Cu-catalyzed cross-coupling reactions of vinyl epoxide with organoboron compounds: access to homoallylic alcohols

Article abstract of DOI:10.1039/c8ra09048c

Copper-catalyzed cross-coupling reactions of vinyl epoxide with arylboronates to obtain aryl-substituted homoallylic alcohols are described. The reaction selectivity was different to that of previously reported vinyl epoxide ring-opening reactions using aryl nucleophiles. The reaction proceeded under mild conditions, affording aryl-substituted homoallylic alcohols with high selectivity and in good to excellent yields. The reaction provides convenient access to aryl-substituted homoallylic alcohols from vinyl epoxide.

Full text of DOI:10.1039/c8ra09048c

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Cu-catalyzed cross-coupling reactions of vinyl
epoxide with organoboron compounds: access to
homoallylic alcohols†
Cite this: RSC Adv., 2018, 8, 41561
ab
a
Jin-Song Li,a Jin-Yu Wang,
Shi-Qun Wang,a Yue-Ming Li,a
*
Xiao-Yu Lu,
Yu-Jing Zhu,a Ran Zhoua and Wen-Jing Maa
Copper-catalyzed cross-coupling reactions of vinyl epoxide with arylboronates to obtain aryl-substituted
homoallylic alcohols are described. The reaction selectivity was different to that of previously reported
vinyl epoxide ring-opening reactions using aryl nucleophiles. The reaction proceeded under mild
conditions, affording aryl-substituted homoallylic alcohols with high selectivity and in good to excellent
yields. The reaction provides convenient access to aryl-substituted homoallylic alcohols from vinyl epoxide
Received 1st November 2018
Accepted 28th November 2018
DOI: 10.1039/c8ra09048c
rsc.li/rsc-advances
aryl Grignard reagents,9 aryl boron compounds,10 aryl siloxane
reagents,11 and organotin compounds (Scheme 1a). However,
Introduction
these previously reported works all afford aryl-substituted allylic
alcohols. Exploring new chemical reaction selectivity is an
interesting and challenging area of organic synthesis.
Based on previous work on Cu-catalyzed ring-opening reac-
tions of epoxides with organoboron,5c we now report the rst
example of the Cu-catalyzed ring-opening/cross-coupling of
vinyl epoxides with arylboronates, which afforded aryl-
substituted homoallylic alcohols (Scheme 1b). The selectivity
of the ring-opening reaction was different to that observed
previously for ring-opening reactions of vinyl epoxide with aryl
nucleophiles. This methodology provides access to synthetically
valuable aryl-substituted homoallylic alcohols from vinyl epox-
ides, which are valuable structural fragments in organic
synthesis.
Transition-metal-catalyzed cross-couplings are among the most
valuable C–C bond-forming reactions in modern organic
synthesis.1 Compared with traditional carbon–halogen or
carbon–OSO2R electrophiles,2 epoxides possess ring strain that
makes them susceptible to ring opening. Through ring-opening
reactions of epoxides, alcohol compounds can be easily ob-
tained with the construction of a C–C bond.3 In recent years,
various epoxide ring-opening reactions have been reported,
including transition-metal-catalyzed Kumada and Negishi-type
ring-opening/cross-coupling reactions of epoxides.4 Organo-
boron compounds have excellent stability and are commercially
available. Therefore, many groups have reported Suzuki-type
ring-opening/coupling reactions of epoxides.5 Furthermore,
reductive ring-opening/coupling reactions and Heck-type reac-
tions of epoxides have recently been reported.6
Vinyl epoxide is a special type of epoxide with rich chemical
reactivity. The chemistry of vinyl epoxides is uniquely charac-
terized by the conjugated reactivity of the epoxide and carbon–
carbon double bond. Vinyl epoxides are easily prepared using
simple synthetic routes and are important building blocks with
vast potential in organic synthesis.7 Owing to its unique struc-
tural features, vinyl epoxide is prone to SN20-type ring-opening/
coupling reactions with aryl nucleophiles, affording alcohols
containing a C]C bond. Some research groups have reported
ring-opening/coupling reactions of vinyl epoxide with various
types of aryl nucleophiles, including aryl bismuth compounds,8
Experimental
We began our study by selecting m-methoxy phenylboronate
(1a) and 3,4-epoxy-1-butene (2a) as model reaction substrates
(Table 1). We rst examined previously reported catalytic
aCollege of Materials and Chemical Engineering, Chuzhou University, Hui Feng Road
1, Chuzhou 239000, P. R. China
bSchool of Chemistry and Chemical Engineering, AnHui University, Hefei, 230601,
China. E-mail: xiaoyulu@mail.ustc.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra09048c
Scheme
vucleophiles.
1 Cross-couplings reactions of vinyl epoxide with aryl
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Table 1 Optimization of the reaction conditions
Table 2 Scope of the reactiona
Entry
Catalyst
Ligand
Base
Solvent
Yielda %
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuCl
CuCl
CuCl
CuCl
—
L1
L2
L3
PPh3
Xantphos
TMEDA
Xantphos
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOMe
LiOtBu
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
21
18
12
15
41
52
63
89
Trace
Trace
Trace
0
9
10
11
12b
Dioxane
DMF
DMF
a
Reaction conditions: catalyst (10 mol%), base (2.5 equiv.), ligand
(15 mol%) in 0.6 mL solvent at 60 ꢀC for 10 h under Ar atmosphere.
b
No CuCl. Saturated NH4Cl was added aer the reaction. The yield
was determined by GC using benzophenone as internal standard
(average of two GC runs).
conditions for similar Cu-catalyzed ring-opening reactions of
epoxides with organoboron compounds.5c,12 The product was
observed, but in low yield (entry 1). Therefore, the previously
reported conditions were not suitable for the ring-opening
cross-coupling of vinyl epoxide. To assess the roles of dike-
tone, nitrogen, and phosphine ligands, CuI was next evaluated
a
Reaction conditions: vinyl Epoxides (0.25 mmol), arylboronic esters (2
equiv.), LiOtBu (2.5 equiv.). Saturated NH4Cl was added aer the
b
c
as a copper source (entries 2–6). Using other diketone ligands reaction was completed. 1–2 mL EtOAc was added aer the reaction
afforded a lower yield (entries 2 and 3). Using phosphine
was completed, then stirred at room temperature for 1–4 h.
(entries 4 and 5) and nitrogen (entry 6) ligands instead of
diketone ligands increased the reaction yield, but still only ob-
tained a moderate yield. Next, we explored the effect of copper
sources on the reaction efficiency (entries 7 and 8). Under the
same conditions, using CuCl instead of CuI signicantly
increased the reaction yield (entries 7 and 8 vs. entries 5 and 6).
Pleasingly, using CuCl as the copper source resulted in good
yields (89% GC yield and 85% isolated yield, entry 8). This
might be due to strongly nucleophilic iodide ions affecting the
reaction. In ether solvents, hardly any product was obtained
(entries 9 and 10). Similarly, almost no product was obtained
when using LiOMe as base (entry 11). In the absence of a copper
source, no product formation was observed (entry 12).
With optimized conditions in hand, we next examined the
substrate scope (Table 2). To obtain aryl-substituted homo-
allylic alcohols, it was necessary to add saturated NH4Cl aer
the reaction was complete. Both electron-rich and electron-poor
arylboronates afforded good product yields. A series of relevant
functional groups, including ether (3a), halogen (3b and 3c),
triuoromethoxy (3d), cyano (3e), and triuoromethyl (3f)
groups, were well tolerated, affording good yields. Notably, aryl
halides, including aryl chloride and aryl bromide (3b and 3c),
did not hinder the transformation. Therefore, it was possible to
perform subsequent cross-coupling reactions at the haloge-
nated positions. A substrate bearing a bicyclic naphthyl group
(3g) also participated in the reaction. Unfortunately, alke-
nylboronate did not participate in the reaction.
Free hydroxyl groups are relatively active functional groups.
In many reactions, it is necessary to protect the hydroxyl groups.
Hydroxyl groups can be protected with acetyl groups, which
requires the use of acetyl chloride or acetic anhydride reagents.
Use of these reagents is disadvantageous owing to certain
hazards, such as severe irritation and corrosion. Aer the
reaction was completed, then added 1–2 mL EtOAc and stirred
at room temperature for 1–4 hour, we obtained acetyl-protected
homoallylic (Table 2). Aryl halides, including aryl chloride and
aryl bromide (4a and 4b) were also tolerated in this reaction.
Notably, the higher activity of aryl iodide (4c) did not affect the
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Scheme
2 Synthesis of homoallylic alcohbbols via ring opening
reaction.
transformation. Both electron-rich and electron-poor substrates
afforded good yields of acetyl-protected products. A series of
relevant functional groups, including triuoromethyl (4d),
halogen (4e), triuoromethoxy (4h), and cyano (4g) groups, were
well tolerated, affording good yields. Arylboronate bearing
a sulfur atom (4f) also participated in the reaction. Other
aromatic ring substrates, such as biphenyl (4i), naphthyl (4j),
furan (4k), thiophene (4l), and pyridine (4m), also participated
in the reaction, affording high yields. Steric hindrance at the
ortho position resulted in a mixture of protected homoallylic
and allylic alcohols (4n and 4o). The homoallylic alcohol
compound was detected as the only product except for ortho-
substituted substrate.13
To demonstrate the scalability of this method for homo-
allylic alcohol preparation, we performed the Cu-catalyzed
opening-ring reaction of vinyl epoxide on a gram scale,
obtaining 3a in 87% yield (Scheme 2). Aryl-substituted homo-
allylic alcohols are an important organic synthesis fragment,
and can be easily converted into b-chlorotetrahydrofurans (3aa).
Under chiral catalysis, they can also be converted into chiral b-
chlorotetrahydrofurans.14 Furthermore, homoallylic alcohols
can also be oxidized by m-CPBA to 3,4-epoxyalcohols (3ab). 3,4-
Epoxyalcohols are important organic synthons that can partic-
ipate in many reactions.15 In addition to these transformations,
aryl-substituted homoallylic alcohols can also be converted into
b-bromotetrahydrofuran, b-uorotetrahydrofuran, and b-tri-
uoromethyl tetrahydrofuran.16 Previously, aryl-substituted
homoallylic alcohols were generally synthesized through Wit-
tig or alkene metathesis reactions. The Wittig reaction involves
a long reaction route, relatively harsh conditions, and requires
the use of strong bases. Meanwhile, the reaction can be
Scheme 3 Proposed catalytic cycle.
controlled at low temperature (see, ESI†).17 For alkene metath-
esis, Grubbs catalyst is expensive, while commercial styrene is
relatively less (see ESI†).18 The Heck reaction of aryl halides with
3-buten-1-ol, generally affords 4-arylbutanal as the major
product (see ESI†).19 Therefore, to synthesize aryl-substituted
homoallylic alcohols, the metal-catalyzed Sonogashira reac-
tion of aryl halides with but-3-yn-1-ol is necessary, followed by
alkyne reduction.20 These alternative methods clearly show that
the reaction reported herein provides an efficient, economical,
and convenient method for the synthesis of aryl-substituted
homoallylic alcohols.
To illustrate the reaction mechanism, we performed a series
of reactions using (E)-4-phenylbut-2-en-1-ol (Table 3, eqn (1)).
The isomerization product could not be obtained without
adding reagents (entry 1). Adding 10 mol% CuCl or 15 mol%
TMEDA also did not afford any isomerized product (entries 2
and 3). When 2.5 equiv. of LiOtBu was added, the isomerization
product was obtained in high yield and no residual material was
detected (entry 4). In contrast, adding 2.5 equiv. of LiCl did not
afford any isomerization products (entry 5). This conrmed that
lithium ions did not cause isomerization. Similarly, the LiOtBu
can also promote the alkene isomerization of allylbenzene (eqn
(2)). It is conrmed by these experiments that the LiOtBu is the
cause of the alkene migration. Previous studies have indicated
that the base, such as K3PO4, KF, KOH, NaOtBu, KOtBu,21 can
promote the alkene isomerization of allylbenzene. Researchers
have conrmed that the isomerization goes through an intra-
molecular base-promoted hydrogen transfer process (carbanion
intermediate).21a,21e From these experiments, we proposed
a possible catalytic cycle (Scheme 3). The copper salt rst reacts
with LiOtBu, generating LCu-OtBu (I). Transmetalation then
produces LCu-Ar(II), which reacts with vinyl epoxide via an SN20-
type ring-opening/coupling to afford intermediate (III).
Table 3 Support experiments for the proposed mechanism
Entry
Conditions
RSM of 5a
Yield of 5b
1
2
3
4
5
—
>99%
>99%
>99%
trace
0
0
0
10% CuCl
15% TMEDA
2.5 equiv. LiOtBu
2.5 equvi. LiCl
>95%
0
100%
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Intermediate III then undergoes intramolecular hydrogen
transfer and alkene isomerization to afford the aryl-substituted
homoallylic alcohols.
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.
4 (a) M. Alam, C. Wise, C. A. Baxter, E. Cleator and
A. Walkinshaw, Org. Process Res. Dev., 2012, 16, 435; (b)
C. Bonini, L. Chiummiento, M. T. Lopardo, M. Pullez,
(1)
´
F. Colobert and G. Solladie, Tetrahedron Lett., 2003, 44,
2695; (c) C. Y. Huang and A. G. Doyle, J. Am. Chem. Soc.,
2012, 134, 9541; (d) K. L. Jensen, E. A. Standley and
T. F. Jamison, J. Am. Chem. Soc., 2014, 136, 11145; (e)
D. K. Nielsen, C. Y. Huang and A. G. Doyle, J. Am. Chem.
Soc., 2013, 135, 13605.
(2)
5 (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; (c) X. Y. Lu,
C. T. Yang, J. H. Liu, Z. Q. Zhang, X. Lu, X. Lou, B. Xiao
and Y. Fu, Chem. Commun., 2015, 51, 2388.
6 (a) Y. Zhao and D. J. Weix, J. Am. Chem. Soc., 2013, 136, 48; (b)
Y. Zhao and D. J. Weix, J. Am. Chem. Soc., 2015, 137, 3237; (c)
S. Teng, M. E. Tessensohn, R. D. Webster and J. S. Zhou, ACS
Catal., 2018, 8, 7439.
Conclusions
In summary, we have developed the rst Cu-catalyzed ring-
opening reaction of vinyl epoxides with arylboronates. This
reaction affords (E)-aryl-substituted homoallylic alcohols. The
reaction selectivity was different to that of previous ring-
opening reactions of vinyl epoxide with aryl nucleophiles.
This reaction provides an effective method for the synthesis of
aryl-substituted homoallylic alcohols, which are valuable
synthetic intermediates in modern organic synthesis. The mild
reaction conditions tolerate a wide variety of functional groups.
7 J. He, J. Ling and P. Chiu, Chem. Rev., 2014, 114, 8037.
8 S.-K. Kang, H.-C. Ryu, Y.-T. Hong, M.-S. Kim, S.-W. Lee and
J.-H. Jung, Synth. Commun., 2001, 31, 2365.
9 Z. Zhao, G. L. Araldi, Y. Xiao, A. P. Reddy, Y. Liao, S. Karra,
N. Brugger, D. Fischer and E. Palmer, Bioorg. Med. Chem.
Lett., 2007, 17, 6572.
Conflicts of interest
There are no conicts to declare.
10 (a) J. Kjellgren, J. Aydin, O. A. Wallner, I. V. Saltanova and
´
K. J. Szabo, Chem.–Eur. J., 2005, 11, 5260; (b)
J. P. Patterson, P. Cotanda, E. G. Kelley, A. O. Moughton,
A. Lu, T. H. Epps 3rd and R. K. O'Reilly, Polym. Chem.,
2013, 4, 2033; (c) G. W. Roffe, G. J. Tizzard, S. J. Coles,
H. Cox and J. Spencer, Org. Chem. Front., 2016, 3, 957.
11 J. R. Herron, V. Russo, E. J. Valente and Z. T. Ball, Chem.–Eur.
J., 2009, 15, 8713.
12 (a) C. T. Yang, Z. Q. Zhang, Y. C. Liu and L. Liu, Angew.
Chem., Int. Ed., 2011, 50, 3904; (b) G. Z. Wang, J. Jiang,
X. S. Bu, J. J. Dai, J. Xu, Y. Fu and H. J. Xu, Org. Lett., 2015,
17, 3682; (c) Z. Q. Zhang, C. T. Yang, L. J. Liang, B. Xiao,
X. Lu, J. H. Liu, Y. Y. Sun, T. B. Marder and Y. Fu, Org.
Lett., 2014, 16, 6342; (d) Z. Q. Zhang, B. Zhang, X. Lu,
J. H. Liu, X. Y. Lu, B. Xiao and Y. Fu, Org. Lett., 2016, 18,
952; (e) Y. Y. Sun, J. Yi, X. Lu, Z. Q. Zhang, B. Xiao and
Y. Fu, Chem. Commun., 2014, 50, 11060.
Acknowledgements
This work was supported by 2017qd11, 2016GH15, and Anhui
Province Major Special Projects (16030801108).
Notes and references
1 F. Diederich and P. J. Stang, Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, Weinheim, 1998.
2 (a) R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011,
111, 1417; (b) S. Z. Tasker, E. A. Standley and T. F. Jamison,
Nature, 2014, 509, 299; (c) A. Suzuki, Angew. Chem., Int. Ed.,
2011, 50, 6722; (d) X. Y. Lu, M. L. Hong, H. P. Zhou,
Y. Wang, J. Y. Wang and X. T. Ge, Chem. Commun., 2018,
54, 4417; (e) X. Y. Lu, J. H. Liu, X. Lu, Z. Q. Zhang,
T. J. Gong, B. Xiao and Y. Fu, Chem. Commun., 2016, 52, 13 (a) L. A. Batory, C. E. McInnis and J. T. Njardarson, J. Am.
5324; (f) X.-Y. Lu, J.-S. Li, M.-L. Hong, J.-Y. Wang and
W.-J. Ma, Tetrahedron, 2018, 74, 6979.
Chem. Soc., 2006, 128, 16054; (b) M. Brichacek, L. A. Batory
and J. T. Njardarson, Angew. Chem., Int. Ed., 2010, 49, 1648.
3 (a) P. Crotti and M. Pineschi, in Aziridines and Epoxides in 14 (a) X. Zeng, C. Miao, S. Wang, C. Xia and W. Sun, Chem.
Organic Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA,
2006, pp. 271–313; (b) V. V. Fokin and P. Wu, in Aziridines
Commun., 2013, 49, 2418; (b) W. Sun, X. Zeng, C. Miao,
S. Wang and C. Xia, Synthesis, 2013, 45, 2391.
and Epoxides in Organic Synthesis, Wiley-VCH Verlag GmbH 15 (a) A. Banerjee and H. Yamamoto, Org. Lett., 2017, 19, 4363;
& 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
(b) C. Wang and H. Yamamoto, J. Am. Chem. Soc., 2014, 136,
1222; (c) Y. Q. Zhang, N. Funken, P. Winterscheid and
A. Gansauer, Angew. Chem., Int. Ed., 2015, 54, 6931.
41564 | RSC Adv., 2018, 8, 41561–41565
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RSC Advances
16 (a) R. Lin, H. Sun, C. Yang, Y. Yang, X. Zhao and W. Xia, 20 (a) X. Su, Y. Sun, J. Yao, H. Chen and C. Chen, Chem.
Beilstein J. Org. Chem., 2015, 11, 31; (b) Y. Wang, M. Jiang
and J.-T. Liu, Adv. Synth. Catal., 2016, 358, 1322.
Commun., 2016, 52, 4537; (b) J. Tummatorn, S. Ruchirawat
and P. Ploypradith, Chem.–Eur. J., 2010, 16, 1445.
17 (a) B. J. Stokes, S. M. Opra and M. S. Sigman, J. Am. Chem. 21 (a) D. J. Cram and R. T. Uyeda, J. Am. Chem. Soc., 1962, 84,
Soc., 2012, 134, 11408; (b) A. M. Del Hoyo, A. G. Herraiz
and M. G. Suero, Angew. Chem., Int. Ed., 2017, 56, 1610.
18 P. R. Walker, C. D. Campbell, A. Suleman, G. Carr and
E. A. Anderson, Angew. Chem., Int. Ed., 2013, 52, 9139.
19 M. van Gemmeren, M. Borjesson, A. Tortajada, S. Z. Sun,
K. Okura and R. Martin, Angew. Chem., Int. Ed., 2017, 56,
6558.
4358; (b) R. Neumann and Y. Sasson, J. Mol. Catal., 1985,
33, 201; (c) T. X. Luu, T. Lam, T. Le and F. Duus, Molecules,
2009, 14, 3411; (d) I. Al-Maskery, K. Girling, S. D. Jackson,
L. Pugh and R. R. Spence, Top. Catal., 2010, 53, 1163; (e)
N. Qasheh, S. Mukhopadhyay, A. V. Joshi, Y. Sasson,
G.-K. Chuah and S. Jaenicke, Ind. Eng. Chem. Res., 2007,
46, 3016.
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