Alkene-assisted nickel-catalyzed regioselective 1,4-addition of organoboronic acid to dienones: A direct route to all-carbon quaternary centers

Article abstract of DOI:10.1021/ol500838h

A nickel-catalyzed highly regioselective 1,4-addition reaction of boronic acids to dienones to form products with an all-carbon quaternary center is described. The 3-alkenyl group of dienones is the key for the reaction to proceed smoothly. A mechanism involving the coordination of the dienyl group to the nickel center is proposed.

Full text of DOI:10.1021/ol500838h

Letter
pubs.acs.org/OrgLett
Alkene-Assisted Nickel-Catalyzed Regioselective 1,4-Addition of
Organoboronic Acid to Dienones: A Direct Route to All-Carbon
Quaternary Centers
Ya-Chun Hong, Parthasarathy Gandeepan, Subramaniyan Mannathan, Wei-Tse Lee,
and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
S
* Supporting Information
ABSTRACT: A nickel-catalyzed highly regioselective 1,4-addition
reaction of boronic acids to dienones to form products with an all-
carbon quaternary center is described. The 3-alkenyl group of dienones
is the key for the reaction to proceed smoothly. A mechanism involving
the coordination of the dienyl group to the nickel center is proposed.
addition reactions to α,β-unsaturated alkenes, but none of them
were reported for the addition to dienones and the formation of
all-carbon quaternary centers.7 As we have been interested in
nickel-catalyzed organic transformations,8 herein we report a
nickel-catalyzed, highly regioselective 1,4-addition reaction of
boronic acids to dienones to form products with an all-carbon
quaternary center.
ll-carbon quaternary centers are an important feature
1
Afound in many natural and bioactive molecules.
In
particular, cyclohexane rings bearing an all-carbon quaternary
center are often found in natural products and are an important
building block in organic synthesis (Scheme 1).2 Formation of
an all-carbon quaternary center is challenging synthetically due
to the steric hindrance of the four carbon groups and the
limited reliable methods available.3
The reaction of 3-styrylcyclohex-2-enone (1a) with trans-
styrylboronic acid (2a) in the presence of Ni(cod)2 (10 mol
%), PPh3 (20 mol %) and H2O (1.5 equiv) in 1,4-dioxane at
100 °C for 20 h gave 1,4-addition product 3aa in 90% isolated
yield (Table 1, entry 15). The product was thoroughly
Scheme 1. Natural Products Containing an All-Carbon
Quaternary Center
1
characterized by H and 13C NMR and HRMS data. The
catalytic reaction depends greatly on the ligand, the amount of
water, and solvent used, and the results are summarized in
Table 1. Among the solvents tested, 1,4-dioxane appeared to
afford the best yield (entries 3 and 15). MeOH and EtOAc also
gave product 3aa in 77 and 45% yields, respectively. The
catalytic reaction proceeds less effectively in the absence of
PPh3 or with chelating ligands (entries 8−12). The reaction
conducted in the absence of water gave only a trace of product
(entry 13). No product 3aa was observed in the absence of
Ni(cod)2 or using NiI2 and NiBr2 as the catalyst.
Next, to understand the scope of the present catalytic
reaction, we tested the reactivity of various aryl and
styrylboronic acids with 1a. Thus, the reaction of 1a with 4-
Me and 4-OMe substituted styrylboronic acids under standard
reaction conditions gave the respective products 3ab and 3ac in
98% and 66% yields, respectively (Table 2, entries 2−3). The
reaction of phenylboronic acid (2d) with 1a gave the desired
product 3ad in 91% yield. Similarly, different para substituted
phenylboronic acids 2e−g reacted smoothly with 1a to form
the respective products 3ae−ag in excellent yields (entries 5−
7). Treatment of 3-methoxyphenylboronic acid (2h) and o-
Transition-metal-catalyzed conjugate addition of carbon
nucleophiles (R−MXn; where M is Mg, Al, Zr, Li, Zn, B, or
Si) to α,β-unsaturated carbonyl compounds is considered a
prevailing method for the construction of all-carbon quaternary
centers.1,4,5 However, controlling the regioselectivity of
conjugate addition to a polyconjugated substrate is a
challenging task due to the presence of several competitive
electrophilic sites (1,2-, 1,4-, and 1,6-additions).6 In addition,
most of these reactions are effective only with highly air- and
moisture-sensitive organometallic reagents such as organozinc,
organoaluminum, organomagnesium, and organozirconium
compounds. The less reactive boron and silyl reagents worked
well only with catalysts containing noble metals such as Rh and
Pd.1−6 Nickel complexes are also known to catalyze conjugate
Received: March 20, 2014
Published: May 9, 2014
© 2014 American Chemical Society
2806
dx.doi.org/10.1021/ol500838h | Org. Lett. 2014, 16, 2806−2809

Organic Letters
Letter
a
a
Table 1. Reaction Optimization
Table 2. Scope of the Ni-Catalyzed Reaction
b
entry
ligand/mol %
H2O/mmol
solvent
MeOH
yield (%)
1
PPh3/20
PPh3/20
PPh3/20
PPh3/20
PPh3/20
PPh3/20
PPh3/20
dppe/10
dppp/10
dppb/10
rac-BINAP/10
−
PPh3/20
PPh3/20
PPh3/20
PPh3/10
PPh3/10
PPh3/10
0.90
0.90
0.90
0.90
0.90
0.90
0.90
0.90
0.90
0.90
0.90
0.90
0
77
2
toluene
trace
99
3
1,4-dioxane
ClCH2CH2Cl
CH3CN
4
trace
−
45
5
6
EtOAc
7
DMF
−
29
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
9
14
10
11
12
13
14
15
16
17
18
53
trace
47
c
trace
d
0.90
0.450
0.450
0.450
0.450
81
e
91(90)
73
f
51
62 ,
fg
a
Unless otherwise mentioned, all reactions were carried out using 1a
(0.30 mmol), 2a (0.90 mmol), and Ni(cod)2 (0.030 mmol) in 1.2 mL
b
1
of solvent at 100 °C for 20 h. The yields were determined by H
c
NMR integration using mesitylene as an internal standard. Reaction
was conducted in dry 1,4-dioxane in the absence of H2O. Reaction
was conducted at 80 °C. Reaction was carried out using 2a (0.450
mmol). 5 mol % Ni(cod)2 was used. Reaction was conducted for 36
h. Yield in the parentheses was isolated.
d
e
f
g
tolylboronic acid (2i) with 1a under similar reaction conditions
afforded conjugate addition products 3ah−i in 72% and 80%
isolated yields, respectively (entries 8−9). Highly substituted
arylboronic acids 2j−k also underwent the expected addition
reaction with 1a to afford products 3aj−k in good yields
(entries 10 and 11). A heterocyclicboronic acid such as
thiophen-2-ylboronic acid (2l) was also compatible in the
present catalytic reaction to form product 3al in 62% yield. In
addition to different boronic acids, we also examined the effect
of different substitutions on the dienone moiety. Thus, the
reaction of (3-propenyl)cyclohex-2-enone 1b with 2a and 2d
under the standard reaction conditions afforded products 3ba
and 3bd in 47% and 50% yields, respectively. In a similar
manner, bulkier alkyl substituted dienones 1c−d reacted with
2a to give the desired products in good yields (entries 14−15).
In addition to alkyl substituted dienones, differently substituted
styrylcyclohexenones 1e−g also provide the desired products
under standard reaction conditions (entries 16−18, 22−24).
Furthermore, a cyclopentenone substrate (1h) reacted
smoothly with 2a to afford desired product 3ha in 54% yield.
Unfortunately, the reaction using alkylboronic acids did not
proceed to give the expected products under similar reaction
conditions.
The presence of a vinyl moiety at the 3-position of
cyclohexenone is essential for the success of the present
catalytic reaction. Cyclohexenones with a methyl-, phenyl-, and
allyl-substitution at the 3-position (1i−l) did not react with
styryl- or phenylboronic acid to form 1,4-addition products
a
Unless otherwise mentioned, all reactions were carried out using 1
(0.30 mmol), 2 (0.45 mmol), Ni(cod)2 (0.030 mmol), PPh3 (0.060
mmol), and H2O (0.45 mmol) in 1.2 mL of 1,4-dioxane at 100 °C for
b
20 h. Isolated yield.
2807
dx.doi.org/10.1021/ol500838h | Org. Lett. 2014, 16, 2806−2809

Organic Letters
Letter
under similar reaction conditions (Scheme 2). Similarly, methyl
vinyl ketone showed a trace of the expected 1,4-addition
Scheme 4. A Proposed Reaction Mechanism
Scheme 2. Effect of Substitution on 3-Substituted
Cyclohexenone
product in the crude NMR. The results suggested that the
alkene moiety in substrate 1 is essential and probably acts as a
chelating ligand to the nickel catalyst center.9 In this context,
we tried to stabilize Ni-complexes (Scheme 4, intermediates I
and II) by addition of an external olefin (styrene or
norbornene)10 to the reaction of 1j with 2d shown in Scheme
2, but no expected 1,4-addition products were detected.
To understand the reaction scope further, we examined the
reactivity of acyclic dienones under similar reaction conditions.
Thus, the reaction of hepta-3,5-dien-2-one (1m) and 1-
phenylhexa-2,4-dien-1-one (1n) with 2a afforded the desired
1,4-addition products 3ma and 3na in 70% and 75% yields,
respectively (Scheme 3). It is interesting to note that 6,6-
The formation of 1,6-addition product 3pd (Scheme 3) is
intriguing in view of the unusual regiochemistry. A Ni-complex
(VI, Scheme 4), with the η3-allyl at the β, γ, and δ carbons of
the dienone moiety and the coordinated PPh3 adjacent to the
less substituted β carbon and the phenyl substituent close to
the more substituted terminal carbon, is proposed as an
intermediate for the formation of 3pd. Reductive elimination
affords the final product 3pd. It is not clear how VI is formed. A
plausible pathway is that an η3-allyl Ni-complex similar to
intermediate IV is formed first and then σ,π-allyl rearrangement
gives VI.5d,6c,e
Scheme 3. Ni-Catalyzed Conjugate Addition to Acyclic
Dienones
In conclusion, we have developed a nickel-catalyzed, highly
regioselective conjugate addition of boronic acids to dienones
to give 1,4-addition products with an all-carbon quaternary
center. The presence of a 3-alkenyl substituent assisting the
coordination of the dienone substrate to the nickel catalyst
center is essential for the substrate to undergo 1,4-conjugate
addition. The catalytic reaction is compatible with a variety of
aryl- and styrylboronic acids and dienones and does not require
any additive for the activation of the boronic acids. Application
of the present novel addition reactions to bioactive molecule
synthesis and enantioselective synthesis is in progress in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
dimethyl substituted dienones 1o and 1p reacted with
benzeneboronic acid 2d regioselectively to give 1,4-addition
product 3od in 15% yield and 1,6-addition product 3pd in 20%
yield, respectively (Scheme 3).
General experimental procedures, characterization details, and
1H and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
A plausible catalytic cycle for the present alkene assisted Ni-
catalyzed conjugate addition reaction, based on our exper-
imental observations and known literature,7−9 is presented in
Scheme 4. The catalytic cycle is initiated by the reaction of Ni0
with dienone 1a to form η4-coordinated nickel complex I.7c−f
The boronic acid then acts as a Lewis acid, and the
coordination to enone carbonyl oxygen promotes the formation
of η3-allyl complex III.7c−f Transmetalation of the aryl group
leads to the formation of intermediate IV. Further reductive
elimination regenerates the active Ni0-complex and a boron
enolate product V, which provides the final product 3ad upon
hydrolysis.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chcheng@mx.nthu.edu.tw.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of the
Republic of China (NSC-102-2628-M-007-005 and NSC-102-
2633-M-007-002) for support of this research.
2808
dx.doi.org/10.1021/ol500838h | Org. Lett. 2014, 16, 2806−2809

Organic Letters
Letter
(9) (a) Rogers, R. L.; Moore, J. L.; Rovis, T. Angew. Chem., Int. Ed.
2007, 46, 9301. (b) Canovese, L.; Visentin, F.; Levi, C.; Santo, C. J.
REFERENCES
■
(1) Christoffers, J.; Baro, A. Quaternary Stereocenters: Challenges and
Solutions for Organic Synthesis; Wiley-VCH; Weinheim, 2005.
Organomet. Chem. 2008, 693, 3324. (c) Defieber, C.; Grutzmacher, H.;
̈
Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482. (d) Johnson, J.
B.; Rovis, T. Angew. Chem., Int. Ed. 2008, 47, 840. (e) Herndon, J. W.
Coord. Chem. Rev. 2009, 253, 1517. (f) Gandeepan, P.; Cheng, C.-H. J.
Am. Chem. Soc. 2012, 134, 5738. (g) Gandeepan, P.; Cheng, C.-H. Org.
Lett. 2013, 15, 2084. (h) Chen, Q.; Chen, C.; Guo, F.; Xia, W. Chem.
Commun. 2013, 49, 6433. (i) Kantchev, E. A. B. Chem. Sci. 2013, 4,
1864.
(2) (a) Zdero, C.; Jakupovic, J.; Bohlmann, F. Phytochemistry 1990,
29, 1231. (b) Jeong, J.-H.; Chang, Y.-C. Biochem. Biophys. Res.
Commun. 2010, 398, 68. (c) Nagashima, F.; Murakami, Y.; Asakawa, Y.
Chem. Pharm. Bull. 1999, 47, 138. (d) Krish, S. F.; Bach, T. Chem.
Eur. J. 2005, 11, 7007. (e) Garneau, F. X.; Collin, G.; Gagnon, H.;
́
Belanger, A.; Lavoie, S.; Savard, N.; Pichette, A. J. Essent. Oil Res. 2008,
20, 250. (f) Cho, H.-J.; Kang, H.-H.; Jeong, J.-H.; Jeong, Y.-J.; Park, K.-
K.; Park, Y.-Y.; Moon, Y.-S.; Kim, H.-T.; Chung, I.-K.; Kim, C.-H.;
Chang, H.-W.; Chang, Y.-C. Mol. Biol. Rep. 2012, 39, 4597.
(g) Kawaguchi, M.; Fukuda, T.; Uchida, R.; Nonaka, K.; Masuma,
R.; Tomoda, H. J. Antibiot. 2013, 66, 23. (h) Li, X.-L.; Zhao, B.-X.;
Huang, X.-J.; Zhang, D.-M.; Jiang, R.-W.; Li, Y.-J.; Jian, Y.-Q.; Wang,
Y.; Li, Y.-L.; Ye, W. C. Org. Lett. 2014, 16, 224.
(10) (a) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
(b) Giovannini, R.; Studemann, T.; Devasagayaraj, A.; Dussin, G.;
̈
Knochel, P. J. Org. Chem. 1999, 64, 3544. (c) Devasagayaraj, A.;
Studemann, T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1995, 34,
̈
2723.
(3) (a) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005, 347, 1473.
(b) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5363.
(4) For selected reviews, see: (a) Krause, N.; Hoffmann-Roder, A.
̈
Synthesis 2001, 171. (b) Christoffers, J.; Koripelly, G.; Rosiak, A.;
Rossle, M. Synthesis 2007, 1279. (c) Alexakis, A.; Backvall, J. E.;
̈
̈
Krause, N.; Pam
́
ies, O.; Dieg
́
uez, M. Chem. Rev. 2008, 108, 2796.
(d) Jerphagnon, T.; Pizzuti, M. G.; Minnaard, A. J. Chem. Soc. Rev.
2009, 38, 1039. (e) Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.;
Frost, C. G. Chem. Soc. Rev. 2010, 39, 2093. (f) Hawner, C.; Alexakis,
A. Chem. Commun. 2010, 46, 7295.
(5) For selected papers: (a) Lee, K. S.; Brown, M. K.; Hird, A. W.;
Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182. (b) Shintani, R.;
Takeda, M.; Nishimura, T.; Hayashi, T. Angew. Chem., Int. Ed. 2010,
49, 3969. (c) Kikushima, K.; Holder, J. C.; Gatti, M.; Stoltz, B. M. J.
Am. Chem. Soc. 2011, 133, 6902. (d) Tissot, M.; Poggiali, D.; Hen
́
on,
H.; Muller, D.; Guenee
́
́
, L.; Mauduit, M.; Alexakis, A. Chem.Eur. J.
̈
2012, 18, 8731. (e) Endo, K.; Hamada, D.; Yakeishi, S.; Shibata, T.
Angew. Chem., Int. Ed. 2013, 52, 606. (f) Bleschke, C.; Tissot, M.;
Muller, D.; Alexakis, A. Org. Lett. 2013, 15, 2152. (g) Sidera, M.; Roth,
̈
P. M. C.; Maksymowicz, R. M.; Fletcher, S. P. Angew. Chem., Int. Ed.
2013, 52, 7995. (h) Gottumukkala, A. L.; Suljagic, J.; Matcha, K.; de
Vries, J. G.; Minnaard, A. J. ChemSusChem 2013, 6, 1636. (i) Magrez-
Chiquet, M.; Morin, M. S. T.; Wencel-Delord, J.; Amraoui, S. D.;
Basle,
19, 13663.
(6) (a) Hen
́
O.; Alexakis, A.; Crev
́
isy, C.; Mauduit, M. Chem.Eur. J. 2013,
́
on, H.; Mauduit, M.; Alexakis, A. Angew. Chem., Int. Ed.
2008, 47, 9122. (b) Sawano, T.; Ashouri, A.; Nishimura, T.; Hayashi,
T. J. Am. Chem. Soc. 2012, 134, 18936. (c) Ma, Z.; Xie, F.; Yu, H.;
Zhang, Y.; Wu, X.; Zhang, W. Chem. Commun. 2013, 49, 5292.
(d) Hata, T.; Nakada, T.; Oh, Y. T.; Hirone, N. Adv. Synth. Catal.
2013, 355, 1736. (e) Tissot, M.; Alexakis, A. Chem.Eur. J. 2013, 19,
11352. (f) Kitanosono, T.; Xu, P.; Kobayashi, S. Chem.Asian J. 2014,
9, 179. (g) Lu, J.; Ye, J.; Duan, W.-L. Chem. Commun. 2014, 50, 698.
(h) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052.
(7) (a) Shirakawa, E.; Yasuhara, Y.; Hayashi, T. Chem. Lett. 2006, 35,
768. (b) Lin, P.-S.; Jeganmohan, M.; Cheng, C.-H. Chem.Asian J.
2007, 2, 1409. (c) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett.
2007, 9, 5031. (d) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008,
130, 4978. (e) Lillo, V.; Geier, M. J.; Westcott, S. A.; Fernadez, V. Org.
́
Biomol. Chem. 2009, 7, 4674. (f) Shrestha, R.; Dorn, S. C. M.; Weix, D.
J. J. Am. Chem. Soc. 2013, 135, 751.
(8) (a) Mannathan, S.; Cheng, C.-H. Chem. Commun. 2013, 49, 1557.
(b) Yang, C.-M.; Mannathan, S.; Cheng, C.-H. Chem.Eur. J. 2013,
19, 12212. (c) Shih, W.-C.; Teng, C.-C.; Parthasarathy, K.; Cheng, C.-
H. Chem.Asian J. 2012, 7, 306. (d) Chen, H.; Huang, Z.; Hu, X.;
Tang, G.; Xu, P.; Zhao, Y.; Cheng, C.-H. J. Org. Chem. 2011, 76, 2338.
(e) Korivi, R. P.; Cheng, C.-H. Chem.Eur. J. 2010, 16, 282.
(f) Wong, Y.-C.; Parthasarathy, K.; Cheng, C.-H. Org. Lett. 2010, 12,
1736. (g) Yang, C.-M.; Jeganmohan, M.; Parthasarathy, K.; Cheng, C.-
H. Org. Lett. 2010, 12, 3610. (h) Mannathan, S.; Jeganmohan, M.;
Cheng, C.-H. Angew. Chem., Int. Ed. 2009, 48, 2192.
2809
dx.doi.org/10.1021/ol500838h | Org. Lett. 2014, 16, 2806−2809