Highly Enantioselective Nickel-Catalyzed Intramolecular Hydroalkenylation of N- and O-Tethered 1,6-Dienes to Form Six-Membered Heterocycles

Article abstract of DOI:10.1021/jacs.8b04703

A highly enantioselective nickel-catalyzed intramolecular hydroalkenylation of N- or O-tethered 1,6-dienes was developed by using monodentate chiral spiro phosphoramidite ligands. The reaction provides an efficient and straightforward method for preparing very useful six-membered N- and O-heterocycles with high regioselectivity as well as excellent stereoselectivity from easily accessible starting materials under mild reaction conditions. The chiral spiro nickel catalyst developed in this study represents one of the few catalysts for highly enantioselective cyclization of unconjugated dienes.

Full text of DOI:10.1021/jacs.8b04703

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Communication
Highly Enantioselective Nickel-Catalyzed Intramolecular Hydroal-kenylation
of N- and O-Tethered 1,6-Dienes to Form Six-Membered Heterocycles
Ke Li, Mao-Lin Li, Qi Zhang, Shou-Fei Zhu, and Qi-Lin Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 Jun 2018
Downloaded from http://pubs.acs.org on June 4, 2018
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Highly Enantioselective Nickel-Catalyzed Intramolecular Hydroal-
kenylation of N- and O-Tethered 1,6-Dienes to Form Six-Membered
Heterocycles
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Ke Li,1 Mao-Lin Li,1 Qi Zhang,1 Shou-Fei Zhu,1,* and Qi-Lin Zhou1,2,*
1 State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
2 Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
E-mail: sfzhu@nankai.edu.cn; qlzhou@nankai.edu.cn
Supporting Information
Scheme 1. Nickel-Catalyzed Intramolecular Hydroal-
kenylation of N- or O-tethered 1,6-Dienes. BArF- =
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
Abstract: A highly enantioselective nickel-catalyzed intramo-
lecular hydroalkenylation of N- or O-tethered 1,6-dienes was
developed by using monodentate chiral spiro phospho-
ramidite ligands. The reaction provides an efficient and
straightforward method for preparing very useful six-mem-
bered N- and O-heterocycles with high regioselectivity as well
as excellent stereoselectivity from easily accessible starting
materials under mild reaction conditions. The chiral spiro
nickel catalyst developed in this study represents one of the
few catalysts for highly enantioselective cyclization of uncon-
jugated dienes.
Chiral N- and O-heterocyclic moieties are ubiquitous in
natural products, pharmaceuticals, and agrochemicals,1 and
the development of efficient methods for their construction
has attracted considerable attention in organic synthesis.
Transition-metal-catalyzed enantioselective cyclization of N-
and O-tethered unsaturated substrates is a straightforward,
100% atom-economical approach to chiral N- and O-hetero-
cycles. Enantioselective cyclizations of N- and O-tethered
enynes and allenynes have been achieved with chiral transi-
tion metal catalysts.2 In contrast, enantioselective cyclizations
of N- and O-tethered dienes are rare.3 Leitner and co-workers4
explored intramolecular hydroalkenylations of N-tethered 1,6-
dienes using a nickel complex with chiral phosphineamine lig-
and L1 as a catalyst; however, five-membered-ring N-hetero-
cyclic products were obtained with moderate enantioselectiv-
ities (up to 59% ee, Scheme 1a). Herein, we report a highly en-
antioselective intramolecular hydroalkenylation of N- and O-
tethered 1,6-dienes mediated by a nickel catalyst modified
with monodentate chiral spiro phosphorus ligands; this reac-
tion provides six-membered-ring N- and O-heterocycles with
excellent regioselectivity and enantioselectivity (Scheme 1b).
Some of the reaction products, for example, 3-substituted-4-
arylpiperidines and 3-substituted-4-aryltetra hydropyrans, are
Figure 1. Selected chiral drugs and natural products with 3-
substituted-4-arylpiperidine and 3-substituted-4-aryltetrahy-
dropyran as core structures.
core structures of many chiral drugs and natural products, in-
cluding the anticancer drug alvocidib,5 the antidepressants
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(–)-paroxetine and (+)-femoxetine,6 and the natural products
temperature in the presence of a nickel catalyst prepared in
situ from 5 mol % [Ni(methallyl)Cl]2, 10 mol % monodentate
phosphorus ligand, and 12 mol % NaBArF. First, we evaluated
various monodentate chiral spiro phosphorus ligands devel-
oped in our laboratory.9 Although phosphite L2, phosphonite
L3, and phosphoramidite L5 gave low conversions, reactions
carried out with phosphine L4 and 6,6-diaryl-substituted
phosphoramidite L6 proceeded smoothly and gave six-mem-
bered-ring N-heterocyclic product 2a in good yield with excel-
lent enantioselectivity (Table 1, entries 1–11). (Sa)-L6c, which
has a 6,6-di-9-phenanthryl group, afforded the highest enan-
tioselectivity (99% ee, entry 11). The regioselectivity was excel-
lent: no five-membered-ring product was detected. The only
side reaction was migration of the terminal double bond of the
diene to afford N-cinnamyl-4-methyl-N-(prop-1-en-1-yl)ben-
zenesulfonamide (<5%). Bidentate phosphine ligands, such as
BINAP and DuPhos, were inactive under the tested reaction
conditions (entries 12 and 13). Using ligand (Sa)-L6c, we sys-
tematically optimized the reaction conditions. In addition to
[Ni(methallyl)Cl]2, [Ni(allyl)Br]2 was also a suitable catalyst
precursor (entry 14). NaBArF played a crucial role: the use of
additives containing different anions markedly lowered the
catalyst activity (Table S1). The bulky, noncoordinative BArF
ion may have prevented deactivation of the catalyst. Chlorin-
ated solvents and toluene were suitable for the reaction, with
dichloromethane giving the highest enantioselectivity (Table
S1). Lower catalyst loading resulted in a decreased yield but
with retained excellent enantioselectivity (entry 15). The
nickel catalyst degraded before getting full conversion. The re-
action could be performed on a gram scale without decreasing
the yield or enantioselectivity (entry 16).
morphine, daphenylline,7 and (–)-calopin8 (Figure 1).
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Table 1. Enantioselective Nickel-Catalyzed Intramo-
lecular Hydroalkenylation of N-Tethered 1,6-Diene 1a:
Optimization of the Reaction Conditions.a
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entry
1
L*
conv. (%)
27
yield (%)b
ee (%)c
NDd
ND
92
(Sa)-L2
10
8
2
(Sa)-L3
18
3
(Sa)-L4a
(Sa)-L4b
(Sa)-L5a
>95
>95
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73
75
39
<5
<5
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51
4
95
Under the optimal reaction conditions (Table 1, entry 11), we
evaluated the substrate scope of this nickel-catalyzed intra-
molecular hydroalkenylation of N-tethered 1,6-diene sub-
strates 1 (Scheme 2). Substrates in which R2 was H and R1 was
a para- or meta-substituted aryl group (2b–2k) smoothly un-
derwent the cyclization to give the corresponding six-mem-
bered-ring N-heterocycles in moderate to good yields (50–
90%) with excellent enantioselectivities (98–99% ee). Func-
tional groups, including halogen (1b, 1c, 1i), -OMe (1e), -NO2
(1f), -CO2Me (1g), and -OH (1h) groups were compatible to
this reaction. In contrast, the functional groups with strong
coordinative nature (e.g. -NMe2, -CN) fully prevented the re-
action. X-ray diffraction analysis of a single crystal of 2a re-
vealed that its absolute configuration was R.10 A gram-scale re-
action of 2b gave essentially the same outcome as that of the
small-scale reaction. The catalyst was sensitive to the steric
bulk of the substrate, and only a trace amount of the cycliza-
tion product was isolated when R1 was an ortho-substituted
aryl group (data not shown). Moreover, the reaction is highly
sensitive to the configuration of the olefin because E-1a cannot
afford the desired product under standard reaction conditions.
To our delight, 1,6-diene (1l, lm and 1n), which bears a trisub-
stituted olefin moiety, also underwent the cyclization reaction
to give corresponding products (2l, 2m and 2n), which has
two chiral centers, as a single anti-isomer. The substrate with
a thienyl ring (1o) smoothly afforded the desired product 2o
in high yield (98%) with excellent enantioselectivity (99% ee).
The substrate with N-Ns (1p) gave satisfactory results while
the one with N-Boc was inactive for this reaction. The six-
membered-ring selectivity of this cyclization reaction rests
mainly on the nature of the R1 substituent of the substrate.
5
13
6
(Sa,R,R)-L5b
(Ra,R,R)-L5b
(Sa)-L5c
<5
ND
ND
75
7
<5
8
85
9
(Sa)-L6a
(Sa)-L6b
(Sa)-L6c
>95
>95
>95
<5
89
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11
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95
69
<5
<5
68
42
61
99
12
13
14e
15f
(R)-BINAP
(S,S)-DuPhos
(Sa)-L6c
ND
ND
99
<5
>95
62
(Sa)-L6c
99
16g
(Sa)-L6c
>95
97
a
Reaction conditions: [Ni(methallyl)Cl]2 (0.0050 mmol),
ligand (0.010 mmol), NaBArF (0.012 mmol), 1a (0.10 mmol), in
b
c
1.5 mL CH2Cl2, at 30 °C, 16 h. Isolate yield. The ee values
d
were determined by HPLC using IC-3 column. Not deter-
mined. e Replaced [Ni(methallyl)Cl]2 with [Ni(allyl)Br]2. f Per-
g
formed with 2 mol % catalyst, at 30 °C, 48 h. Performed at
gram-scale: [Ni(methallyl)Cl]2 (0.24 mmol), (Sa)-L6c (0.49
mmol), NaBArF (0.58 mmol), 1a (4.9 mmol), in 20 mL solvent,
at 30 °C, 48 h.
We began by investigating the cyclization of N-tethered 1,6-
diene 1a. The reactions were performed in CH2Cl2 at room
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When R1 was H or Me as well as R2 was H, five-membered-ring
N-heterocyclic products 2q and 2r were isolated in moderate
to good yields and enantioselectivities.
From product 2a, the antidepressant (+)-femoxetine could be
readily synthesized (Scheme 4b). Bromohydroxylation of the
exocyclic olefin of 2a gave bromo alcohol 6, which underwent
radical debromination to form 7 by means of a procedure de-
veloped by Hong and co-workers.13 Introduction of a para-
methoxyphenol moiety afforded 8,14 and methylation of the N
atom of the ring15 produced (+)-femoxetine. The structure and
absolute configuration of 8 were confirmed by single-crystal
X-ray diffraction analysis.
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Scheme 2. Enantioselective Nickel-Catalyzed Intra-
molecular Hydroalkenylation of N-Tethered 1,6-
Dienes.a
Scheme 3. Enantioselective Nickel-Catalyzed Intra-
molecular Hydroalkenylation of O-Tethered 1,6-
Dienes.a
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a
Reaction conditions: [Ni(methallyl)Cl]2 (0.020 mmol), (Sa)-
L6c (0.020 mmol), NaBArF (0.025 mmol), 3 (0.50 mmol), in 1.5
mL CH2Cl2, at 25 °C, 12 h.
a
Reaction conditions: [Ni(methallyl)Cl]2 (0.013 mmol), (Sa)-
L6c (0.026 mmol), NaBArF (0.030 mmol), 1 (0.25 mmol), in 1.5
mL CH2Cl2, at 30 °C, 16 h. The isolated yields are given. b Per-
formed using 10 mol % catalyst at 45 °C, 24 h. c Performed with
10 mol % catalyst with L4b, at 30 °C, 24 h. d Performed with 5
mol % catalyst, at 10 °C, 28 h. e Performed with 5 mol % catalyst,
at -10 °C, 48 h.
Scheme 4. Transformations of the Products.
Chiral spiro nickel catalyst Ni/(Sa)-L6c (4 mol %) also effi-
ciently catalyzed intramolecular hydroalkenylations of O-
tethered 1,6-dienes 3 in moderate to good yield and generally
excellent enantioselectivity (Scheme 3). In addition to substi-
tuted phenyl groups, the R group of 3 could also be 1-naphthyl
(3g), 2-naphthyl (3e), benzodioxole (3f), thienyl (3h), ferro-
cenyl (3i), or cinnamenyl (3j). The substrate (3b) with an or-
tho-substituent exhibited very modest yield but still with high
enantioselectivity (92% ee). The structure and absolute con-
figuration of product (R)-4f were confirmed by X-ray diffrac-
tion analysis of a single crystal. The major side-reactions we
detected are terminal carbon-carbon double bond isomeriza-
tion and oligomerization of 1,6-dienes (see Figure S1).11
To demonstrate the synthetic utility of this reaction, we per-
formed several transformations of the products (Scheme 4).
Product 2g was oxidized to ketone 5 with ruthenium(III) chlo-
ride and sodium periodate in high yield with retained ee
(Scheme 4a). Compound 5 is a typical 4-aryl piperidin-3-one,
which is a very useful building block in organic synthesis.12
We put forward the mechanism shown in Scheme 5 on the
basis of our observations and literature results.4b,16 The cata-
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lytic cycle starts with cationic Ni(II)-hydride A,17 which coor-
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Crystallographic information for compound 2a (CIF)
Crystallographic information for compound 4f (CIF)
Crystallographic information for compound 8 (CIF)
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8
dinates with the 1,6-diene to form intermediate B. After a mi-
gratory insertion of the Ni–H into the double bond of the cin-
namic moiety of 1a, π-allyl-Ni intermediate C is generated. Cy-
clization of C forms alkyl-nickel intermediate D. Finally, β-hy-
dride elimination from D gives product 2a and regenerates
Ni(II)-hydride A. The phenyl group of 1a induces hydride mi-
gration to the β-position to form relatively stable allylic nickel
species C, which ensures the regioselectivity of the reaction.
AUTHOR INFORMATION
Corresponding Authors
*sfzhu@nankai.edu.cn
*qlzhou@nankai.edu.cn
Scheme 5. Proposed Mechanism.
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PRCID
Shou-Fei Zhu: 0000-0002-6055-3139
Qi-Lin Zhou: 0000-0002-4700-3765
Notes
Notes The authors declare no competing financial interest.
Metrical parameters for the structures are available free of
charge from the Cambridge Crystallographic Data Centre un-
der reference numbers CCDC-1527598, 1527599 and 1540871.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China
(21625204, 21532003, 21421062), the “111” project (B06005) of
the Ministry of Education of China, and the National Program
for Special Support of Eminent Professionals for financial sup-
port.
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In summary, we developed a highly enantioselective nickel-
catalyzed intramolecular hydroalkenylation of N- and O-teth-
ered 1,6-dienes mediated by a nickel catalyst bearing mono-
dentate chiral spiro phosphoramidite ligands. The cyclization
reaction provides a mild, efficient, straightforward method for
preparing six-membered-ring N- and O-heterocycles, which
are core structures in number of bioactive compounds, with
high regioselectivity and excellent stereoselectivity. The cata-
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