Chiral N-Heterocyclic Carbene Ligand Enabled Nickel(0)-Catalyzed Enantioselective Three-Component Couplings as Direct Access to Silylated Indanols

Article abstract of DOI:10.1021/acs.orglett.6b01492

An enantioselective nickel(0)-catalyzed reductive three-component coupling between aromatic aldehydes, norbornenes, and silanes affords directly silyl-protected indanol derivatives. A new bulky chiral C₂-symmetric NHC (NHC = N-heterocyclic carbene) ligand basing on the 1,2-di(napthalen-1-yl)ethylene diamine backbone allows accessing the annulated products as single diastereoisomers in high enantioselectivity.

Full text of DOI:10.1021/acs.orglett.6b01492

Letter
pubs.acs.org/OrgLett
Chiral N‑Heterocyclic Carbene Ligand Enabled Nickel(0)-Catalyzed
Enantioselective Three-Component Couplings as Direct Access to
Silylated Indanols
Joachim S. E. Ahlin and Nicolai Cramer*
́ ́
Laboratory of Asymmetric Catalysis and Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de
Lausanne, EPFL SB ISIC LCSA, BCH 4305, CH-1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: An enantioselective nickel(0)-catalyzed reduc-
tive three-component coupling between aromatic aldehydes,
norbornenes, and silanes affords directly silyl-protected
indanol derivatives. A new bulky chiral C2-symmetric NHC
(NHC = N-heterocyclic carbene) ligand basing on the 1,2-
di(napthalen-1-yl)ethylene diamine backbone allows accessing
the annulated products as single diastereoisomers in high enantioselectivity.
etal-catalyzed multicomponent reactions in which several
the transformation highly attractive to showcase the abilities of
Mcomponents are assembled in a single transformation new ligand scaffolds. Despite the direct generation of four
have emerged as a powerful tool for molecular complexity.1
stereocenters in this transformation, a challenging but very
valuable enantioselective process could not be realized so far.
In contrast to the growing number of publications describing
the use and influence of NHCs in nickel-catalyzed reductive
couplings,9 only scarce examples of enantioselective reductive
couplings with chiral NHCs as ligand have been reported so
far.10−12 In part, these shortcomings may be attributed to the
limited choice of powerful chiral NHC ligands. For instance, the
influence of the flanking aryl groups on the selectivity has been
described for Grubbs’ chiral imidazolidin-2-ylidene derivative,13
whereas modifications of chiral diaryl ethylenediamine backbone
have been so far largely neglected.14,15
Among them, nickel-catalyzed reductive couplings between
aldehydes and alkynes providing access to allylic alcohols have
been well investigated.2 Besides the development of intra- and
intermolecular transformations, the alkyne coupling partner
could be replaced by allenes,3 1,3-dienes,4 terminal olefins,5 and
methylenecyclopropanes.6 Norbornene was recently used as a
coupling partner together with borane reductants and phosphine
ligands by Fukuzawa, giving disubstituted carbinols (Scheme 1).7
Replacing the phosphine with an NHC (NHC = N-heterocyclic
carbene) ligand altered the reaction outcome, and silylated
indanols were obtained in the presence of triisopropyl silane.8
The reaction was proposed to occur through an aromatic ortho-
C−H activation. This significant response to ligand tuning makes
The relevance of the indanol scaffold as a structural motif in
natural products16 and the attractive rapid assembly of an
enantioenriched versatile building block make an efficient
catalytic asymmetric transformation highly desirable. Herein,
we report an enantio- and diastereoselective nickel(0)-catalyzed
three-component coupling of aromatic aldehydes, norbornenes,
and silanes. The use of a new chiral NHC ligand allows access to
enantioenriched silyl-protected indanols in high selectivity. We
started our investigations by evaluating a variety of different
established chiral NHC-scaffolds (Figure 1) using available
benzaldehyde, norbornene, and triisopropylsilane for the model
Scheme 1. Divergent Pathways of Nickel-Catalyzed Reductive
Couplings and Tuning Opportunities of Chiral NHC Ligands
transformation (Table 1). Kundig ligand L1,17 C1-symmetric L2
̈
developed by us,12a and Glorius’ IBiox L318 furnished 3aa in low
yields and selectivity (entries 1−3). In contrast, Grubbs’ C2-
symmetric imidazolidin-2-ylidene L413 gave silylated indanol 3aa
in almost quantitative yield, with exclusive diastereoselectivity
and promising enantioselectivity of 71.5:28.5 (entry 4).
Installation of o-isopropyl groups at the flanking aryl substituents
on the nitrogen atom increased the selectivity to 86:14 (entry 5).
Received: May 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
different conditions. For instance, the use of other ethereal or
saturated hydrocarbon solvents resulted in a sharp drop of the
reactivity (entries 12−14). Toluene afforded 3aa in excellent
yield, albeit with reduced enantioselectivity (entry 15).
Increasing the concentration of the reaction to 1.0 molar
increased the reactivity and provided 3aa in a nearly quantitative
chemical yield and with 93.5:6.5 er (entry 16).
With the aforementioned reactions conditions, we then
explored the generality of the enantioselective nickel-catalyzed
three-component coupling (Table 2). First, a range of p-
substituted electron-rich and electron-deficient aryl aldehydes
were tested (entries 1−6). Electron-neutral or -rich substituents
provided the products in high yields and selectivities. Electron-
poor substituents reduced the yields but provided consistently
high enantioselectivities. A methyl substituent in the meta-
position of the aldehyde steered the aromatic C−H activation
with a selectivity of 9:1 toward the less hindered ortho C−H
group (entry 7). The ortho-tolyl aldehyde largely reduced the
reactivity for the annulation, producing noncyclized product 3ia′
in moderate yield and 92.5:7.5 er and very little indanol 3ia
(entry 8). A constraining 3,5-dimethyl substitution is tolerated,
although a drop in yield and selectivity was observed (entry 9).
For piperonal, functionalization of the more hindered ortho-C−
H bond was favored (4.6:1, entry 10). Such behavior was already
observed earlier,20 suggesting coordination and stabilization
involving the oxygen atom. We next examined different
norbornene acceptors. With methylenealkoxy-substituted de-
rivatives 1b and 1c, we observed an influence of the exo/endo
isomer for the reactivity (entries 11−12). Whereas both provided
the annulated products in high enantioselectivity, exo-norbor-
nene 1b displayed a substantially higher reactivity. Performing
the reaction with benzonorbornadiene furnished the desired
annulated products 3ad with good enantioselectivity (entry 13).
Unstrained alkenes like cyclopentene failed to react under these
reaction conditions. Moreover, the transformation works also
with a range of additional silanes (entries 14−16), maintaining
similar enantioselectivities and the yields. In this respect, the
most common and versatile silyl protecting groups with variable
stabilities such as TES (5), TBS (6), and TBDPS (7) were
conveniently introduced.
Figure 1. Chiral NHC ligands L* used in this study.
Table 1. Optimization of the Enantioselective Three-
a
Component Coupling
b
c
entry
L*
solvent
3aa (%)
er
1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L7
L7
L7
L7
L7
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
Et2O
hexane
toluene
THF
5
74:26
61:39
2
41
0
3
4
99
53
55
74
89
13
<5
57
51
56
39
92
96
71.5:28.5
86:14
5
6
80:5:19.5
93:7
7
8
91:9
9
84:16
10
11
12
13
14
15
91:9
93:7
84:16
87:13
82:18
93.5:6.5
d
The scalability of the transformation was tested, furnishing
annulated indanol 3aa in gram-scale amounts (eq 1). In terms of
yield and enantioselectivity, the reaction performs well and
reliably.
16
a
Conditions: 0.10 mmol benzaldehyde, 0.20 mmol norbornene, 0.20
mmol triisopropylsilane, 10.0 μmol [Ni(COD)2], 10.0 μmol L*, 0.3 M
b
c
in solvent at 23 °C for 17 h. Isolated yields. Determined by HPLC
d
with a chiral stationary phase with the free indanol. At 1.0 M.
We found that replacement of the 1,2-diphenylethylene diamine
backbone with other diaryl- or dialkyl ethylenediamines strongly
influenced the reaction outcome. To our surprise, despite the
convenient availability of enantiopure 1,2-diarylethylene dia-
mines,19 no NHCs besides the ones featuring the parent 1,2-
diphenylethylene diamine backbone are known. From the tested
diamines, the best compromise between reactivity and selectivity
was achieved with L7, possessing the 1,2-di(napthalen-1-
yl)ethylene diamine scaffold, substantially increasing the
selectivity with respect to the parent phenyl substituted one
(entry 7). Evaluation of the flanking nitrogen substituent
confirmed the ortho-isopropylphenyl group as best performer
(entries 7−9). Related C1-symmetric ligands L10 and L11
proved to be less suited (entries 10−11). Bulkier L10 completely
shut down the reaction, and L11 was slightly inferior to the
related C2-symmetric ligands. L7 was further evaluated under
The absolute configuration of indanols 3 was unambiguously
determined by X-ray crystallographic analysis.21 Compound 3aa
was smoothly desilylated with TBAF and subsequently
converted to its p-bromobenzoate derivative 8 (Scheme 2).
The enantiomeric ratio of 8 was further upgraded by
crystallization, and the configuration of the stereogenic center
C1 bearing the hydroxyl group was determined to be (R).
The following mechanistic pathway for the nickel-catalyzed
enantioselective three component coupling is suggested
(Scheme 3).8 Coordination of the aldehyde and norbornene to
the low-valent NHC−Ni0 complex with the aryl group of the
aldehyde placed away from the methylene bridge avoiding steric
congestion, two orientations are possible (I-a and I-b). The
B
DOI: 10.1021/acs.orglett.6b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Scope of the Nickel-Catalyzed Enantioselective
Three-Component Coupling
Scheme 2. Determination of the Absolute Configuration of
Indanol 3aa
a
Scheme 3. Suggested Mechanism for the Enantioselective
Three-Component Coupling
molecule of norbornene involves a hydrometalation; a
subsequent C(sp2)−H activation proceeds, and the release of
norbornane forms cyclometalated species IV. This is in
agreement with the experimental findings that less than two
equivalents of olefin reduce the yield of 3aa and the observation
of formed norbornane. The excess of norbornene acts as a
hydrogen acceptor, similarly to the role of an alkyne in other
transformations.20a,22 Finally, reductive elimination closes the
catalytic cycle, delivering silyl indanol ether 3aa and regenerating
the Ni0 species. However, an alternative mechanism involving the
formation of a dimeric nickel(I) hydride from an oxidative
addition of the NHC−Ni0 complex into the Si−H bond,
followed by a comproportionation cannot be ruled out.23 The
higher enantioselectivities for the carbinol products suggest that
the major and minor diastereoisomers of nickel-hydride III
might have different rates for the C−H activation and reductive
elimination steps. Alternatively, a scenario involving different
mechanisms can be invoked.
a
Conditions: 0.10 mmol 2, 0.20 mmol 1, 0.20 mmol 4, 10.0 μmol
b
[Ni(COD)2], 10.0 μmol L7, 1.0 M at 23 °C for 17 h. Isolated yields.
c
Determined by HPLC with a chiral stationary phase with the free
d
indanol. With 20.0 μmol [Ni(COD)2] and 20.0 μmol L7.
flanking bulky arene groups of the chiral NHC lead to a preferred
orientation of I-a. The enantio-determining oxidative cyclization
forms oxanickelacycle II. Subsequently, the silane reacts with the
nickel alkoxide forming nickel-hydride III. At this stage, a straight
reductive elimination would form noncyclized product 3aa′,
which is observed in some instances.9 Alternatively, another
In summary, we reported an enantio- and diastereoselective
nickel(0)-catalyzed three-component coupling of aldehydes,
norbornenes, and silanes giving direct access to chiral silyl-
protected indanols. We have introduced a new chiral C2-
symmetric NHC ligand deriving from 1,2-di(napthalen-1-
C
DOI: 10.1021/acs.orglett.6b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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yl)ethylene diamine, providing high selectivities in this trans-
formation. This NHC/Ni catalyst system underscores the high
potential of chiral NHCs in asymmetric nickel(0) catalysis and
should enable further enantioselective transformations.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01492.
Experimental procedures and analytical and spectral data
for all new compounds (PDF)
X-ray data for 8 (CIF)
(13) (a) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3,
3225. (b) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc.
2006, 128, 1840. (c) Berlin, J. M.; Goldberg, S. D.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2006, 45, 7591.
(14) Solely, a m-CF3-phenyl derivative was used as chiral organo-
catalyst: Sereda, O.; Blanrue, A.; Wilhelm, R. Chem. Commun. 2009,
1040.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nicolai.cramer@epfl.ch.
Notes
The authors declare no competing financial interest.
(15) Examples with complementary dialkyl backbones: (a) Fournier,
P.-A.; Collins, S. K. Organometallics 2007, 26, 2945. (b) Fournier, P.-A.;
Savoie, J.; Stenne, B.; Bedard, M.; Grandbois, A.; Collins, S. K. Chem. -
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ACKNOWLEDGMENTS
■
This work is supported by the Swiss National Science
Foundation (no. 155967). We thank Dr. R. Scopelliti for X-ray
crystallographic analysis of 8.
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DOI: 10.1021/acs.orglett.6b01492
Org. Lett. XXXX, XXX, XXX−XXX