Nickel Catalyzed Regio-, Diastereo-, and Enantioselective Cross-Coupling of 3,4-Epoxyalcohol with Aryl Iodides

Article abstract of DOI:10.1021/acs.orglett.7b02076

The first catalytic, regioselective cross-coupling of 3,4-epoxyalcohol with aryl iodides is reported. The combination of NiCl₂·DME and a newly developed C₂-symmetric oxazoline ligand plays a key role in selective ring opening of seve

Full text of DOI:10.1021/acs.orglett.7b02076

Letter
pubs.acs.org/OrgLett
Nickel Catalyzed Regio‑, Diastereo‑, and Enantioselective Cross-
Coupling of 3,4-Epoxyalcohol with Aryl Iodides
Amit Banerjee* and Hisashi Yamamoto*
Molecular Catalyst Research Center, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
S
* Supporting Information
ABSTRACT: The first catalytic, regioselective cross-coupling
of 3,4-epoxyalcohol with aryl iodides is reported. The
combination of NiCl2·DME and a newly developed C2-
symmetric oxazoline ligand plays a key role in selective ring
opening of several 3,4-epoxy alcohols at the C4 position. This
general protocol furnishes a new type of enantioenriched 4,4-
diaryl alkane which also incorporates an additional 1,3-diol that
can be easily transformed to a variety of functional groups. The
products are formed with excellent regioselectivity (>99:1),
diastereoselectivity (up to 99:1), and enantiopurity (up to
>99.9% ee).
Scheme 1. Regio- and Enantioselective Opening of Epoxides
n recent years our group has been involved in the
1
Iasymmetric epoxidation of allylic and homoallylic alcohols
followed by regio- and enantioselective ring opening by using
nitrogen nucleophiles to generate enantiomerically pure amino
alcohols.2 The selective ring opening of 3,4-epoxy alcohols with
carbon nucleophiles is a challenging task which would provide a
straightforward access to 4,4-diaryl alkanes. As diaryl alkane
moieties are present in various bioactive molecules, they play a
significant role in living organisms that is reflected in their wide
application in the pharmaceutical industry (Figure 1).3
Depending on their importance and synthetic utility, various
attempts have been made toward the enantioselective synthesis
of diaryl alkanes, including asymmetric hydrogenation of diaryl
alkenes,4 1,4-addition to α,β-unsaturated carbonyl compounds,5
and asymmetric cross-coupling at benzylic centers.6 Meanwhile,
transition metal catalyzed asymmetric cross-coupling methods
have enormous scope, but enantioselective synthesis of 1,1-
diaryl alkanes has rarely been investigated.7 Recently, the
synthesis of enantioenriched diaryl alkanes reported by Fu,8a
Doyle,8b and Reisman.8c Moreover, Weix reported cooperative
Ni/Ti- catalyzed enantioselective cross-coupling of meso-
epoxide with aryl bromides.9a Unfortunately, nickel catalyzed
nonenantioselective cross-coupling of unsymmetrical aromatic
epoxide suffers from regioselectivity issues (Scheme 1a).9b We
envisioned that regioselective ring opening of epoxide by
carbon nucleophiles can be controlled by using a hydroxy
directing group in combination with nickel complexes (Scheme
1c).
Received: July 8, 2017
Figure 1. Biologically active chiral 1,1-diaryl alkane.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02076
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Organic Letters
Letter
a
Table 1. Optimizaton of Nickel Catalyzed Cross-Coupling of
3,4-Epoxy Alcohol with Aryl Iodide
Scheme 3. Scope of Aryl Iodides
a
b
c
entry
reaction condition
standard conditions
yield (%)
dr
1
61
14
56
40
37
12
38
0
90:10
92:8
79:21
79:21
73:27
70:30
86:14
−
2
L1 instead of L6
L2 instead of L6
L3 instead of L6
L4 instead of L6
L5 instead of L6
L7 instead of L6
No NiCl2·DME
3
4
5
6
7
8
9
No ligand
0
−
10
11
12
13
14
No Mn
0
−
Ar−Br instead of Ar−I
Zn instead of Mn
m-CO2Et-PhI instead of p-CO2Et-PhI
No Et3NHCl, No NaI
33
10
53
21
89:11
20:80
80:20
92:8
a
All the reactions were performed in 0.4 mmol scale, NiCl2·DME
a
Reaction conditions: epoxide 1 (0.4 mmol, 1.0 equiv), 3 (0.6 mmol,
1.5 equiv), NiCl2·DME (0.08 mmol, 0.2 equiv), Ligand (0.1 mmol,
0.25 equiv), Mn (1.2 mmol, 3.0 equiv), NaI (0.2 mmol, 0.5 equiv),
Et3NHCl (0.44 mmol, 1.1 equiv), Pyridine (0.8 mmol, 0.2 equiv),
(0.08 mmol, 0.2 equiv), Ligand (0.1 mmol, 0.25 equiv), Mn (1.2
mmol, 3.0 equiv), NaI (0.2 mmol, 0.5 equiv), Et3NHCl (0.44 mmol,
1.1 equiv), Pyridine (0.8 mmol, 0.2 equiv), DMPU (3 mL), rt, 12 h.
b
c
1
Isolated yield. Determined by H NMR spectroscopy.
b
c
DMPU (3 mL), rt, 12 h. Isolated yield. Diastereomeric ratio was
determined by NMR of crude reaction mixture.
yield albeit moderate diastereoselectivity (entry 3). Further, L3
and L4 also show similar results with slightly lower yields of the
product (entries 4, 5). Interestingly, L5 also gave a very low
yield of the product with poor dr (entry 6). We then
hypothesized that steric hindrance at the α-position of nitrogen
could be a deciding factor which ultimately effects the
formation of a reactive nickel ligand complex to determine
the selectivity and yield. Subsequent investigation showed that
the presence of a methylene group at the α-position of the bis-
oxazoline moiety is preferable to a tertiary carbon to improve
yield and selectivity. Gratifyingly, promising diastereoselectivity
(90:10) and excellent regioselectivity (>99:1) were observed
with a 61% yield in the case of L6, which was derived from L-
serine (entry 1), whereas L7 also gave a similar dr albeit in a
lower yield of the product (entry 7). Further, using ArBr
instead of ArI did not improve the yield (entry 11). Again
replacing p-CO2Et-PhI with m-CO2Et-PhI showed slight
improvement in dr but a lower yield (entry 13). Furthermore,
Zn instead of Mn provided a very low yield of the product
(entry 12). The addition of Et3NHCl and NaI were found to be
necessary to improve the yield probably due to activation and
ring opening of epoxide (entry 14).9a,b The complete
conversion of epoxyalcohol 1 was observed under the reaction
conditions in the given time. Notably, no cross-coupling
product was observed in the absence of NiCl2·DME (entry 8),
Ligand (entry 9), and Mn (entry 10). From further
investigation, DMPU was found to be the best solvent.10
Encouraged by these initial results we focused our attention
toward the enantio- and diastereoselective cross-coupling of
Scheme 2. Preparation of Chiral 3,4-Epoxy Alcohol
Very recently, our group reported Ni/BINAM complex-
catalyzed regio- and enantioselective aminolysis of 3,4-epoxy
alcohol with aryl amine directed by a hydroxyl group (Scheme
1b).2 Based on these observation, we tested the regio-,
diastereo-, and enantioselective cross-coupling of 3,4-epox-
yalcohol with aryl iodides catalyzed by a new Ni/bisoxazoline
complex (Table 1).
Initially, we commenced our investigation using trans-2-(3-
phenyloxiran-2-yl)ethanol which is readily accessible from the
corresponding olefin by mCPBA epoxidation and ethyl 4-
iodobenzoate as substrate. To challenge this scheme, we first
tested commercial L1; however, cross-coupling was observed
with good diastereoselectivity but in very low yield (entry 2).
Gratifyingly, L2 provided the cross-coupling product in 56%
B
DOI: 10.1021/acs.orglett.7b02076
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Organic Letters
Letter
a
Table 2. Scope of Chiral Epoxides
Scheme 4. Effect of Hydroxy Group in Cross-Coupling
diastereoselectivity (96:4) as well as enantioselectivity (96%) in
63% yield.
With this inspiring result in hand, we started to evaluate the
substrate scope of this reaction. First, we tested commercially
available aryl iodide to reveal the generality of this method
(Scheme 3). For iodides, substitution at various positions of the
aromatic ring is well tolerated to provide the 4,4-diaryl alkane
product with moderate to good yields (48−69%) and with
excellent diastereoselectivity. In order to check the accuracy of
dr, chiral HPLC analysis was used for substrates 2b and 2f, and
as anticipated, excellent dr was observed (99:1 and >96:4
respectively). Furthermore, a variety of functional groups
including ester (2b, 2f), aldehyde (2c) and ketone (2d), nitrile
(2e), trifluoromethyl (2g), and halides such as fluoride (2i, 2j)
and chloride (2h, 2k) were tolerated under these mild reaction
conditions.
Encouraged by this broad iodide scope, we then began to
evaluate the substrate scope of epoxides for this cross-coupling
reaction (Table 2). A variety of enantioenriched 3,4-
epoxyalcohols having different substituents were successfully
synthesized by using our previous epoxidation method.1a
Generally, all the reactions proceeded smoothly at ambient
temperature affording products with excellent regioselectivity
(>99:1) in good yields. Substrates 1b and 1k having
substitution at the m-position of the aromatic ring provided a
66% yield, whereas p-substituted substrates such as 1e, 1f, 1g,
1h, 1i and m-substituted ones such as 1g provided a slightly
diminished yield (42−57%). Interestingly, a significant
improvement of ee of cross-coupling product was observed
over the corresponding epoxy alcohol which might indicate that
an unprecedented kinetic resolution occurs under the reaction
conditions. As anticipated various functional groups such as
halides, −CF3, and −OMe were well tolerated under these
reaction conditions. Gratifyingly, all the diaryl alkane products
were achieved with excellent enantiopurity (up to 99.9%) and
diastereoselectivity (up to 97:3). All the ee and dr were
determined by chiral HPLC analysis (see Supporting
Information).
In order to test the directing effect of the hydroxyl group of
the substrate, we subjected 2-methyl-3-phenyloxirane (5) to the
same reaction conditions furnishing a 4:1 diastereomeric
mixture of cross-coupling product. However, trans-2-(3-phenyl-
oxiran-2-yl)ethanol (1) furnished a 12:1 dr which clearly
supports the hydroxy group playing a significant role to
determine the diastereoselectivity (Scheme 4).
In conclusion, we have developed the first hydroxy directed,
nickel catalyzed cross-coupling of a 3,4-epoxy alcohol with aryl
iodides. The C4-selective opening approach shows excellent
enantio- and diastereoselectivity for diverse epoxides with
a
Reaction conditions: epoxide 1 (0.4 mmol, 1.0 equiv), 3 (0.6 mmol,
1.5 equiv), NiCl2·DME (0.08 mmol, 0.2 equiv), Ligand (0.1 mmol,
0.25 equiv), Mn (1.2 mmol, 3.0 equiv), NaI (0.2 mmol, 0.5 equiv),
Et3NHCl (0.44 mmol, 1.1 equiv), Pyridine (0.8 mmol, 0.2 equiv),
b
DMPU (3 mL), rt, 12 h. Enantioenriched epoxide was synthesized
c
d
using our previous report. ee of epoxide. Isolated yield.
e
f
Enantiomeric excess was determined by Chiral HPLC. Diastereo-
meric ratio was determined by Chiral HPLC.
3,4-epoxyalcohol. We chose enantioenriched trans-2-(3-phenyl-
oxiran-2-yl)ethanol (1a, 95% ee) which is easily prepared using
our previous method and 3 for the ring opening reaction
(Scheme 2).1a To our delight, cross-coupling of enantioen-
riched epoxide 1a with 3 in the presence of Ni/L6 complex
provided the product (4a) with excellent regio- (>99:1) and
C
DOI: 10.1021/acs.orglett.7b02076
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Organic Letters
Letter
Andersson, P. G. J. Am. Chem. Soc. 2009, 131, 8855. (c) Woodmansee,
D. H.; Pfaltz, A. Chem. Commun. 2011, 47, 7912.
(5) (a) Yasukawa, T.; Suzuki, A.; Miyamura, H.; Nishino, K.;
Kobayashi, S. J. Am. Chem. Soc. 2015, 137, 6616. (b) Paquin, J.−F.;
Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 10850.
various aryl iodides. Moreover, an enantioenriched 4,4-diaryl
alkane with additional 1,3-diol functionality will provide a broad
scope for further functionalization and can furnish new
pathways for the synthesis of building blocks and synthetically
useful intermediates. A new C2-symmetric bisoxazoline ligand
was identified to achieve excellent selectivity. Further study
related to mechanism and application is in progress.
(6) (a) Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J.
Am. Chem. Soc. 2009, 131, 5024. (b) Maity, P.; Shacklady-McAtee, D.
M.; Yap, G. P. A.; Sirianni, E. R.; Watson, M. P. J. Am. Chem. Soc.
2013, 135, 280. (c) Zhou, Q.; Srinivas, H. D.; Dasgupta, S.; Watson,
M. P. J. Am. Chem. Soc. 2013, 135, 3307. (d) Harris, M. R.; Hanna, L.
E.; Greene, M. A.; Moore, C. E.; Jarvo, E. R. J. Am. Chem. Soc. 2013,
135, 3303.
(7) For selected review in nickel catalysis, see: (a) Tasker, S. Z.;
Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299. (b) Mont-
gomery, J. Organonickel Chemistry. In Organometallics in Synthesis;
Lipshutz, B. H., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2013; pp
319−428. (c) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang,
N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111,
1346. (d) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem. Rev.
2015, 115, 9587. For the selected reaction of racemic 1,1-diaryl
alkane, see: (e) He, Y.; Cai, Y.; Zhu, S. J. Am. Chem. Soc. 2017, 139,
1061. (f) Arendt, K. M.; Doyle, A. G. Angew. Chem., Int. Ed. 2015, 54,
9876.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02076.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: banerjeeam07@isc.chubu.ac.jp.
*E-mail: hyamamoto@isc.chubu.ac.jp.
ORCID
(8) (a) Do, H.; Chandrashekar, E. R. R.; Fu, G. C. J. Am. Chem. Soc.
2013, 135, 16288. (b) Woods, B. P.; Orlandi, M.; Huang, C.-Y.;
Sigman, M. S.; Doyle, A. G. J. Am. Chem. Soc. 2017, 139, 5688.
(c) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.;
Reisman, S. E. J. Am. Chem. Soc. 2017, 139, 5684.
Hisashi Yamamoto: 0000-0001-5384-9698
Notes
The authors declare no competing financial interest.
(9) (a) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2015, 137, 3237.
(b) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2014, 136, 48. For the
selected nonenantioselective cross-coupling of epoxides, see: (c) Miller,
K. M.; Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am.
Chem. Soc. 2004, 126, 4130. (d) Miller, K. M.; Huang, W.-S.; Jamison,
T. F. J. Am. Chem. Soc. 2003, 125, 3442. (e) Nielsen, D. K.; Doyle, A.
G. Angew. Chem., Int. Ed. 2011, 50, 6056. (f) Ikeda, Y.; Yorimitsu, H.;
Shinokubo, H.; Oshima, K. Adv. Synth. Catal. 2004, 346, 1631.
(10) DMPU and DMI were found to be the best solvents for this
reaction, although DMI provided a slightly lower yield (54%), whereas
DMF and DMA provided very low yields of the product (<15%). No
cross-coupling product was observed in the case of DMSO, THF,
toluene, and diethyl ether.
ACKNOWLEDGMENTS
■
This work was supported by JST ACT-C Grant Number
JPMJCR12ZD, Japan. The authors thank Dr. Y. Shimoda and
Prof. E. Ishikawa for helpful discussions.
REFERENCES
■
(1) For enantioselective epoxidation of homoallylic alcohol, bis-
homoallylic alcohol, and allylic alcohols, see: (a) Zhang, W.;
Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286. (b) Barlan, A. U.;
Zhang, W.; Yamamoto, H. Tetrahedron 2007, 63, 6075. (c) Li, Z.;
Zhang, W.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 7520.
(d) Li, Z.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 7878.
(e) Olivares-Romero, J. L.; Li, Z.; Yamamoto, H. J. Am. Chem. Soc.
2013, 135, 3411. (f) Wang, C.; Yamamoto, H. J. Am. Chem. Soc. 2014,
136, 1222. (g) Bhadra, S.; Yamamoto, H. J. Am. Chem. Soc. 2015, 137,
15612. (h) Li, Z.; Yamamoto, H. Acc. Chem. Res. 2013, 46, 506.
(2) For 3,4-epoxyalcohol opening by amine nucleophile, see:
(a) Wang, C.; Yamamoto, H. J. Am. Chem. Soc. 2015, 137, 4308.
For 2,3-epoxy alcohol opening by amine nucleophile, see: (b) Wang,
C.; Yamamoto, H. J. Am. Chem. Soc. 2014, 136, 6888. (c) Wang, C.;
Yamamoto, H. Angew. Chem., Int. Ed. 2014, 53, 13920.
(3) For references on various pharmaceuticals and biologically active
molecules containing 1,1-diarylalkanes, see: (a) Hills, C. J.; Winter, S.
A.; Balfour, J. A. Drugs 1998, 55, 813. (b) McRae, A. L.; Brady, K. T.
Expert Opin. Pharmacother. 2001, 2, 883. (c) Malhotra, B.; Gandelman,
K.; Sachse, R.; Wood, N.; Michel, M. C. Curr. Med. Chem. 2009, 16,
4481. (d) Pathak, T. P.; Gligorich, K. M.; Welm, B. E.; Sigman, M. S. J.
Am. Chem. Soc. 2010, 132, 7870. (e) Messaoudi, S.; Hamze, A.; Provot,
O.; Treg
Wdzieczak- Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M.
ChemMedChem 2011, 6, 488. (f) Abad, A.; Lopez-Perez, J. L.; del
Olmo, E.; García- Fernandez, L. F.; Francesch, A.; Trigili, C.;
́
uier, B.; Rodrigo De Losada, J.; Bignon, J.; Liu, J.-M.;
́
́
́
Barasoain, I.; Andreu, J. M.; Díaz, J. F.; San Feliciano, A. J. Med. Chem.
2012, 55, 6724. (g) Silva, D. H. S.; Davino, S. C.; de Moraes Barros, S.
B.; Yoshida, M. J. Nat. Prod. 1999, 62, 1475. (h) Ameen, D.; Snape, T.
J. MedChemComm 2013, 4, 893.
(4) (a) Wang, Z.; Ai, F.; Wang, Z.; Zhao, W.; Zhu, G.; Lin, Z.; Sun, J.
J. Am. Chem. Soc. 2015, 137, 383. (b) Tolstoy, P.; Engman, M.;
Paptchikhine, A.; Bergquist, J.; Church, T. L.; Leung, A. W.-M.;
D
DOI: 10.1021/acs.orglett.7b02076
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