Nickel-Catalyzed Intramolecular C?O Bond Formation: Synthesis of Cyclic Enol Ethers

Article abstract of DOI:10.1002/anie.201601991

An efficient and exceptionally mild intramolecular nickel-catalyzed carbon–oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. Zinc powder was found to be an essential additive for obtaining

Full text of DOI:10.1002/anie.201601991

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201601991
German Edition: DOI: 10.1002/ange.201601991
Cross-Coupling
À
Nickel-Catalyzed Intramolecular C O Bond Formation: Synthesis of
Cyclic Enol Ethers
Seo-Jung Han, Ryohei Doi, and Brian M. Stoltz*
Abstract: An efficient and exceptionally mild intramolecular
nickel-catalyzed carbon–oxygen bond-forming reaction
between vinyl halides and primary, secondary, and tertiary
alcohols has been achieved. Zinc powder was found to be an
essential additive for obtaining high catalyst turnover and
yields. This operationally simple method allows direct access to
cyclic vinyl ethers in high yields in a single step.
have been significantly developed, most of these reactions
require high temperatures and thus can limit their utility in
the synthesis of multifunctional complex molecules. More-
over, the vast majority of these examples are for aryl ether
synthesis, not enol ether synthesis.[9–11] To our knowledge,
a mild and efficient nickel-catalyzed intramolecular cross-
coupling cyclization between aliphatic hydroxy nucleophiles
and tethered vinyl halides is unprecedented.
T
ransition metal-catalyzed cross-coupling reactions have
In the course of an alkaloid synthesis effort, we attempted
a nickel-catalyzed reductive Heck reaction of the vinyl iodide
1 with the aim of producing the tricycle 2 (Scheme 1, red
served as a powerful tool for efficient carbon–carbon and
carbon–heteroatom bond formations over the past several
decades.[1] Recently, nickel catalysis has emerged in the
synthetic community as an exceptionally useful strategy for
cross-coupling.[2] Although tremendous advances in nickel-
catalyzed carbon–carbon bond formation have been achieved
(e.g., Negishi, Suzuki, Stille, Kumada, Hiyama couplings),[3]
nickel-catalyzed carbon–oxygen bond-forming processes
have proven significantly more challenging. The rationale
behind this is that reductive elimination of nickel(II) alkoxide
complexes is often cited as being significantly challenging,
even at elevated temperatures.[4] To circumvent this challenge,
stoichiometric oxidation of nickel(II) to the less stable
nickel(III) analogues has been required. Additionally, reduc-
tive elimination of nickel(II) alkoxides is reported to be
endothermic by computational analysis. This data is in
contrast to that of palladium(II) alkoxides, which are
exothermic.[5] In 1997, Hartwig and co-workers developed
the first nickel-catalyzed cross-coupling between electron-
deficient aryl halides and either preformed sodium alkoxides
or sodium siloxides.[6] In 2014, the group of Ranu reported
a copper-assisted nickel-catalyzed coupling of phenol deriv-
atives and vinyl halides.[7] However, both of these reactions
require high temperatures, and the scope with respect to the
nucleophiles is limited to either preformed alkoxides or
phenols. Most recently, MacMillan and co-workers developed
the nickel-catalyzed intermolecular cross-coupling of aryl
bromides and aliphatic alcohols in the presence of light and
a photoredox catalyst.[8] Importantly, MacMillan and co-
À
Scheme 1. Nickel-catalyzed C O bond formation. cod=1,5-cycloocta-
diene, DMF=N,N-dimethylformamide, PMB=para-methoxybenzyl.
arrows).[12] Surprisingly, instead of the desired intramolecular
À
À
C C bond-forming reaction, a C O bond-forming cyclization
between the vinyl iodide and the free hydroxy group
furnished the morpholine derivative 3 (Scheme 1, blue
arrows). Given the lack of precedent in the literature for
such a transformation with nickel catalysis, we set out to
explore the generality of this reaction. Herein, we describe
the first nickel-catalyzed cycloetherification of aliphatic
alcohols with pendant vinyl halides.
À
workers did not observe their desired C O coupling products
in the absence of either the photocatalyst or light. Although
Given this interesting preliminary data, we chose the
aminocyclohexanols 4a and 4b as simplified substrates for
reaction optimization studies (Table 1). Our initial reaction
conditions afforded the corresponding morpholines 5a and
5b in 53 and 42% yield, respectively (entries 1 and 2). A wide
variety of bases and additives were investigated to improve
the yield and catalytic efficiency (entries 3–10). We found
triethylamine to be superior to others examined (entries 3–5).
The use of a 1:1 mixture of triethylamine and DABCO
allowed etherification in 69% yield with a reduced catalyst
loading (i.e., 20 mol % [Ni(COD)2]; entry 6). Gratifyingly,
the use of 2 equivalents of zinc powder as an additive resulted
À
palladium- or copper-catalyzed C O bond-forming reactions
[*] S.-J. Han, R. Doi, Prof. Dr. B. M. Stoltz
The Warren and Katharine Schlinger Laboratory for Chemistry and
Chemical Engineering, Division of Chemistry and Chemical Engi-
neering, California Institute of Technology
1200 East California Blvd, MC101-20, Pasadena, CA 91125 (USA)
E-mail: stoltz@caltech.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601991.
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Table 1: Optimization of reaction parameters.[a]
Ph)[19] furnished the vinyl ether 5c in high yield and without
loss of olefin stereochemical fidelity. Aminocyclohexanols
bearing isopropyl and allyl substituents on the nitrogen atom
afforded the corresponding products in reduced yields (5d
and 5e). Electronically variable benzyl groups were compat-
ible under the reaction conditions, and even an aryl bromide
was well tolerated (5 f–h). Additionally, a silyl ether group
remained intact, thus generating the substituted morpholine
5i in good yield. Moreover, we discovered that a cis-amino-
cyclohexanol-derived substrate was competent in the reac-
tion, thus providing the cis-fused bicyclic product 5j.
entry sub-
conc. mol% base
additive
(equiv)
yield
[%][b]
strate [m]
Ni
(equiv)
1[c]
2[c]
3[c]
4[c]
5[c]
6
7
8
9
10
4a
4b
4a
4a
4a
4b
4b
4a
4a
4b
0.02
0.02
0.02
0.02
0.02
0.10
0.10
0.04
0.04
0.15
50
50
35
35
35
20
20
20
20
5
Et3N (10)
Et3N (10)
Et3N (10)
Cs2CO3 (3.0)
K3PO4 (3.0)
Et3N (1.0)
Et3N (1.0)
DABCO (1.0)
DABCO (2.0)
Et3N (1.1)
–
–
–
–
–
53
42
42[d]
30[d]
34[d]
To our delight, we found that the nickel-catalyzed intra-
molecular etherification reactions also proceeded with linear
aminoalcohol substrates to generate monocyclic morpholine
derivatives in moderate to high yields (Table 3). The steric
DABCO (1.0) 69
CsF (1.0)
–
–
51
24
50[d]
84
Table 3: Intramolecular cross-coupling of linear aminoalcohols.[a,b]
Zn (2.0)
[a] Reactions were performed in a N2-filled glove box. [b] Yield of isolated
product. [c] DMF (0.04m) was used as a co-solvent. [d] The reaction
proceeded with incomplete conversion of the starting material.
DABCO=1,4-diazabicyclo[2.2.2]octane.
in a significant improvement in yield (84%) with only
5 mol% of [Ni(COD)2] (entry 10).[13–17]
With optimized reaction conditions in hand, we inves-
tigated the substrate scope of the transformation (Table 2). In
addition to simple vinyl iodides (e.g., 4b, R1 = Me, R2 = H,
R3 = H),[18] a Z-styrenyl iodide (i.e., 4c, R1 = Me, R2 = H, R3 =
[a] Reactions were performed in a N2-filled glove box. [b] Yield of isolated
product.
Table 2: Intramolecular cross-coupling of amino-cyclohexanols.[a,b]
environment of the alcohol fragment did not hinder the
performance, as substrates containing primary, secondary, or
highly congested tertiary hydroxy nucleophiles furnished the
corresponding cyclic vinyl ethers in excellent yields (7a–c).
Finally, a benzyl-substituted linear aminoalcohol substrate
was transformed into the desired vinyl ether in modest yield
(7d).
We were pleased to discover that additional acyclic
substrates undergo the nickel-catalyzed carbon–oxygen
cross-coupling to furnish alkylidene tetrahydrofurans and
dihydropyrans (Table 4). Intramolecular etherification of the
vinyl iodide 8a furnished the cyclic ether 9a in good yield
after only 1 hour (entry 1). Although less reactive, a vinyl
bromide (8b) also fared well in the reaction, thus affording
the corresponding product in 52% yield after 12 hours
(entry 2). Unfortunately, attempts to employ a vinyl chloride
as the coupling partner led predominantly to recovery of the
starting material (entry 3). Monomethyl- and monophenyl-
substituted vinyl iodides (8d and 8e)[20] afforded the desired
ethers (9d and 9e) in good yields with retention of olefin
stereochemistry (entries 4 and 5). Gratifyingly, the tetrasub-
stituted vinyl bromide 8 f[21] furnished the corresponding
tetrahydrofuran product 9 f in excellent yield (entry 6). Di-
tert-butyl and dibenzyl malonates (8g and 8h) were tolerated
under the standard reaction conditions to afford the desired
[a] Reactions were performed in a N2-filled glove box. [b] Yield is that of
isolated product. [c] 96 h. TBS=tert-butyldimethylsilyl.
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Table 4: Synthesis of substituted tetrahydrofuran and dihydropyran
ethers (9g and 9h) in good yields (entries 7 and 8). Addi-
rings.[a]
tionally, carbon–oxygen bond formations were achieved with
nitrile- and amide-containing substituents in 61 and 70%
yield, respectively (entries 9 and 10). Formation of a six-
membered cyclic vinyl ether (9k) from the substrate 8k was
found to be challenging with only low levels of conversion
(entry 11). Interestingly, cycloetherification of 8l did indeed
produce a pyran derivative in good yield, but only the
isomerized product 9l was isolated (entry 12).[22]
In conclusion, a highly efficient, mild, and operationally
simple nickel-catalyzed intramolecular carbon–oxygen bond-
forming reaction between vinyl halides and aliphatic alcohols
has been developed. We discovered that zinc powder plays an
important role in improving catalyst turnover and isolated
yields. The reaction is tolerant of many functional groups, thus
affording various cyclic vinyl ethers in good to excellent
yields. This work further expands the capability of nickel
catalysis in the context of small-molecule chemical synthesis.
Additional studies are ongoing to expand the scope of the
reaction, to understand the mechanism, and to deploy the
cyclization in the context of a complex molecular target.[23]
These efforts will be reported in due course.
entry
1
substrate
product
t [h]
yield [%][b]
87
1
2
3
4
12
60
2
52
[c]
–
87
91
Acknowledgments
5
12
We wish to thank the NIH-NIGMS (R01GM080269), Amgen,
the Gordon and Betty Moore Foundation, the Caltech Center
for Catalysis and Chemical Synthesis, and Caltech for
financial support. S.-J.H. thanks the Fulbright program
(Foreign Student Program, No. 15111120) and the Ilju
Foundation of Education & Culture (Pre-doctoral Research
Fellowship) for financial support. R.D. is grateful for support
as a JSPS research fellow. Dr. Mona Shahgholi (Caltech) and
Naseem Torian (Caltech) are acknowledged for high-reso-
lution mass spectrometry assistance. Dr. Scott C. Virgil
(Caltech) is thanked for helpful discussions.
6
7
48
1
98
87
Keywords: alcohols · cross-coupling · ethers · heterocycles ·
nickel
8
9
1
66
61
How to cite: Angew. Chem. Int. Ed. 2016, 55, 7437–7440
Angew. Chem. 2016, 128, 7563–7566
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À
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[14] Importantly, if the [Ni(COD)2] catalyst was omitted, no carbon–
oxygen bond formation was observed. Addition of other
additives such as Mg and CuI decreased the yields (36% and
0% yield, respectively).
[15] Intramolecular etherification of the vinyl iodide 4b proceeded
with 5 mol% of either NiI2 or [NiBr2(dme)] to furnish the vinyl
ether 5b (see entries 1 and 2 below). An increased rate of
cycloetherification was observed with 10 mol% of [NiBr2(dme)]
(entries 2 and 3). Unfortunately, attempts to convert the vinyl
iodide 4b into the enol ether 5b outside a N2-filled glove box
were unsuccessful (entries 4 and 5).
[16] No significant improvement in yield or catalyst turnover was
observed when various ligands (e.g., various NHC, PYBOX,
BOX, diamine, BiOX ligands) were employed.
[17] Since intramolecular etherifications of either the aminocyclo-
hexanol 4a or 4b proceeded, even without Zn powder, despite
Received: February 25, 2016
Published online: May 9, 2016
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