(3) (a) Juhl, K.; Gathergood, N.; Jorgensen, K. A. Chem. Commun.
2000, 2211–2212. (b) Gathergood, N.; Juhl, K.; Poulsen, T. B.; Thordrup,
K.; Jorgensen, K. A. Org. Biomol. Chem. 2004, 2, 1077–1085. (c) Juhl, K.;
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2421. (e) Lu, G.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew.
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Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 3353–3356. (g) Nakamura,
A.; Lectard, S.; Hashizume, D.; Hamashima, Y.; Sodeoka, M. J. Am.
Chem. Soc. 2010, 132, 4036–4037. (h) Xu, Y.; Matsunaga, S.; Shibasaki,
M. Org. Lett. 2010, 12, 3246–3249. (i) Shi, D.; Xie, Y.; Zhou, H.; Xia, C.;
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Chem. Soc. 2010, 132, 14373–14375. (c) Saxena, A.; Choi, B.; Lam,
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10.1021/ol400578c
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Scheme 1. Soft Enolization of 2-Acylazaarenes and Reaction
with Electrophiles
Given the successful use of 1,2-dicarbonyls in metal-
catalyzed enantioselective additions to nitroalkenes by the
groups of Sodeoka,3g Shibasaki,3h and Huang,3i our pre-
liminary experiments focused upon the enantioselective
reaction of the commercially available compounds 2-acetyl-
pyridine (1a) and nitroalkene 2a.8 After a survey of chiral
metal complexes and reaction conditions,9 we were pleased
to find that treatment of a mixture of 1a (1.2 equiv) and 2a
(1.0 equiv) with the complex composed of Ni(OAc)2
4H2O (5 mol %) and the bis(oxazoline) ligand L110,11 in
3
Figure 1. Enantioselective nickel-catalyzed additions of
2-acetylazaarenes to nitroalkene 2a. Reactions were conducted
using 0.60 mmol of acetylazaarene and 0.50 mmol of 2a in 5 mL
of i-PrOH. Yields are of isolated material. Enantiomeric excesses
were determined by chiral HPLC analysis.
(4) For selected examples of catalytic enantioselective reactions of
R,β-unsaturated acylazaarenes that rely upon two-point binding to chiral
metal complexes for activation and enantioinduction, see: (a) Evans,
D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942–
8943. (b) Roelfes, G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44,
3230–3232. (c) Roelfes, G.; Boersma, A. J.; Feringa, B. L. Chem. Commun.
2006, 635–637. (d) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt,
K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129, 10029–10041. (e) Rosati, F.;
Boersma, A. J.; Klijn, J. E.; Meetsma, A.; Feringa, B. L.; Roelfes, G.
i-PrOH at room temperature afforded the Michael adduct
3a in 86% yield and 93% ee (Figure 1).12 Further investiga-
tion revealed that, in addition to 1a, 2-acetylazaarenes
containing quinoline, pyrazine, thiazole, benzothiazole, or
N-methylimidazole groups reacted smoothly with 2a to
provide products 3bÀ3f, respectively, in 64À94% yield and
94À99% ee. Unfortunately, replacement of the methyl
ketone in the pronucleophile with higher homologues such
as an ethyl ketone was problematic; although good reac-
tivity was observed with these substrates, the resulting
products were prone to epimerization at the stereogenic
center adjacent to the ketone during handling and purifica-
tion, resulting in unwieldy mixtures of diastereomers.
The requirement for the CdN moiety in the azaarene to
be adjacent to the carbonyl group for reactivity was
confirmed by the attempted reaction of 4-acetylpyridine
(1g) with 2a, which gave no Michael product under our
reaction conditions (eq 1).13
ꢀ
Chem.;Eur. J. 2009, 15, 9596–9605. (f) Coquiere, D.; Bos, J.; Beld, J.;
Roelfes, G. Angew. Chem., Int. Ed. 2009, 48, 5159–5162. (g) Roe, S.;
Ritson, D. J.; Garner, T.; Searle, M.; Moses, J. E. Chem. Commun. 2010,
46, 4309–4311. (h) Podtetenieff, J.; Taglieber, A.; Bill, E.; Reijerse, E. J.;
Reetz, M. T. Angew. Chem., Int. Ed. 2010, 49, 5151–5155. (i) Boersma,
A. J.; de Bruin, B.; Feringa, B. L.; Roelfes, G. Chem. Commun. 2012, 48,
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Angew. Chem., Int. Ed. 2012, 51, 9352–9355. (k) Blay, G.; Incerti, C.;
~
Munoz, M. C.; Pedro, J. R. Eur. J. Org. Chem. 2013, 1696–1705.
(5) For examples of related enantioselective metal-catalyzed addi-
tions of 1,3-dicarbonyl compounds to nitroalkenes, see: (a) Ji, J.; Barnes,
D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.; Morton, H. E. J. Am.
Chem. Soc. 1999, 121, 10215–10216. (b) Barnes, D. M.; Ji, J.; Fickes,
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11592. (f) Zhu, Q.; Huang, H.; Shi, D.; Shen, Z.; Xia, C. Org. Lett. 2009,
11, 4536–4539. (g) Tsubogo, T.; Yamashita, Y.; Kobayashi, S. Angew.
Chem., Int. Ed. 2009, 48, 9117–9120. (h) Chen, W.-Y.; Ouyang, L.; Chen,
R.-Y.; Li, X.-S. Tetrahedron Lett. 2010, 51, 3972–3974.
(6) For pioneering examples of enantioselective organocatalytic ad-
ditions of aldehydes or ketones to nitroalkenes, see: (a) List, B.;
Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423–2425. (b) Betancort,
J. M.; Barbas, C. F. Org. Lett. 2001, 3, 3737–3740.
(7) For reviews covering enantioselective organocatalytic additions
of aldehydes or ketones to nitroalkenes, see: (a) Sulzer-Mosse, S.;
Alexakis, A. Chem. Commun. 2007, 3123–3135. (b) Roca-Lopez, D.;
Sadaba, D.; Delso, I.; Herrera, R. P.; Tejero, T.; Merino, P. Tetrahedron:
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Trifonidou, M.; Kokotos, C. G. Tetrahedron 2012, 68, 8630–8635.
(8) For related enantioselective nickel-catalyzed additions of
N-carbamoyl oxindoles to nitroalkenes, see: Han, Y.-Y.; Wu, Z.-J.;
Chen, W.-B.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2011, 13,
5064–5067.
The Michael additions of 1aÀ1f to various other
(hetero)aryl-substituted nitroalkenes also proceeded
(10) Desimoni, G.; Faita, G.; Mella, M. Tetrahedron 1996, 52, 13649–
13654.
(11) For application of L1 in enantioselective Pd-catalyzed additions
of alkylazaarenes to imines and nitroalkenes, see ref 1e.
(12) The absolute configurations of the products in this study were
assigned by analogy to that of 4g, which was determined by X-ray
crystallography (Figure 3).
(13) In addition, no reaction was observed using 3-acetylpyridine,
2-acetylthiophene, or acetophenone as the pronucleophile.
(9) See the Supporting Information for further details.
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Org. Lett., Vol. XX, No. XX, XXXX

Figure 2. Enantioselective nickel-catalyzed additions of 2-acety-
lazaarenes to various β-(hetero)aryl-substituted nitroalkenes.
Reactions were conducted using 0.60 mmol of acetylazaarene
and 0.50 mmol of nitroalkene in 5 mL of i-PrOH. Yields are of
isolated material. Enantiomeric excesses were determined by
chiral HPLC analysis.
Figure 4. Enantioselective nickel-catalyzed additions of 2-acet-
ylazaarenes to β-alkyl-substituted nitroalkenes 2j and 2k. Reac-
tions were conducted using 0.60 mmol of acetylazaarene and
0.50 mmol of nitroalkene in 1 mL each of PrOH and CH2Cl2.
Yields are of isolated material. Enantiomeric excesses were
determined by chiral HPLC analysis.
smoothly, providing products in uniformly high enantio-
selectivities (92À99% ee, Figure 2). Nitroalkenes with
β-phenyl groups containing 2-methyl (products 4e and 4k),
4-methoxy (products 4d and 4i), 4-fluoro (product 4f),
4-bromo (product 4g), 3-nitro (product 4c), or 4-trifluoro-
methyl groups (product 4a) were effective reaction partners.
Furthermore, nitroalkenes containing 1-naphthyl (products
4h and 4l) or 2-thienyl groups (products 4b and 4j) were also
tolerated. The absolute stereochemistry of product 4g was
confirmed by X-ray crystallography (Figure 3).
β-alkyl-substituted nitroalkenes, even after extended reac-
tion times.14 Fortunately, increasing the concentration
of the reaction from 0.1 to 0.5 M with respect to the
nitroalkene was found to be beneficial for reaction rates,
and a 1:1 mixture of i-PrOH/CH2Cl2 proved to be optimal
to maintain good solubility of the reactants. These condi-
tions enabled the addition of 2-acetylazaarenes 1aÀ1f
to nitroalkenes 2j and 2k in reasonable yields (Figure 4).
However, the enantioselectivities of these reactions (65À
82% ee) were lower than those obtained using β-(hetero)-
aryl-substituted nitroalkenes.14
These Michael reactions are also effective on larger scales.
For example, additions of 1bÀ1d to 2a on 10.0 mmol scales
(with respect to 2a) using only 1 mol % of catalyst in 1:1
i-PrOH/CH2Cl2 (0.5 M with respect to 2a) provided
Michael adducts in 66À81% yield and 95À99% ee after
72 h (Figure 5).
Figure 3. X-ray structure of Michael adduct 4g.
To illustrate the potential utility of the products, further
transformations of 3b were conducted. Treatment of 3b
Next, additions to β-alkyl-substituted nitroalkenes
were evaluated. We found that these substrates were
significantly less reactive than the (hetero)aryl-substituted
nitroalkenes in our process; under the conditions shown
in Figures 1 and 2, no reaction was observed using
(14) The lower reactivity and enantioselectivities afforded by β-alkyl-
substituted nitroalkenes compared with their β-aryl counterparts in
related nickel-catalyzed Michael additions of 1,3-dicarbonyl com-
pounds have been observed previously; see ref 5d, 5e.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Asymmetric Transfer Hydrogenation of Product 3b
Figure 5. Larger scale Michael additions. Reactions were con-
ducted using 12.0 mmol of acetylazaarene and 10.0 mmol of 2a
in 10 mL each of i-PrOH and CH2Cl2. Yields are of isolated
material. Enantiomeric excesses were determined by chiral
HPLC analysis.
with Noyori’s RuCl[(S,S)-TsDPEN](p-cymene] complex15
in the presence of HCO2H/Et3N in DMF at room
temperature led to highly diastereoselective (>19:1 dr)
reduction of the ketone to provide secondary alcohol 6a
in >95% yield (Scheme 2).16 Use of the enantiomeric
complex gave diastereomeric alcohol 6b with similarly
high yield and high diastereoselectivity (>19:1 dr). The
high diastereoselectivities of these reactions demonstrate
that catalyst control is dominant, and the existing stereo-
center in 3b has little effect on the stereochemical outcome.
In summary, we have developed the enantioselective
Michael addition of 2-acetylazaarenes to nitroalkenes,
catalyzed by a chiral Ni(II)Àbis(oxazoline) complex.
The process is tolerant of a range of azaarenes in the
pronucleophile, and the reactions proceed under mild,
experimentally convenient conditions. Although the
enantioselectivities are modest with β-alkyl-substituted
nitroalkenes, a range of β-(hetero)aryl-substituted ni-
troalkenes react smoothly to give products in much higher
enantiopurity (93À99% ee). Further investigations of
CdN-containing azaarenes as activating groups for en-
antioselective catalysis are ongoing and will be reported in
due course.
Acknowledgment. This work was supported by the
EPSRC and the University of Edinburgh. We thank Gary
S. Nichol (University of Edinburgh) for X-ray crystal-
lography. The EPSRC National Mass Spectrometry Fa-
cility is gratefully acknowledged for high-resolution mass
spectra.
(15) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1995, 117, 7562–7563. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–
2522. (c) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–102.
(16) For an example of enantioselective transfer hydrogenation of
acylazaarenes, see: Tanis, S. P.; Evans, B. R.; Nieman, J. A.; Parker,
T. T.; Taylor, W. D.; Heasley, S. E.; Herrinton, P. M.; Perrault, W. R.;
Hohler, R. A.; Dolak, L. A.; Hester, M. R.; Seest, E. P. Tetrahedron:
Asymmetry 2006, 17, 2154–2182.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for all new compounds,
and crystallographic data in cif format. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX