Enantioselective Ni-Al Bimetallic Catalyzed exo -Selective C-H Cyclization of Imidazoles with Alkenes

Article abstract of DOI:10.1021/jacs.8b02547

A Ni-Al bimetallic catalyzed enantioselective C-H exo-selective cyclization of imidazoles with alkenes has been developed. A series of bi- or polycyclic imidazoles with β-stereocenter were obtained in up to 98% yield and >99% ee. The bifunctional SPO ligand-promoted bimetallic catalysis proved to be critical to this challenging stereocontrol.

Full text of DOI:10.1021/jacs.8b02547

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Enantioselective Ni–Al Bimetallic Catalyzed exo-
Selective C–H Cyclization of Imidazoles with Alkenes
Yin-Xia Wang, Shao-Long Qi, Yu-Xin Luan, Xing-Wang Han, Shan Wang, Hao Chen, and Mengchun Ye
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02547 • Publication Date (Web): 11 Apr 2018
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Enantioselective Ni–Al Bimetallic Catalyzed exo-Selective C–H
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Cyclization of Imidazoles with Alkenes
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Yin-Xia Wang1, Shao-Long Qi1, Yu-Xin Luan1, Xing-Wang Han1, Shan Wang1, Hao Chen1, Mengchun
Ye1,2*
1State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
2Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China.
Supporting Information Placeholder
cially in the presence of Lewis acid.10 After the seminal work on
ABSTRACT: A Ni–Al bimetallic catalyzed enantioselective C–
H exo-selective cyclization of imidazoles with alkenes has been
Ni–Al bimetallic catalysis by Hiyama and Nakao,11–13 Cramer and
co-workers made an important breakthrough in this field to find
that a diamine-derived secondary phosphine oxide (SPO) ligand
developed. A series of bi- or polycyclic imidazoles with β-
stereocenter were obtained in up to 98% yield and >99% ee. The
could act as a bifunctional ligand to combine Ni and Al for a high-
bifunctional SPO ligand-promoted bimetallic catalysis proved to
ly efficient asymmetric control in the hydrocarbamoylation of
be critical to this challenging stereocontrol.
alkenes.14 Very recently, our group also found that a naphthyl-
containing Taddol-derived SPO ligand greatly facilitated a Ni–Al
catalyzed enantioselective cycloaddition of cyclopropyl amide
with alkyne.15 To continue exploring SPO-bimetallic catalysis,
Bi- or polycyclic imidazole moiety with a stereocenter at the β-
position to the heteroatom N has been found in a wide range of
bioactive molecules and chiral nucleophilic catalysts (see the
Supporting Information).1 However, traditional synthetic methods
relying on either condensation reactions or multiple-step ring
herein we report the first example of enantioselective exo-
selective C–H cyclization of imidazole with alkenes, in which a
proposed bis(t-butyl)phenyl-containing Taddol-SPO ligand pro-
moted Ni–Al bimetallic catalysis could enable this excellent enan-
tioselective control of β-stereocenter (eq 3).
elaborations rarely provide an efficient stereocontrol for β-
Scheme 1. Selective C–H Cyclization of Imidazoles with
alkenes
stereocenter, so that chiral starting materials or chiral resolution
technique has to be used in most cases.1 In 2001, Bergman and
Ellman group gave a pioneering report on Rh-catalyzed intramo-
lecular C–H alkylation of imidazole with alkene, providing an
elegant method for the synthesis of polycyclic imidazoles with
either β- or γ-stereocenter.2 Subsequently, they succeeded in
achieving an enantioselective control for the γ-stereocenter con-
struction by using a unique chiral TangPhos ligand (Scheme 1a).3–
6
However, this asymmetric method is not applicable for the con-
struction of more sterically-hindered β-stereocenter (Scheme 1b,
eq 1), probably because harsher conditions is required, leading to
a more challenging stereocontrol.2,3 Inspired by Cavell’s work in
which a mild exo-selective cyclization was obtained by using
imidazole salts as substrate and nickel(0) as catalyst (eq 2),7 we
envisioned that a Lewis acid-activated imidazole could be used as
a substrate for developing a mild Ni-catalyzed enantioselective
exo-selective C–H cyclization to create the challenging β-
stereocenter in the presence of chiral ligand.
However, although nickel metal has been widely used in nu-
merous coupling reactions during recent years owing to its being
an inexpensive, low-toxic and versatile metal catalyst,8 the effi-
ciency of nickel catalyst is pretty sensitive to ligand structure,
often leading to a very limited selection of both nonchiral and
chiral ligands.9 Recently, an air-stable secondary phosphine oxide
(SPO) has attracted intensive attentions because it not only can be
easily prepared from known chiral backbones but also plays a
powerful phosphine ligand role in the reaction through in-situ
tautomerism between its pentavalent and trivalent tautomer espe-
We commenced our studies by treatment of homoallylic teth-
ered benzoimidazole 1a with 10 mol% of Ni(cod)2 and various
Lewis acid promoters (Table 1 and also see the Supporting Infor-
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mation). Commonly-used AlMe3 was found to be a better one and
to test the generality of the reaction (Table 2). Both (E) and (Z)–
alkenes offered the desired product 2a with the same stereo con-
figuration (Table 2). When the terminal substituent group of al-
kene varied from linear alkyl chain such as n-pentyl (1b), benzyl
(1c), benzyloxyethyl (1d) and phenyl (1e) to bulkier isopropyl
(1f), the yield changed from 92% to 70%, whereas ee still re-
mained at high level (87–98%). And in some cases, using higher
loadings of Ni(cod)2 along with additional ligand (1c and 1e)16 or
higher temperature (1f and 1g) may be required for better results.
Impressively, a sterically-hindered trisubstituted alkene still react-
ed well under the modified conditions, providing the correspond-
ing product 2g in 65% yield and 94% ee. All mono-substituted
alkenes proved to be good substrates for this reaction and excel-
lent ees were obtained (up to >99% ee, 2h–2j). The absolute con-
figuration of major enantiomer of the product was assigned to be
(R) by single crystal X-ray diffraction (see the Supporting Infor-
mation).
the desired product 2a was indeed observed in 19% yield with
exclusively exo-selectivity (entry 1). Decreasing the loading of
AlMe3 to 40 mol% did not have a big influence on the reaction,
whereas less than 40 mol% led to a relatively low yield (entries 2
and 3). Neither trialkylphosphine nor triarylphospine ligand pro-
moted this reaction (entries 4 and 5), whereas IPr gave a signifi-
cant elevation of yield, albeit with a low selectivity between exo-
and endo-cyclization (entries 6 and 7). Surprisingly, SPO ligands
such as Ph2P(O)H and Cy2P(O)H greatly improved the selectivity,
providing the product in 51% and 46%, respectively, with com-
plete exo-selectivity (entries 8 and 9). Encouraged by this result, a
variety of chiral SPO ligands were further investigated (entries
10–17). BINOL-derived SPO (L1) proved ineffective, whereas
chiral diamine-derived SPOs (L2 and L3) gave better yields but
with low enantiomeric excess (ee). Taddol-derived SPO ligands
provided more promising results in both yield and ee (L4–L8).
However, the reaction result was also highly sensitive to the lig-
and structure, 3,5-bis(tert-butyl)phenyl-containing SPO ligand
(L8) proved to be the optimal one, providing the product in 92%
yield and 97% ee. Using L8 as the ligand, we can further reduce
the loading of Ni(cod)2 and AlMe3 to 5 mol% and 20 mol%, re-
spectively, with almost undetectable change in both yield and ee
(entry 18–20).
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Table 2. Scope of Alkenes
R2
Ni(cod)2 (5 mol%)
N
L8
(5 mol%)
R2
R1
N
N
AlMe3 (20 mol%)
toluene, 100 °C
N
H
R1
2a
1
(BIm = 1-benzoimidazolyl)
Table 1. Conditions Optimization
substrate
cyclized product
substrate
cyclized product
N
N
N
N
Et
iPr
BIm
BIm
Et
iPr
1fc
2f
, 70%, 89% ee
2a
2a
E 1a
Z 1a
, 88%, 97% ee
, 92%, 97% ee
nPen
N
N
N
BIm
BIm
N
nPen
1b
2b
1gc
2g
, 65%, 94% ee
, 87%, 97% ee
N
N
N
BIm
BIm
BIm
Bn
N
Bn
1cb
2c
1h
2h
, 92%, 92% ee
, 84%, >99% ee
N
N
N
BIm
BIm
BnO
N
BnO
1d
2d
1i
2i
, 90%, >99% ee
, 90%, 98% ee
N
N
N
BIm
Ph
N
Ph
1eb
2e
1j
2j cis
, 43%, 93% ee
2j trans
, 48%, >99% ee
-
, 86%, 87% ee
-
aReaction conditions: 1 (0.2 mmol), toluene (2 mL), under N2 for
1 h; isolated yield and ee was determined by chiral HPLC. bUsing
Ni(cod)2 (10 mol%) and additional IPr·HCl (5 mol%) for 5 h.
cUsing Ni(cod)2 (10 mol%) at 130 °C for 5 h.
We then proceeded to investigate the substituent effect of
mono-alkene-tethered imidazoles. Various substituents including
either electron-donating groups (4a–4e) or electron-withdrawing
groups (4f–4l) on the phenyl ring of benzoimidazole had little
influence on the yield or enantioselectivity of the reaction, provid-
ing the corresponding product in 68–98% yield and 84–98% ee.
To our delight, Br-containing substrate still survived in this Ni(0)-
catalyzed reaction, providing the readily elaborated bromo-
polycyclic imidazole (4i). Good yield was obtained for naphthyl-
derived imidazole (4m) but with relatively low ee. We reasoned
that possible π–π stacking between the substrate and the ligand
resulted into the diminished selectivity. Other N-containing heter-
ocycles were also compatible with the current reaction (4n–4p),
aReaction conditions: 1a (0.2 mmol), toluene (2 mL), under N2 for
b
1 h; Yield was determined by H NMR using CH2Br2 as the in-
1
c
d
ternal standard. Determined by chiral HPLC. Ni(cod)2 (5 mol%)
and L8 (5 mol%)
With the above optimized reaction conditions in hand, we first
explored an array of tethered alkenes bearing various substituents
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providing good yields and high ees under the assistance of addi-
disappeared very quickly and new peaks appeared in the corre-
1
tional Ph3P ligand.16 Notably, simple imidazole-derived substrate
was completely ineffective for this reaction, only leading to par-
tial alkene isomerization. However, imidazole bearing an elec-
tron-withdrawing substituent greatly facilitated this reaction (4q
and 4r), affording synthetically-useful bicyclic imidazoles with a
β-stereocenter.
sponding H and 31P NMR spectra, suggesting a new complex
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could be formed. When the resulting new complex was subjected
to Ni(cod)2, a quantitative yield of the product was afforded. The-
se results suggested that SPO ligand could simultaneously bind
two metals (Ni and Al) and the substrate. In addition, the com-
plexed aluminum species can be used as a catalyst for the reaction,
suggesting that aluminum species does move from one substrate
benzimidazole to another (see the Supporting Information).
Table 3. Scope of Imidazoles
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Scheme 2. Plausible Mechanism
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In summary, we have developed the first example of nickel-
catalyzed enantioselective exo-selective C–H cyclization of imid-
azole with alkene. The cooperation of SPO ligands with Ni and Al
provides an efficient tool for the enantioselective control, afford-
ing a series of bi- and polycyclic imidazoles with β-stereocenters
in 65–98% yield and 80–>99% ee. Wider applications based on
this bimetallic catalysis system are being explored in our lab.
aReaction conditions: 3 (0.2 mmol), toluene (2.0 mL), under N2
for 1 h; isolated yield and ee was determined by Chiral HPLC.
bUsing Ni(cod)2 (10 mol%) and additional IPr·HCl (5 mol%) for 5
h. Using Ni(cod)2 (10 mol%) and additional Ph3P (15 mol%) for
5 h.
c
To understand the mechanism, some additional experiments
were conducted. Different from the Rh-catalyzed system,2 the
current Ni-catalyzed reaction showed a complete deuterium trans-
fer from the deuterated imidazole (d-1h) to the terminal carbon of
the product (d-2h) (Scheme 2a, eq 4). However, no significant
kinetic isotope effect was observed in the competitive experiment
(KIE = 1.0, eq 5). In addition, a competitive experiment between
two different substrates revealed that there was no deuterium
scrambling distribution (eq 6). These results suggest that the di-
rect ligand-to-ligand H transfer from the imidazole to the alkene
could be the favored pathway (Scheme 2b, path a).17 However, the
pathway involving oxidative addition of Ni(0) to the C–H cannot
be ruled out at this current stage (path b). However, to probe the
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI. Experimental procedures, char-
acterization data, and spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
1
role of SPO ligand, we also performed some H and 13P NMR-
*mcye@nankai.edu.cn
tracing experiments (see the Supporting Information). The result
showed that imidazole can easily form a complex with AlMe3.
When the formed complex was mixed with stoichiometric amount
of Ph2P(O)H, the doublet peak of H adjacent to P of Ph2P(O)H
Notes
The authors declare no competing financial interests.
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Lett. 2014, 16, 5572. (e) Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc.
2011, 133, 15362.
ACKNOWLEDGMENT
1
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Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887. (b) Shih, W.-C.; Chen,
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We thank the National Natural Science Foundation of China
(21672107) for financial support.
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