Nickel-catalyzed enantioselective arylation of pyridinium ions: Harnessing an iminium ion activation mode

Article abstract of DOI:10.1002/anie.201303994

A nickel for your thoughts.?? An enantioselective nickel-catalyzed cross-coupling between N-acylpyridinium salts and organozinc reagents is reported. The catalytic system, which is comprised of an air-stable Ni^II source and a chiral phosphoramidite ligand, affords 2-substituted-2,3-dihydro-4-pyridones with up to >99 % ee. Copyright

Full text of DOI:10.1002/anie.201303994

Angewandte
Chemie
Communications
Cross-Coupling Methods
S. T. Chau, J. P. Lutz, K. Wu,
A. G. Doyle*
&&&& — &&&&
Nickel-Catalyzed Enantioselective
Arylation of Pyridinium Ions: Harnessing
an Iminium Ion Activation Mode
A nickel for your thoughts … An enantio-
selective nickel-catalyzed cross-coupling
between N-acylpyridinium salts and
organozinc reagents is reported. The
catalytic system, which is comprised of an
air-stable NiII source and a chiral phos-
phoramidite ligand, affords 2-substi-
tuted-2,3-dihydro-4-pyridones with up to
>99% ee.
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DOI: 10.1002/anie.201303994
Cross-Coupling Methods
Nickel-Catalyzed Enantioselective Arylation of Pyridinium Ions:
Harnessing an Iminium Ion Activation Mode**
Stephen T. Chau, J. Patrick Lutz, Kevin Wu, and Abigail G. Doyle*
The ability to engage cationic substrates such as iminium and
as building blocks for natural product and pharmaceutical
synthesis.[5] The stereoselective addition of carbon-centered
nucleophiles to activated pyridines is a particularly attractive
route to these core structures.[6] Seminal work from the groups
of Comins and Charette established the possibility of using
stoichiometric chiral acylating agents to control the stereo-
À
oxocarbenium ions in transition-metal-catalyzed C C bond
formation is a challenging task that has recently seen
successful application.[1] In this context, we reported that
a low-valent Ni catalyst facilitates unprecedented Suzuki–
Miyaura cross-coupling reactions with allylic N,O- and O,O-
acetal substrates.[2,3] Mechanistic studies revealed that bor-
chemical outcome of C C bond formation.[7,8] However, only
À
À
onic acids mediate allylic C O activation, with oxidative
two examples have been described for the catalytic enantio-
selective addition of organometallic reagents to prochiral N-
acyl/alkyl pyridinium ions.[9] Both of these reactions likely
proceed through the addition of a chiral [M]-R species into
a prochiral pyridinium salt (M = Cu or Rh). As such, the
strategy is limited to reactions with either highly nucleophilic
R groups or highly electrophilic pyridinium ions. As the
oxidative addition/reductive elimination mechanism that we
elucidated for cross-coupling with N-acyl quinolinium salts
should not be subject to these same limitations, we envisioned
that its application to enantioselective cross-coupling with
pyridinium ions could provide a complementary approach to
these methods. Furthermore, successful development of such
addition occurring between the resulting iminium or oxocar-
benium ion intermediate and the Ni catalyst (Scheme 1a).[4]
a reaction would demonstrate for the first time that iminium
0
À
ion activation by Ni is subject to highly enantioselective C C
bond formation.
One challenge apparent at the outset of our endeavors
was potential catalyst poisoning in the presence of free
pyridine. To address this issue, we chose to use 4-methoxy-
pyridine as a substrate, because it shows substantial formation
of a pyridinium salt with chloroformates at À788C.[10] To
enable facile transmetalation at low temperature, a Negishi
reaction platform was selected.[11] Notably, when we initiated
the reaction at À788C with warming to RT, the combination
of [{(methallyl)NiCl}2] (7.5 mol%) and (R)-Monophos (L1;
18 mol%) was found to promote arylation of 4-methoxypyr-
idine in the presence of phenyl chloroformate and 4-
FC6H4ZnBr with low but measurable ee (Table 1,
entry 1).[12] Commercial phosphoramidite ligands L2–L4,
which bear substituents at the 3 and 3’ positions of the
binaphthyl backbone, induced more promising levels of
asymmetric induction (up to 91% ee, entries 2–4).[13] Accord-
ingly, an extensive library of 3,3’-substituted ligands was
prepared and evaluated, revealing that ligand L7 was optimal
(entry 7). With this ligand, the 2,3-dihydro-4-pyridone prod-
uct 2a was obtained in 95% ee, albeit with moderate reaction
efficiency.
Scheme 1. Nickel-catalyzed cross-coupling with iminium ions.
The demonstration that a transition-metal catalyst can
oxidatively insert into these prochiral intermediates offers
a number of exciting possibilities for reaction design and
enantioselective synthesis. Herein, we demonstrate that this
activation mode enables the enantioselective synthesis of a-
substituted 2,3-dihydro-4-pyridones by Negishi cross-cou-
pling with N-acyl pyridinium ions (Scheme 1b).
a-Substituted piperidines are among the most prevalent
scaffolds in biologically active small molecules, and also serve
[*] S. T. Chau, J. P. Lutz, K. Wu, Prof. A. G. Doyle
Department of Chemistry, Princeton University
Washington Rd, Princeton, NJ 08544-1009 (USA)
E-mail: agdoyle@princeton.edu
Homepage: http://www.princeton.edu/~doylegrp/
[**] We thank Phil Jeffrey for X-ray crystallographic structure determi-
nation of 2b and 3. Financial support provided by Princeton
University and Boehringer Ingelheim is gratefully acknowledged.
A.G.D. is an Alfred P. Sloan Foundation Fellow, an Eli Lilly Grantee,
an Amgen Young Investigator, and a Roche Early Excellence in
Chemistry Awardee.
Upon selection of an optimal ligand (L7), we pursued
further optimization of the reaction parameters. Among the
Ni sources examined, NiBr2·diglyme was most promising, as
its use increased the yield of the reaction while maintaining
high levels of enantioselectivity (Table 2, entry 2). This result
is particularly attractive because NiBr2·diglyme is air stable,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303994.
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Table 1: Ligand optimization.[a]
reactivity (entries 6–8). On the other hand, decreasing the Ni
loading from 15 mol% to 10 mol% provided nearly identical
levels of enantioselectivity and reaction efficiency (entry 9).
A gram-scale reaction set up on the benchtop using a catalyst
loading of 5 mol% delivered 2a in 73% yield and 93% ee
(entry 10).
Having identified conditions to prepare 2a in high yield
and enantiomeric excess, a survey of aryl zinc nucleophiles
was conducted to evaluate the scope of the reaction
(Scheme 2).[14] Phenyl zinc bromide afforded 2,3-dihydro-4-
Entry
Ligand
R
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
L1
L2[d]
L3
L4
L5
L6
L7
L8
L9
H
Me
Ph
OMe
OEt
OiPr
OnPr
OiBu
–
9
11
8
52
54
61
64
57
8
18
À40
79
91
92
96
95
96
À40
[a] Reactions run on a 0.05 mmol scale; [{(methallyl)NiCl}2] (7.5 mol%),
ligand (18 mol%), 4-FC6H4ZnBr (4 equiv; 0.3m solution in THF), and
phenyl chloroformate (4 equiv). [b] Determined by 19F NMR spectros-
copy with 1,4-difluorobenzene as a quantitative internal standard.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] L2 was
derived from (S)-1,1’-bi-2-naphthol.
Table 2: Optimization of reaction conditions.[a]
Entry Deviation from standard conditions
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
none (standard conditions)
NiBr2·diglyme (15 mol%)
NiCl2·glyme (15 mol%)
[Ni(cod)2] (15 mol%)
No nickel or ligand
64
76
51
32
23
21
33
21
95
95
89
72
0
91
90
73
93
93
4-FC6H4ZnBr (2 equiv)
benzyl chloroformate
ethyl chloroformate
NiBr2·diglyme (10 mol%), L7 (12 mol%) 88[d]
NiBr2·diglyme (5 mol%), L7 (6 mol%)
73[e]
Scheme 2. Scope of aryl zinc nucleophiles in the reaction. Yields and
ee values are the average of two runs on a 0.5 mmol scale. [a] Yield
and ee after recrystallization from ether. [b] Reaction warmed to RT.
[c] Reaction warmed to À208C. [d] Derived from an ArZnCl solution
(0.3m in THF). [f] Reaction warmed to À508C.
[a] Reactions run on a 0.05 mmol scale; [{(methallyl)NiCl}2] (7.5 mol%),
ligand (L7; 18 mol%), 4-FC6H4ZnBr (4 equiv; 0.3m solution in THF), and
phenyl chloroformate (4 equiv). [b] Determined by 19F NMR spectros-
copy with 1,4-difluorobenzene as a quantitative internal standard.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] Yield of
isolated product on a 0.5 mmol scale. [e] Yield of isolated product on
a 5 mmol scale with the reaction warmed to À408C. cod=1,5-cyclo-
octadiene.
pyridone 2b in 92% ee, which could be recrystallized to
> 99% ee in 78% yield. Generally, ortho-, meta-, and para-
substituted zinc nucleophiles are well tolerated. Reactions
with electron-withdrawing zinc reagents fared exceptionally
well, delivering products bearing 3,5-difluoro (2c), 4-Cl (2d),
4-CF3 (2e), 4-cyano (2 f), and 4-sulfonamide (2g) groups in
96–99% ee. Notably, zinc reagents substituted with methyl
ester and pivaloate groups afforded products (2j, 2k) that are
otherwise inaccessible by standard Grignard methods. More-
over, a reaction with a heteroaromatic nucleophile furnished
thus permitting the reactions to be set up on the benchtop. In
the absence of a Ni source, the reaction performs poorly,
demonstrating that Ni induces substantial rate acceleration
(entry 5). Additional changes to the reaction conditions, such
as decreasing the amount of nucleophile or changing the
identity of the acylating agent, had a negative effect on
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2l in excellent ee and yield, highlighting the potential of this
strategy to deliver medicinally relevant products. Whereas
electron-neutral aryl zinc nucleophiles such as 4-vinyl (2m),
4-Me (2n) and 2-naphthyl (2o) performed modestly in terms
of enantioselectivity, electron-rich nucleophiles such as 4-
OMe (2p) underwent reaction with no stereoinduction owing
to a competitive racemic background reaction (77% yield of
isolated product without nickel).[15] An additional limitation is
that other electrophile partners, including pyridine, 2-
methoxy-pyridine, and 4-dimethylaminopyridine (DMAP),
are not competent under the optimized conditions.
To understand the mechanism of this transformation, we
studied the stoichiometric reaction of Ni0 with the pyridinium
salt derived from 4-methoxypyridine and phenyl chlorofor-
mate, which was generated in situ. For simplicity, we chose to
conduct our studies with PPh3, as it is a competent ligand for
the reaction of interest, providing (Æ)-2a in 87% yield under
otherwise standard reaction conditions.[13] In the event, an air-
sensitive allyl–NiII adduct 3 was produced in 87% yield
(Scheme 3), the structure of which was confirmed by single
With these data in mind, we propose the reaction
mechanism shown in Scheme 4. Oxidative addition of Ni0
II
À
into the C N p bond of the pyridinium salt provides a Ni
allyl intermediate analogous to complex 3.[16] Subsequent
Scheme 3. Stoichiometric reaction between Ni0 and a pyridinium ion.
crystal X-ray diffraction (Figure 1). When subjected to 4-
À
FC6H4ZnBr, allyl adduct 3 underwent C C bond formation,
providing 2a in 25% yield [Eq. (1)]. Furthermore, 3 is
catalytically competent, providing racemic 2a in 68% yield
at 10 mol% catalyst loading [Eq. (2)]. Taken together, these
data provide compelling evidence for a redox mechanism
distinct from that typically considered for transition-metal-
catalyzed addition reactions to pyridinium ions.
Scheme 4. Proposed catalytic cycle.
transmetalation with ArZnBr gives diorganonickel inter-
mediate 4, which can undergo reductive elimination to
regenerate the Ni0 catalyst and complete the catalytic
cycle.[17] The presence of the methoxy substituent at C4
presumably serves as a blocking group, favoring the observed
regioisomeric dihydropyridine 5.[18] Acid hydrolysis of 5 then
affords the 2,3-dihydro-4-pyridone product 2.
In conclusion, we have described a novel nickel-catalyzed
enantioselective Negishi cross-coupling reaction of 4-
methoxypyridinium salts. A broad range of synthetically
valuable enantioenriched 2,3-dihydro-4-pyridones can be
obtained from commercially available or readily prepared
starting materials and an air-stable, inexpensive NiII precata-
lyst. Preliminary mechanistic data support the intermediacy
of a NiII p-allyl intermediate generated upon ionic oxidative
addition of Ni0 to the pyridinium electrophile. The study
Figure 1. Solid-state structure of allyl NiII complex 3. Ellipsoids set at
30% probability. Hydrogen atoms omitted for clarity.
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Received: May 9, 2013
Published online: && &&, &&&&
Keywords: asymmetric catalysis · cross-coupling ·
.
Negishi reaction · nickel · nitrogen heterocycles
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