Catalyzation of 1,4-additions of arylboronic acids to α,β- unsaturated substrates using nickel(I) complexes

Article abstract of DOI:10.1016/j.tetlet.2014.02.046

Nickel(I) complexes were generated in situ from Ni (PPh₃) ₂Cl₂ using activated iron and the complexes combined with N,N′-bis(4-fluorobenzylidene) ethane-1,2-diamine (BFBED) were then used as a catalyst for the 1,4-addition reaction of arylboronic acids to α,β-unsaturated substrates. The reaction proceeded to completion and did not require the addition of a base but the addition of potassium iodide is crucial to this cross-coupling reaction. Moreover, experimental observations suggested a possible Ni(I)-Ni(III) catalytic cycle mechanism.

Full text of DOI:10.1016/j.tetlet.2014.02.046

Tetrahedron Letters 55 (2014) 2107–2109
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Tetrahedron Letters
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Catalyzation of 1,4-additions of arylboronic acids to
substrates using nickel(I) complexes
a,b-unsaturated
⇑
Jing-Jing Meng, Min Gao, Min Dong, Yu-Ping Wei , Wen-Qin Zhang
Department of Chemistry, School of Science, Tianjin University, No. 92, Weijin Road, Nan kai District, Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Nickel(I) complexes were generated in situ from Ni (PPh3)2Cl2 using activated iron and the complexes
combined with N,N0-bis(4-fluorobenzylidene) ethane-1,2-diamine (BFBED) were then used as a catalyst
Received 22 November 2013
Revised 27 January 2014
Accepted 13 February 2014
Available online 25 February 2014
for the 1,4-addition reaction of arylboronic acids to a,b-unsaturated substrates. The reaction proceeded
to completion and did not require the addition of a base but the addition of potassium iodide is crucial
to this cross-coupling reaction. Moreover, experimental observations suggested a possible Ni(I)–Ni(III)
catalytic cycle mechanism.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Michael addition
Nickel(I) complexes
Arylboronic acid
a,b-Unsaturated substrate
Potassium iodide
Transition metal-catalyzed conjugate addition of organometal-
lics to ,b-unsaturated substrates is regarded as an effective and
complexes has had few significant breakthroughs and remains an
unmet challenge.9 In 2004, the first enantioselective Ni(I)-cata-
lyzed alkynylation involving an asymmetric conjugate addition of
a
powerful method for carbon–carbon bond formation in organic
synthesis.1 Various organometallics such as organoborons, organo-
lithiums, organomagnesiums, dialkyllithium cuprates, and organo-
zinc reagents are widely utilized.2 Particularly, organoboron
reagents are frequently used because they are nontoxic, environ-
mentally benign, and easy to separate from the products. However,
dimethylalumino TMS-acetylide to cyclic
oped by the Corey group.9e However, Ni(I)-catalyzed Michael
additions of arylboronic acids to ,b-unsaturated substrates are
a,b-enones was devel-
a
still extremely undeveloped and need to be explored.
With this background in mind, a univalent nickel complex for
conjugate addition reactions of arylboronic acids to
a,b-unsatu-
the catalysis of 1,4-additions of arylboronic acids to a,b-unsatu-
rated substrates are even more readily effected by noble metal cat-
alyst complexes, principally rhodium, palladium, and platinum
complexes.3 Recently, much attention has been devoted to active
nickel complex-catalyzed CAC bond formation reactions, including
Kumada cross-couplings,4 Suzuki cross-couplings,5 Negishi cou-
plings,6 and Stille couplings.7
rated substrates under completely homogeneous conditions is
reported herein. To approach this challenge, Ni(I) species was
prepared in situ from bivalent nickel complexes using Fe as an
external reductant under base-free conditions.10 In addition, to
better understand the nature of this addition reaction, a possible
mechanism is proposed.
Up until now, only a few examples of zerovalent or bivalent
Initially, methyl vinyl ketone (MVK) (1a) and phenylboronic
acid (2a) were chosen as substrates (Scheme 1). A wide variety
of catalyst/ligand combinations, solvents, bases, and temperatures
were screened. The optimized conditions were determined to be:
MVK (1 mmol), phenylboronic acid (3 mmol), Ni(PPh3)2Cl2
(0.1 mmol), PPh3 (0.1 mmol), Fe (1 mmol), and KI (0.2 mmol) in a
solution of toluene: dimethylacetamide (DMA) (2:1) (7.5 mL) at
90 °C under argon. The corresponding coupling product 3aa was
detected in 84% yield (by GC) using acetophenone as the internal
standard.
nickel catalyzed reactions of arylboronic acids to
a,b-unsaturated
substrates have been reported. Cheng and co-workers observed
that a Michael-type reaction occurred with Ni(acac)2/P(o-anisyl)3
in excellent yields via a base-assisted pathway.8a Later, Hirano
et al. developed a Ni(cod)2/P(t-Bu)3 catalyzed 1,4-addition of
trialkylboranes to
a,b-unsaturated esters in an aqueous/organic
biphasic system and reported that the addition of methanol was
essential for the alkylation reaction with 9-alkyl-9-BBNs.8b In con-
trast, the analogous transformation catalyzed by univalent nickel
Under the optimal conditions in Scheme 1, this synthetic route
was applied to acrylic acid derivatives, typically, n-butyl acrylate,
and the results are shown in Table 1. However, it was found that
⇑
Corresponding author. Tel./fax: +86 22 27403475.
E-mail address: ypw206@myway.com (Y.-P. Wei).
http://dx.doi.org/10.1016/j.tetlet.2014.02.046
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2108
J.-J. Meng et al. / Tetrahedron Letters 55 (2014) 2107–2109
Table 2
O
O
Scope using the optimized conditionsa
conditions
PhB(OH)2
+
Ph
conditions
R
R
ArB(OH)2
2a
3aa
1a
+
Ar
1
2
3
Scheme 1. Reaction of MVK (1a) and phenylboronic acid (2a). Reaction conditions:
MVK (1 mmol), phenylboronic acid (3 mmol), Ni (PPh3)2Cl2 (0.1 mmol), PPh3
(0.1 mmol), Fe (1 mmol), KI (0.2 mmol) in toluene/DMA (2:1) 7.5 mL at 90 °C under
argon, 24 h.
Entry
Ar
R
Products
Yieldb (%)
1
2
3
4
5
6
7
8
2a (Ph)
2a
2a
2a
2a
1a (COMe)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3bb
3bc
3bd
3be
3bf
3bg
3bh
3gb
3gd
3ge
3gh
68
76
71
68
60
55
60
67
62
55
58
30
45
45
42
50
47
56
1b (CO2Bun)
1c (CO2Me)
1d (CO2Et)
1e (CO2But)
the 1,4-addition between 2a and 1b proceeded sluggishly and
afforded the desired product 3ab with only 20% yield (Table 1,
entry 1) and a large amount of n-butyl acrylate was recovered.
Therefore, some of the reaction conditions such as additives,
ligands, and reaction time, were varied in an attempt to improve
the yield. The addition of 4 equiv of MeOH gave an improved yield
of 42%, whereas an excess of MeOH prevented the reaction (entries
2 and 3).8b LiCl and LiBr also produced slightly lower yields when
substituted for KI (entries 4 and 5). The addition of LiX suppresses
the formation of the biphenyl resulting from the homocoupling of
phenylboronic acid (entries 4 and 5 vs entry 1). An attempt to
accelerate the reaction rate using 1,10-phenanthroline11 as the
ligand enhanced the yield, particularly when KI was utilized
(entries 6–8).12 The same procedure was then adopted for
2a
2a
1f [CON(Bun)2]
1g (CN)
1b
1b
1b
1b
1b
1b
1b
1g
2b (2-MeOC6H4)
2c (3-MeOC6H4)
2d (4-MeOC6H4)
2e (3-NO2C6H4)
2f (4-CHOC6H4)
2g (4-FC6H4)
2h (4-CF3C6H4)
2b
9
10
11
12
13
14
15c
16c
17c
18c
2d
2e
2h
1g
1g
1g
a
Reaction conditions:
1 (1 mmol), 2 (3 mmol), Ni(PPh3)2Cl2 (0.1 mmol), L9
(0.05 mmol), Fe (1 mmol), KI (0.2 mmol) in toluene:DMA (2:1) 7.5 mL at 90 °C
a
-diimine ligands in place of 1,10-phenanthroline. Here, N,N0-
under argon for 5 days.
b
Yield: isolated yield.
Reaction time: 24 h.
bis(4-fluorobenzylidene) ethane-1,2-diamine (BFBED, L9) gave
3ab in 86% yield after 5 days (entry 9, see Supporting information).
A prolonged reaction time ensured complete consumption of 1b.13
In view of efficiency, cost, simplicity, and stability, optimal condi-
tions for the 1,4-addition reaction are as follows: 1b (1 mmol), 2a
(3 mmol), Ni(PPh3)2Cl2 (0.1 mmol), L9 (0.05 mmol), Fe (1 mmol), KI
(0.2 mmol) in toluene/DMA (2:1) 7.5 mL at 90 °C under argon for
5 days.
c
acrylonitrile and phenylboronic acid,3e only a mediocre yield was
achieved by our protocol for 3ag (60%, entry 7).
Representative reactions between n-butyl acrylate (1b) and var-
ious arylboronic acids (2b–h) are also summarized in Table 2. The
results show that electron-withdrawing and electron-donating
groups on the arylboronic acids had no impact on efficiency. Aryl-
boronic acids proceeded well with 1b, affording the cross-coupling
products in favorable yields (entries 8–14), although the complete
conversion of 1b to 3bb–bh required prolonged reaction times. For
the electron-rich arylboronic acids, small amounts of unexpected
Mizoroki–Heck-type addition products were also detected
(2–5%). Better yields were obtained for ortho-methoxy substituted
arylboronic acid 2b than for meta- and para-substituted analogues
(Table 2, entries 8–10). In addition, arylboronic acids with elec-
tron-withdrawing groups at the para position exclusively provided
1,4-addition products. Despite the high volatility of acrylonitrile,
the reactions were complete in 24 h, and afforded the products
in favorable yields (entries 15–18). On the whole, the reactions
with the Ni(I)-catalyzed system showed no clear trends for substi-
tuted arylboronic acids.
This nickel-catalyzed 1,4-addition was then successfully ex-
tended to phenylboronic acid with different
a,b-unsaturated al-
kenes. The results of these studies are shown in Table 2. The
optimal conditions for 3ab synthesis were applicable to the acrylic
acid derivatives (entries 1–6), and the substrate reacted smoothly
to give products in fair to moderate yields (55–76%). MVK can also
participate in the cross-coupling reaction and produced 3aa in 68%
isolated yield. Compared with Pd-catalyzed 1,4-additions of
Table 1
Reaction of phenylboronic acid (2a) with n-butyl acrylate (1b)a
O
O
Ph
N
OBun
Ph2
PhB(OH)2
+
OBun
2a
1b
4
3ab
N
A possible Ni(I)–Ni(III) mechanism for this reaction is proposed
as shown in Scheme 2. The reaction likely proceeded through a
typical crosscoupling pathway as follows: (1) The active catalytic
species Ni(I) generated in situ from Ni(II) precursor using activated
14
N
N
F
F
1,10-phenanthroline
BFBED, L9
a
Entry
Ligand
Additive
3abb
4 (mmol)
iron underwent oxidative addition with a,b-unsaturated substrate
to afford intermediate nickelacycle(III) 5.15,16 To rule out the func-
tion of Fe2+, equimolar FeCl2 was employed in place of Fe for this
transformation, and the reaction failed.17 Interestingly, when R2
was hydrogen, the reaction proceeded well. In contrast, both cyclic
1
PPh3
PPh3
PPh3
PPh3
PPh3
KI
KI
KI
LiCl
LiBr
/
LiCl
KI
20
45
0
44
40
57
65
72
86
0.47
0.08
0
0.09
0.12
0.08
0.04
0.02
0.02
2c
3d
4
5
6
7
8
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
L9
enones and internal a,b-unsaturated substrates just yielded traces
of the corresponding 1,4-addition products (detected by GC/MS),
which may suggest the formation of corresponding intermediate
nickelacycle(III) was greatly impeded.15b–d (2) Due to the Lewis
acid features of the B atom in arylboronic acid, the formation of
an OAB bond occurred and resulted in boron enolate 6. Subse-
9
KI
a
Reaction conditions: 1b (1 mmol), 2a (3 mmol), Ni(PPh3)2Cl2 (0.1 mmol), PPh3
(0.1 mmol) or N,N-bidentate ligand (0.05 mmol), Fe (1 mmol), KI (0.2 mmol) in
toluene:DMA (2:1) 7.5 mL at 90 °C under argon for 5 days.
b
quently, protonation of
a position of the ketone moiety by the
Yield (%) are determined by GC with acetophenone as the internal standard.
4.0 equiv of MeOH was added.
An excess of MeOH was added.
boronic acid18 and transmetalation of the aryl groups from the B
c
d
atom to the Ni(III) center led to 7 as a result of the weakened

J.-J. Meng et al. / Tetrahedron Letters 55 (2014) 2107–2109
2109
L2NiX2
Fe
References and notes
H
R1
R2
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OH
OH
Ar
B
2
R2
R1
X Ni
L
O
OH
B
Ar
6
OH
R2= H, L= Ligand, X= Cl or I
Scheme 2. A proposed mechanism for the cross-coupling reaction.
8. (a) Lin, P. S.; Jeganmohan, M.; Cheng, C. H. Chem. Asian J. 2007, 2, 1409–1416;
(b) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 1541–1544.
9. Great efforts have been made to explore Ni(I) catalysts for successful CAC bond
formation reactions. Especially, in the field of metal-catalyzed cross-coupling
reactions, see: (a) Phapale, V. B.; Guisán-Ceinos, M.; Buñuel, E.; Cárdenas, D. J.
Chem. Eur. J. 2009, 15, 12681–12688; (b) Klein, A.; Budnikova, Y. H.; Sinyashin,
O. G. J. Organomet. Chem. 2007, 692, 3156–3166; (c) Jones, G. D.; Martin, J. L.;
McFarland, C.; Allen, O. R.; Hall, R. E.; Haley, A. D.; Brandon, R. J.; Konovalova,
T.; Desrochers, P. J.; Pulay, P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128, 13175–
13183; (d) Anderson, T. J.; Jones, G. D.; Vicic, D. A. J. Am. Chem. Soc. 2004, 126,
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10. Nadal, M. L.; Bosch, J.; Vila, J. M.; Klein, G.; Ricart, S.; Moretó, J. M. J. Am. Chem.
Soc. 2005, 127, 10476–10477.
11. Phenanthroline is broadly applied to metal-catalyzed C–C formation reactions,
see: (a) Ref. 5d.; (b) Mansour, M.; Giacovazzi, R.; Ouali, A.; Taillefer, M.; Jutand,
A. Chem. Commun. 2008, 6051–6053.
12. It has been reported that iodine ions derived from Bu4NI suppress the homo-
coupling of arylboronic acid itself, see: (a) Ref. 5a.; (b) Piber, M.; Jensen, A. E.;
Rottländer, M.; Knochel, P. Org. Lett. 1999, 1, 1323–1326.
CAB bond between aryl and B atom. (3) Then reductive elimination
afforded the corresponding products and regenerated the Ni(I) cat-
alyst. The variation in color from blood red to dark brown helps im-
ply an ongoing Ni(I) to Ni(III) cycle. An alternative mechanism via
Ni(0)/Ni(II) intermediates cannot be totally excluded.
In summary, Ni(I) complexes generated in situ from the combi-
nation of Fe, Ni(PPh3)2Cl2 and BFBED were successfully employed
to catalyze the b-arylation of
a,b-unsaturated substrates. Potas-
sium iodide was an indispensable additive and yields up to 76%
were achieved. The proposed mechanism suggests that a Ni(I)
intermediate is responsible for the 1,4-addition process to take
place.
13. It has been reported that electron-poor chiral diphosphine ligands were
employed in Rh-catalyzed asymmetric 1,4-addition of arylboronic acids, see:
(a) Ref. 3c, and related references therein.; (b) Le.Boucher d’Herouville, F.;
Millet, A.; Scalone, M.; Michelet, V. R. J. Org. Chem. 2011, 76, 6925–6930.
14. Evidence is slowly accumulating that indicates a Ni(I) species participates in
chemistry that is unrelated to its role in the Ni(0)–Ni(II) process. A similar
Ni(I)–Ni(III) catalytic cycle has been observed with organozinc reagents and
with aryl halides and their corresponding Ni(I) species to afford Ni(III) species,
see: (a) Ref. 9c.; (b) Lin, X.; Phillips, D. L. J. Org. Chem. 2008, 73, 3680–3688; (c)
Zhang, K.; Conda-Sheridan, M.; Cooke, S. R.; Louie, J. Organometallics 2011, 30,
2546–2552.
General procedure for the 1,4-addition of arylboronic acids to
a,b-unsaturated substrates
An oven-dried 25-mL Schlenk tube equipped with a magnetic
stir bar was charged with arylboronic acid (3.0 mmol), nickel(II)
complex (0.1 mmol), ligand (0.05 mmol), activated iron
(1.0 mmol), and KI (0.2 mmol), and then sealed tightly with a rub-
ber septum. The tube was evacuated and back filled with argon
three times. To this mixture 7.5 mL of toluene/DMA (2:1, v/v)
15. Nickeladihydrofuran is
a well-recognized and key intermediate in nickel-
catalyzed reactions, see: (a) Ogoshi, S.; Arai, T.; Ohashi, M.; Kurosawa, H. Chem.
Commun. 2008, 1347–1349. and references therein. Moreover, it has been
reported that acyclic enones can adopt an cyclic transition state to produce 1,4
addition products, while cyclic ones fail; (b) Hooz, J.; Layton, R. B. J. Am. Chem.
Soc. 1971, 93, 7320–7322; (c) Sinclair, J. A.; Molander, G. A.; Brown, H. C. J. Am.
Chem. Soc. 1977, 99, 954–956; (d) Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem.
Soc. 2000, 122, 1822–1823.
and an a,b-unsaturated substrate (1.0 mmol) were added sequen-
tially via a syringe under a positive flow of argon. The sealed tube
was then placed into a preheated oil bath and stirred at 90 °C under
argon. After the reaction was completed, the mixture was
quenched with water and filtered through Celite, and then ex-
tracted with dichloromethane (3 ꢀ 5 mL), and then washed with
brine and dried with anhydrous Na2SO4. The solvent was removed
under reduced pressure. The residue was purified by flash column
chromatography on silica gel with petroleum/ethyl acetate (10:1)
as the eluent to give the corresponding products.
16. Iron worked better than zinc in our strategy, due to their difference in redox
potentials. Activated iron dust can reduce Ni(II) to Ni(I) completely, see: (a) Ref.
10.; Whereas zinc dust only partially reduced Ni(II) to give a mixture of Ni(I)
and Ni(0), see: (b) Kanai, H.; Kushi, K.; Sakanoue, K.; Kishimoto, N. Bull. Chem.
Soc. Jpn. 1980, 53, 2711–2715; (c) Gómez-Benítez, V.; Baldovino-Pantaleón, O.;
Herrera-Álvarez, C.; Toscano, R. A.; Morales-Morales, D. Tetrahedron Lett. 2006,
47, 5059–5062.
17. A control experiment was conducted to rule out the possibility of an Fe(II)-
catalyzed conjugate addition mechanism. Iron is a very broadly applicable
catalyst in cross-coupling reactions, see: (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani,
L. Chem. Rev. 2004, 104, 6217–6254; The Fe(II) species formed in the redox
process may enable the CAC bond formation reaction in the presence of the Ni,
see: (b) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 9717–
9720.
Acknowledgment
This work was supported by National Natural Science Founda-
tion of China (No. 20972109).
18. Deuterated boronic acid has been used to verify similar process by Cheng et al.
see: Jayanth, T. T.; Cheng, C. H. Angew. Chem., Int. Ed. 2007, 46, 5921–5924.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
02.046.