Copper(I)-catalyzed intramolecular hydroalkoxylation of unactivated alkenes

Article abstract of DOI:10.1021/acs.orglett.5b00758

A Cu(I)-Xantphos system catalyzed the intramolecular hydroalkoxylation of unactivated terminal alkenes, giving five- and six-membered ring ethers. This system is applicable to both primary and secondary alcohols. A reaction pathway involving the addition of the Cu-O bond across the C-C double bond is proposed. A chiral Cu(I) catalyst system based on the (R)-DTBM-SEGPHOS ligand promoted enantioselective reaction with moderate enantioselectivity.

Full text of DOI:10.1021/acs.orglett.5b00758

Letter
pubs.acs.org/OrgLett
Copper(I)-Catalyzed Intramolecular Hydroalkoxylation of
Unactivated Alkenes
Hiroaki Murayama, Kazunori Nagao, Hirohisa Ohmiya,* and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
S
* Supporting Information
ABSTRACT: A Cu(I)−Xantphos system catalyzed the intra-
molecular hydroalkoxylation of unactivated terminal alkenes,
giving five- and six-membered ring ethers. This system is
applicable to both primary and secondary alcohols. A reaction
pathway involving the addition of the Cu−O bond across the C−
C double bond is proposed. A chiral Cu(I) catalyst system based
on the (R)-DTBM-SEGPHOS ligand promoted enantioselective reaction with moderate enantioselectivity.
xygen-containing heterocyclic compounds are found in
many biologically active natural products and pharma-
decreased (82%). DPPE was much less effective, giving only
18% yield. Monophosphines such as PPh3 and PCy3 gave low
product yields (30% and 15%), while no reaction occurred in
the absence of a ligand.
O
ceuticals.1 Metal-catalyzed intramolecular hydroalkoxylation of
unactivated alkenes is a straightforward method for the
preparation of O-heterocycles.2 To date, these types of
reactions have been realized by using various catalysts with
different metals such as Pt(II), Au(I), Ag(I), Al(III), Fe(III),
Ru(II), and Cu(II).3,4 Notably, all of these reactions were
achieved through electrophilic activation of hydroxyalkenes at
the C−C double bond by π Lewis acid metals that promote
outer-sphere nucleophilic addition of the hydroxy group to the
alkene.
It is well-known that σ-bond metathesis between the Cu−C
bond of mesitylcopper(I) and the O−H bond of alcohols
produces the corresponding copper(I) alkoxides, which are
generally poor Lewis acids.8 Accordingly, a π Lewis acid
mechanism involving outersphere nucleophilic addition of the
hydroxy group to the alkene should be ruled out for the present
Cu(I)-catalyzed intramolecular hydroalkoxylation. Instead, we
propose a mechanism involving the insertion of the alkene into
the Cu−O bond of the copper(I) alkoxide as illustrated in
Figure 1. The catalytic cycle would be initiated by the reaction
between the mesitylcopper−Xantphos complex and the H−O
bond of the substrate (1) to form copper alkoxide A.
Subsequently, the terminal alkene forms Cu−alkene π-complex
B. Next, the intramolecular addition of the Cu−O bond across
Herein, we report that a Cu(I)−Xantphos catalyst system
promotes the intramolecular hydroalkoxylation of unactivated
terminal alkenes to give five- or six-membered ring ethers.5,6
This new copper catalysis should be mechanistically different
from the previously reported intramolecular hydroalkoxylations
of unactivated alkenes. Instead, addition of the Cu−O bond of
an alkoxocopper(I) intermediate across the C−C double bond
followed by alcoholysis of the Cu−C bond is proposed. A chiral
Cu(I) catalyst system based on the (R)-DTBM-SEGPHOS
ligand promoted enantioselective reaction with moderate
enantioselectivity.
Our ligand screening for the reaction of 2,2-diphenyl-4-
penten-1-ol (1a) revealed that Xantphos, featuring an
extraordinary large bite angle, was the most effective. The
reaction of 1a in the presence of mesitylcopper(I) (10 mol %)
and Xantphos (10 mol %) in toluene at 100 °C over 24 h
afforded five-membered ring ether 2a in 97% yield (Scheme
1).7 DPPF was also effective, but the product yield was slightly
Scheme 1. Copper-Catalyzed Intramolecular
Hydroalkoxylation
Figure 1. Possible catalytic cycle.
Received: March 16, 2015
Published: April 7, 2015
© 2015 American Chemical Society
2039
DOI: 10.1021/acs.orglett.5b00758
Org. Lett. 2015, 17, 2039−2041

Organic Letters
Letter
the C−C double bond affords alkylcopper intermediate C with
an oxygen heterocycle. Finally, protonolysis of the Cu−C bond
of C with the H−O bond of 1 gives the product (2).
quaternary carbon center (entries 7−9). The hydroalkoxylation
of a 1,2-disubstituted alkene did not proceed at all (data not
shown).
The extension of this methodology to six-membered ring
formation was feasible (Table 1, entries 10 and 11). Thus, the
reaction of 5-hexene-1-ol derivatives 1k and 1l occurred to give
the corresponding tetrahydrofuran derivatives (2k,l) in good
yields.
We examined various hydroxyalkenes as substrates for the
Cu-catalyzed hydroalkoxylation for preparing tetrahydrofuran
derivatives (Table 1). The Cu(I)−Xantphos catalyst system
a
Table 1. Substrate Scope
Next, we explored the catalytic enantioselective hydro-
alkoxylation. Copper complexes prepared from mesitylcopper
(10 mol %) and various chiral bisphosphine ligands were
examined in the reaction of 1a in toluene at 60 °C for 24 h
(Table 2). The catalyst prepared from (S,S)-Chiraphos (L1) or
a
Table 2. Enantioselective Reaction
b
c
entry ligand
additive
solvent
temp (°C) yield (%) ee (%)
1
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
none
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
hexane
60
60
60
60
60
60
60
30
30
30
0
0
2
none
3
none
22
23
7
9
4
4
none
5
none
51
51
51
62
67
71
6
none
60
94
46
30
39
7
none
8
none
9
t-BuOH
t-BuOH
10
a
Conditions: CuMes (10 mol %), ligand (10 mol %), 1a (0.15 mmol),
b
c
solvent (0.3 mL), 24 h. Yield of the isolated product. The
enantiomeric excess was determined by HPLC analysis.
(R,S)-Josiphos (L2) did not promote the reaction at all (entries
1 and 2). (S,S)-(R,R)-Ph-TRAP (L3)9 and (R)-SEGPHOS
(L4) induced only low catalytic activity and enantioselectivity
(entries 3 and 4). Further screening of chiral ligands revealed
that introducing 3,5-di-tert-butyl-4-methoxyphenyl (DTBM)
substituents on the phosphorus atoms of chiral bisphosphines
was important not only for enantiocontrol but also catalytic
activity (entries 5−7).10 Thus, (R)-DTBM-BINAP (L5)
induced a moderate enantioselectivity, albeit with a poor
product yield (entry 5). The use of DTBM-MeO-BIPHEP (L6)
increased product yield, but this change did not improve the
enantioselection (entry 6). The use of (R)-DTBM-SEG-
PHOS11 (L7) led to a significant improvement in the product
yield with the enantioselectivity unchanged (entry 7). To our
knowledge, this is the first metal-catalyzed enantioselective
intramolecular hydroalkoxylation of unactivated alkenes.
a
Conditions: CuMes−Xantphos (10 mol %), 1 (0.15 mmol), toluene
b
(0.3 mL), 100 °C, 24 h. Yield of the isolated product.
c
d
Diastereomeric ratio (3:1). Diastereomeric ratio (1:1).
was also effective for the reaction of secondary alcohols (1b−d)
(entries 1−3), tolerating various substituents such as Me, n-Bu,
and Ph groups at the position α to the hydroxy group. The
hydroxyalkenes with a dibenzylmethylene (1e) or a di-
(benzyloxymethyl)methylene (1f) inserted in the linker chain
underwent the reaction in moderate yields (entries 4 and 5).
Spirocyclization of the cyclohexanone acetal derivative 1g
proceeded efficiently and cleanly with the acetal moiety
untouched (entry 6). The geminally disubstituted alkenes
1h−j also underwent the hydroalkoxylation to construct a
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DOI: 10.1021/acs.orglett.5b00758
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Organic Letters
Letter
(6) For Cu(II)-catalyzed intramolecular carboalkoxylation of alkenes,
see: (a) Miller, Y.; Miao, L.; Hosseini, A. S.; Chemler, S. R. J. Am.
Chem. Soc. 2012, 134, 12149. (b) Bovino, M. T.; Liwosz, T. W.;
Kendel, N. E.; Miller, Y.; Tyminska, N.; Zurek, E.; Chemler, S. R.
Angew. Chem., Int. Ed. 2014, 53, 6383. For asymmetric Cu(I) catalysis
involving intramolecular oxycupration of allenes, see: (c) Kawai, J.;
Chikkade, P. K.; Shimizu, Y.; Kanai, M. Angew. Chem., Int. Ed. 2013,
52, 7177.
(7) All copper-catalyzed reactions were carried out under nitrogen
atmosphere. See the Supporting Information.
(8) Stollenz, M.; Meyer, F. Organometallics 2012, 31, 7708.
(9) Sawamura, M.; Hamashima, H.; Sugawara, M.; Kuwano, R.; Ito,
Y. Organometallics 1995, 14, 4549.
(10) For discussion on the effect of the DTBM groups in the
enantioselective Cu-catalyzed hydrosilylation of aryl ketones, see:
Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A. J. Am. Chem. Soc.
2003, 125, 8779.
(11) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264.
(12) The absolute configuration of 2a* was not determined.
The enantioselection could be improved to 62% ee by
carrying out the reaction at 30 °C, but with a serious reduction
of the yield (Table 2, entry 8). Interestingly, the enantiose-
lectivity could be increased to 67% ee by adding a catalytic
amount of t-BuOH (10 mol %), also with a reduction of the
yield (30%) (entry 9). The enantioselectivity was further
improved to 71% ee using hexane as a solvent with an increase
in the product yield (39%) (entry 10).12 This result suggested
the reversibility of the Cu−alkene π-complex B and alkylcopper
intermediate C (see Figure 1).
In summary, the Cu−Xantphos system catalyzed the
intramolecular hydroalkoxylation of unactivated terminal
alkenes, giving five- and six-membered ring ethers. This system
is applicable to both primary and secondary alcohols. A reaction
pathway involving the addition of the Cu−O bond across the
C−C double bond is proposed. A chiral Cu(I) catalyst system
based on the (R)-DTBM-SEGPHOS ligand promoted
enantioselective reaction with moderate enantioselectivity.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ohmiya@sci.hokudai.ac.jp.
*E-mail: sawamura@sci.hokudai.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Young Scientists
(A) and Challenging Exploratory Research, JSPS to H.O., and
CREST, JST, to M.S. K.N. thanks JSPS for scholarship support.
REFERENCES
■
(1) (a) Elliott, M. C. J. Chem. Soc., Perkins Trans. 1 2000, 1291.
(b) Elliott, M. C.; Williams, E. J. Chem. Soc., Perkins. Trans. 1 2001,
2303. (c) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999,
62, 504.
(2) For a review, see: Patil, N. T.; Kavthe, R. D.; Shinde, V. S.
Tetrahedron 2012, 68, 8079.
(3) (a) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 9536. (b) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett.
2005, 7, 4553. (c) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127,
6966. (d) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7,
4553. (e) Coulombel, L.; Rajzmann, M.; Pons, J.-M.; Olivero, S.;
Dunach, E. Chem.Eur. J. 2006, 12, 6356. (f) Kamiya, I.; Tsunoyama,
̃
H.; Tsukuda, T.; Sakurai, H. Chem. Lett. 2007, 36, 646. (g) Komeyama,
K.; Morimoto, T.; Nakayama, Y.; Takaki, K. Tetrahedron Lett. 2007,
48, 3259. (h) Ohta, T.; Kataoka, Y.; Miyoshi, A.; Oe, Y.; Furukawa, I.;
Ito, Y. J. Organomet. Chem. 2007, 692, 671. (i) Ito, Y.; Kato, R.;
Hamashima, K.; Kataoka, Y.; Oe, Y.; Ohta, T.; Furukawa, I. J.
Organomet. Chem. 2007, 692, 691. (j) Adrio, L. A.; Quek, L. S.; Taylor,
J. G.; Hii, K. K. Tetrahedron 2009, 65, 10334.
(4) For lanthanide-catalyzed intramolecular hydroalkoxylation of
alkenes, see: Dzudza, A.; Marks, T. J. Org. Lett. 2009, 11, 1523.
(5) For a Cu-catalyzed intramolecular hydroamination of unactivated
alkenes from our groups, see: (a) Ohmiya, H.; Moriya, T.; Sawamura,
M. Org. Lett. 2009, 11, 2145. (b) Ohmiya, H.; Yoshida, M.; Sawamura,
M. Synlett 2010, 2136.
2041
DOI: 10.1021/acs.orglett.5b00758
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