Cu-Catalyzed cross-coupling reactions of epoxides with organoboron compounds

Article abstract of DOI:10.1039/c4cc09321f

A copper-catalyzed cross-coupling reaction of epoxides with arylboronates is described. This reaction is not limited to aromatic epoxides, because aliphatic epoxides are also suitable substrates. In addition, N-sulfonyl aziridines can be successfully converted into the products. This reaction provides convenient access to β-phenethyl alcohols, which are valuable synthetic intermediates.

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Cu-Catalyzed Cross-Coupling Reactions of Epoxides
with Organoboron Compounds
Cite this: DOI: 10.1039/x0xx00000x
Xiao-Yu Lu,a Chu-Ting Yang,a Jing-Hui Liu,a Zheng-Qi Zhang,a Xi Lu,a Xin
Lou,a Bin Xiao,a Yao Fu a *
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
valuable synthetic intermediates in a variety of C-C bond-forming
manifolds.2e, 10
A copper-catalyzed cross-coupling reaction of epoxides with
arylboronates is described. The reaction is not limited to
aromatic epoxides, because aliphatic epoxides are also
suitable substrates. In addition, N-sulfonyl aziridines can be
successfully converted into the products. The reaction
provides convenient access to β-phenethylalhocols, which are
valuable synthetic intermediates.
Transition metal catalyzed C-C bonds cross-coupling reactions
play an important role in modern organic synthesis,1 which usually
use carbon−halogen or carbon−OSO2R as electrophiles.2 Compared
with the traditional electrophiles, epoxides and aziridines possess
ring strain that make them susceptible to nucleophilic ring opening,3
and various carbon-based nucleophiles have been investigated over
the past several years.4 After the ring-opening reaction, expoxides
can be easily converted to β-substituentalhocol.5 Traditional methods
of the
ring-opening
reaction
used
strong
nucleophilic
organometallics,6 such as Grignard reagents or organolithium
reagents (Scheme 1a). The drawback of these reactions is the
functional-group tolerance. In this context, Doyle and Jamison have
reported nickel-catalyzed Negishi-type cross-coupling of aziridines
(Scheme 1b).7 It is recognized that organoboron compounds show
excellent stability and commercial availability. Thus, Takeda and
Minakata, as well as Michael have achieved the Suzuki-type
coupling reaction of organoboron and aziridines (Scheme 1c).8
As a continuation of our previous work about Cu-catalyzed cross-
coupling reactions,2b,11 we report the first example Cu-catalyzed of
epoxides with arylboronates ring-opening cross-coupling reaction
(Scheme 1c). It's worth pointing out that Doyle reported nickel-
catalyzed cross-coupling of styrenyl epoxides with arylboronic
acids.9 In the reaction nickel was inserted into the C-O bond,
followed by β-hydride elimination and isomerized to aldehyde,
generating rearranged products. In contrast with this research, our
work realized the direct ring-opening reaction, and the configuration
of C-O can be retained. This methodology allows access to
synthetically valuable secondary alcohols and tertiary alcohols from
readily available and inexpensive terminal epoxides, which are
Scheme 1 Previously Reported Cross-Couplings Reactions of E
oxides and Aziridines. Neop = (OCH2CMe2CH2O).
Table 1 Optimization of the reaction conditions.
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Table 2 Scope of cross-coupinga,b
.
Entry
Ligand
Base
Yielda
Solvent
KI
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
-
PPh3
Johnphos
TMEDA
xantphos
xantphos
L1
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
DMF
DMF
DMF
DMF
DMF
DMF 1.0 eq
DMF 1.0 eq
DMF 1.0 eq
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
-
6
5
-
-
-
-
15c
8c
40
48b
75b
35b
trace
30b
traceb
L2
L2
L3
L4
L1
L1
L1
L1
0.5eq
0.5 eq
0.5 eq
1.5 eq 88b(83e)
-
36
1.5 eq
1.5 eq
1.5eq
0d
61f
44g
L1
a Reaction conditions: CuI (10 mol%), Base (2 equiv), ligand (10 mol%) in 0.5 mL
solvent at 80 C for 14h under Ar atmosphere. KI was added. 60 C for 14h.
o
b
c
o
d
no CuI. The yield was determined by GC using dodecyl alcohol as internal
standard (average of two GC runs).. e Isolated yield. aryl-Bpin was used in the
f
g
coupling.
Boronic acid was used in the coupling. DMF = N,N-
dimethylformamide. DMSO = dimethyl sulfoxide.
We began our study by choosing commercial availability 1-octene
epoxide (1a) and phenylboronate (2a) as the model substrates (Table
1). On the basis of recent studies on Cu-catalyzed cross-coupling
reaction of alkyl electrophilic reagents with arylboronates,2b,11 we
first examined previously reported catalytic systems for the coupling
of 1-octene epoxide and arylboronates. Gratifyingly, we observed
the product, albeit in low yield (entry 1). The result indicated that the
conditions previously reported for the coupling were not suitable. To
assess the role of various nitrogen and phosphine ligands, CuI was
next evaluated as a copper source (entry 2-5). With PPh3, Johnphos
and TMEDA reaction efficiencies remained poor (entry 2-4).
Unexpectedly, the use of xantphos as the ligand improved reaction
efficiency (entry 5), but the yield was not high even after screening
of a series of bases and solvents with the xantphos ligand (see
Supporting Information). Next we examined the role of iodide for
the opening-ring cross-coupling, but the effect was not good (entry 6
vs entry 5). In consideration of our previous work utilizing the
diketone as ligands in catalytic cross-coupling reactions,11 we tested
the diketone family ligands to see whether they can accelerate the
reaction (entry 7-12). Excitedly, we obtained a good result (88% GC
yield and 83% isolated yield, entry 12) in a further evaluation of
these reaction parameters. However, once we took out KI in the
optimal conditions we only obtained 36% yield (entry 13). In the
absence of copper source, no product formation was observed (entry
14). Compared with other organoboron compounds, using neopentyl
boranes as substrate, the yield is the highest (entry 15-16).
With the optimized conditions in hand, we decided to examine the
substrate scope (Table 2). First, for the simple 2-monosubstituted
epoxides, electron-rich and electron-poor substrates provided good
yields (3a-3r, 3y). A series of relevant functional groups including
olefin (3c), ether (3e), methylthio (3f), trifluoromethoxy (3g), cyano
(3i), amino (3j), trifluoromethyl (3m) can be well tolerated to give
the products in yields of 68-84%. Aryl-X (X= F, Cl, Br) bond (3d,
3h, 3k, 3l) did not hinder the transformation, so that it was possible
to conduct additional cross-coupling reactions at the halogenated
positions. The epoxides with different chain lengths (3p, 3q) did not
interfere the reaction. Steric hindrance (3r) was tolerated to a certain
a Reaction conditions: Epoxides (0.25 mmol), Arylboronic esters (2 equiv),
LiOtBu(2 equiv). b Isolated yields. p-Tolyl = 4-methylphenyl.
extent. Naphthyl (3n), furan (3o) and thiophene (3y) can also be
present in the reaction. Second, we smoothly obtained tertiary
alcohols, when we utilized 2,2-disubstituted epoxides as substrates
(3s-3x). Electron-rich or electron-poor arylboronates, for instance
amino (3s), methoxyl (3t) and ketal (3v), can also be well tolerated.
In particular ester (3u) and amide (3v, 3w), which were sensitive to
metallic reagents, can also be used in the reaction. Unfortunately,
when both carbons of the epoxide are substituted, the yield is very
low.
Next, we examined whether more highly active aromatic epoxides
could involve in the reaction. Under the present conditions aromatic
epoxides were not viable substrates. Fortunately, after a variety of
screening experiments, the desired products were obtained in high
yield (Table 3). Arylboronate bearing methoxy (3ba), sulphur (3bb)
atom or bromine (3bc) groups reacted under these conditions to
afford the desired products in moderate to good yields (43-78 yield).
Naphthalene substrate (3bd) was also reacted in 66% yield. The
selectivity of aromatic epoxides was different from the Doyle and
Weix’s work.9,12 Moreover, in Weix’s study a mixture of products
were obtained.
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Table 3. Scope of aromatic epoxidesa,b
.
Scheme 5 Support experiments for the proposed mechanism of the opening
cross-coupling reaction reaction.
a
Reaction conditions: Epoxides (0.25 mmol), arylboronic esters (2 equiv),
In summary, for the first time, we have developed a Cu-catalyzed
ring-opening reaction of epoxides with arylboronates. A series of
aromatic and aliphatic epoxides could be smoothly converted into
the products. The reaction is also applicable to N-Ts aziridines.
Additionally, this reaction expands the scope of electrophilic
reagents in copper-catalyzed cross-coupling. The reaction provides
effective methods for the synthesis of secondary alcohols and
tertiary alcohols, which are valuable synthetic intermediates in C-C
bond-forming reactions. In contrast to traditional nucleophilic
epoxides and aziridines ring-opening chemistry, the mild conditions
of this methodology tolerate a wide variety of functional groups.
This work was supported by the 973 Program
(2012CB215306), NSFC (21325208, 21172209, 21272050,
21361140372), SRFDP(20133402120034), CAS (KJCX2-EW-
J02), FRFCU (WK2060190025).
LiOtBu(2 equiv). b Isolated yields.
Scheme 2 Cross-couping of N-sulfonyl aziridine.
The β-phenethylamine fragment exists in many important
neurotransmitters and often be used in syntheses of drug targets. The
condition for aromatic epoxides is also applied to N-sulfonyl
aziridines. As illustrated in Scheme 2, it provides a method in
synthesis of such compounds (eg. 3ca, 70% yield).
Notes and references
a
X.Y.Lu, C.T. Yang, J.H. Liu, Z.Q. Zhang, X. Lu, B. Xiao, Y. Fu. Anhui
Province Key Laboratory of Biomass Clean Energy Department of Chemistry,
University of Science and Technology of China, Hefei 230026 (PR China), E-
mail: fuyao@ustc.edu.cn
Scheme 3 Cross-couping of chiral epoxide.
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
Chiral compounds play a leading role in many applications,
particularly for the production of active pharmaceutical ingredients.
As expected, the ring-opening of (S)-configuration epoxide with
arylboronate afforded product (3aa) with high enantiospecificity
(Scheme 3, 75% yield, > 99% ee).
1
2
F. Diederich and P. J. Stang, Metal-Catalyzed Cross-Coupling Reactions,
Wiley-VCH, Weinheim, 1998.
(a) S. L. Zultanski and G. C. Fu, J. Am. Chem. Soc., 2011, 133, 15362; (b)
C. T. Yang, Z. Q. Zhang, Y. C. Liu and L. Liu, Angew. Chem. Int. Ed.,
2011, 50, 3904; (c) A. Wilsily, F. Tramutola, N. A. Owston and G. C. Fu,
J. Am. Chem. Soc., 2012, 134, 5794; (d) Z. Lu and G. C. Fu, Angew.
Chem. Int. Ed., 2010, 49, 6676; (e) C.-T. Yang, Z.-Q. Zhang, J. Liang, J.-
H. Liu, X.-Y. Lu, H.-H. Chen and L. Liu, J. Am. Chem. Soc., 2012, 134,
11124. (f) T. Hatakeyama, T. Hashimoto, K. K. A. D. S. Kathriarachchi,
T. Zenmyo, H. Seike and M. Nakamura, Angew. Chem. Int. Ed., 2012,
51, 8834.(h)M. Kuriyama, M. Shinozawa, N. Hamaguchi, S. Matsuo and
O. Onomura, J. Org. Chem., 2014, 79, 5921.
Scheme 4. A gram-scale cross-coupling reaction.
3
4
R. E. Parker and N. S. Isaacs, Chem. Rev., 1959, 59, 737.
To demonstrate the scalability of this reaction, we also performed
this copper-catalyzed opening-ring reaction on a gram scale and
gained 3ab in 90% yield (Scheme 4).
(a) J. He, J. Ling and P. Chiu, Chem. Rev., 2014, 114, 8037; (b) N. Jiang,
Q. Hu, C. S. Reid, Y. Lu and C.-J. Li, Chem. Commun., 2003, 2318; (c) U.
K. Roy and S. Roy, Tetrahedron, 2006, 62, 678; (d) J. Muzart, Eur. J.
Org. Chem., 2011, 2011, 4717; (e) A. Gansäuer, M. Behlendorf, D. von
Laufenberg, A. Fleckhaus, C. Kube, D. V. Sadasivam and R. A. Flowers,
Angew. Chem. Int. Ed., 2012, 51, 4739. (f) J. Kjellgren, J. Aydin, O. A.
Wallner, I. V. Saltanova and K. J. Szabó, Chem. Eur. J., 2005, 11, 5260;
(g) B. Olofsson and P. Somfai, in Aziridines and Epoxides in Organic
Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2006, pp. 315-347.
(h) H. Ohno, in Aziridines and Epoxides in Organic Synthesis, Wiley-
VCH Verlag GmbH & Co. KGaA, 2006, pp. 37-71; (i) J. He, J. Ling and
P. Chiu, Chem. Rev., 2014, 114, 8037.
To illustrate the mechanism of the reaction, we chose
(CH3CN)4CuBF4 as the copper source, and didn’t add any iodide.
Fortunately, we also obtained 35% yield. A preformed iodohydrin
substrate only yielded little product, even though we increased the
LiOtBu to 4 equivalent (Scheme 5). The exact reaction process is
not clear, but the preformed iodohydrin substrates can not replace
our epoxides. Further investigations on the possible mechanism were
underway.
5
(a) P. Crotti and M. Pineschi, in Aziridines and Epoxides in Organic
Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2006, pp. 271-313;
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(b) V. V. Fokin and P. Wu, in Aziridines and Epoxides in Organic
Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2006, pp. 443-477;
(c) P. A. S. Lowden, in Aziridines and Epoxides in Organic Synthesis,
Wiley-VCH Verlag GmbH & Co. KGaA, 2006, pp. 399-442; (d) H.
Ohno, in Aziridines and Epoxides in Organic Synthesis, Wiley-VCH
Verlag GmbH & Co. KGaA, 2006, pp. 37-71; (e) B. Olofsson and P.
Somfai, in Aziridines and Epoxides in Organic Synthesis, Wiley-VCH
Verlag GmbH & Co. KGaA, 2006, pp. 315-347. (f) C.-Y. Huang and A.
G. Doyle, Chem. Rev, 2014, 114, 8153; (g) J. A. Kalow, D. E. Schmitt
and A. G. Doyle, J. Org. Chem., 2012, 77, 4177; (h) J. A. Kalow and A.
G. Doyle, J. Am. Chem. Soc., 2011, 133, 16001; (i) J. Am. Chem. Soc.,
2010, 132, 3268; (j) T. J. A. Graham, R. F. Lambert, K. Ploessl, H. F.
Kung and A. G. Doyle, J. Am. Chem. Soc., 2014, 136, 5291.
6
7
(a) M. Alam, C. Wise, C. A. Baxter, E. Cleator and A. Walkinshaw, Org.
ProcessRes. Dev., 2012, 16, 435; (b) C. Bonini, L. Chiummiento, M. T.
Lopardo, M. Pullez, F. Colobert and G. Solladié, Tetrahedron Lett., 2003,
44, 2695.
(a) C. Y. Huang and A. G. Doyle, J. Am. Chem. Soc., 2012, 134, 9541; (b)
K. L. Jensen, E. A. Standley and T. F. Jamison, J. Am. Chem. Soc., 2014,
136, 11145; (c) D. K. Nielsen, C. Y. Huang and A. G. Doyle, J. Am.
Chem. Soc., 2013, 135, 13605.
8
9
(a) M. L. Duda and F. E. Michael, J. Am. Chem. Soc., 2013, 135, 18347;
(b) Y. Takeda, Y. Ikeda, A. Kuroda, S. Tanaka and S. Minakata, J. Am.
Chem. Soc., 2014, 136, 8544.
D. K. Nielsen and A. G. Doyle, Angew. Chem. Int. Ed., 2011, 50, 6056.
10 (a) R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011, 111, 1417;
(b) J. E. Steves and S. S. Stahl, J. Am. Chem. Soc., 2013, 135, 15742.
11 Y.-Y. Sun, J. Yi, X. Lu, Z.-Q. Zhang, B. Xiao and Y. Fu, Chem.
Commun., 2014, 50, 11060.
12 Y. Zhao and D. J. Weix, J. Am. Chem. Soc., 2014, 136, 48.
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