Nickel-catalyzed coupling of arynes, alkenes, and boronic acids: Dual role of the boronic acid

Article abstract of DOI:10.1002/anie.200701063

(Chemical Equation Presented) Taking on a second job: Nickel catalyzes the three-component coupling of arynes, alkenes, and boronic acids in very high yields under mild conditions. The boronic acid also acts as the proton source in this reaction. cod = 1,5-cyclooctadiene.

Full text of DOI:10.1002/anie.200701063

Angewandte
Chemie
DOI: 10.1002/anie.200701063
Multicomponent Reactions
Nickel-Catalyzed Coupling of Arynes, Alkenes, and Boronic Acids:
Dual Role of the Boronic Acid**
Thiruvellore Thatai Jayanth and Chien-Hong Cheng*
Nickel-catalyzed domino reactions that involve the coupling
of two p components with main-group organometallic
reagents or metal hydrides have emerged as highly useful
methods for assembling complex molecular structures from
simple starting materials.[1] This class of reactions has evolved
significantly in scope as well as substrate choice. Most
commonly employed p systems include alkynes, alkenes,
dienes, allenes, aldehydes, imines, and allylic halides. The
organometallic reagents employed are usually based on zinc,
aluminum, zirconium, tin, boron, and silanes.[2] The utility of
this concept has been demonstrated well in organic syn-
thesis.[3] A similar reaction sequence employing arynes as a
p component would be highly interesting and useful, consid-
ering that arynes are generally very reactive and generated
in situ and that the reaction would lead to the formation of
ents such as 3,4-dimethoxy and 1,3-benzodioxole derivatives
1d and 1e, respectively, gave products in excellent yields
(Table 1, entries 4 and 5). Furthermore, the difluoro substi-
tuted benzyne precursor 1 f gave the corresponding three-
Table 1: Three-component coupling of arynes with ethyl vinyl ketone (2a)
and styrenyl boronic acid (3a).[a]
Entry
1
1
4
Yield [%][b]
92
À
two different C C bonds in ortho positions of a benzene
ring.[4] A mild method for the preparation of arynes in situ at
moderate temperatures from commercially available o-silyl
aryl triflates 1[5] has rekindled the interest, especially in the
past few years, in employing arynes as substrates in organic
synthesis.[6] As part of our ongoing efforts in employing
arynes as useful substrates in organic synthesis,[7] we report an
unprecedented nickel-catalyzed three-component coupling of
arynes, enones, and organoboronic acids. Thus, when a
solution of benzyne precursor 1a (2-(trimethylsilyl)phenyl
triflate), ethyl vinyl ketone (2a), and trans-2-phenylvinylbor-
onic acid (3a) in the presence of [Ni(cod)2] (cod = 1,5-
cyclooctadiene; 10 mol%), PPh3 (20 mol%), and CsF in
CH3CN was stirred for 8 h at 408C, coupling product 4a was
obtained in 92% yield (Table 1, entry 1).[8] This process is the
first example involving arynes and is also one of the first to
utilize organoboronic acids in nickel-catalyzed multicompo-
nent coupling reactions.[9]
2
3
4
5
6
93
84
95
88
67
A variety of arynes are compatible with this three-
component coupling reaction (Table 1). The aryne precursor
1b with two methyl groups on the phenyl ring furnished
product 4b in 93% yield (Table 1, entry 2) and indanyl
derivative 1c afforded 4c in 84% yield (Table 1, entry 3).
Aryne precursors that bear other electron-donating substitu-
85[c]
(85:15)
7
8
[*] T. T. Jayanth, Prof. Dr. C.-H. Cheng
Department of Chemistry
87[d]
(1:1)
National Tsing Hua University
Hsinchu 30013 (Taiwan)
Fax: (+886)3-572-4698
E-mail: chcheng@mx.nthu.edu.tw
[a] Reaction conditions: aryne precursor
1 (0.30 mmol), enone 2
[**] We thank the National Science Council of the Republic of China
(NSC 95-2119M-007-005) for support of this research.
(0.45 mmol), boronic acid 3 (0.30 mmol), [Ni(cod)2] (0.030 mmol),
PPh3 (0.060 mmol), and CsF (0.90 mmol) in CH3CN (1 mL) at 408C for
8 h. [b] Yields of isolated products. [c] The structure of the major isomer
is represented. [d] Mixture of regioisomers (1:1).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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component product 4 f (Table 1, entry 6). Very interestingly,
were also found to be compatible in the present reaction
(Table 2, entries 5 and 6). When acrylonitrile (2h) was
employed the three-component coupling product 4o was
obtained in 71% yield (Table 2, entry 7). When boronic acid
3a was replaced by its pinacol ester the reaction did not
proceed to give the expected product, and boroxine ((4-
MeOC6H5)3B3O3) gave trace amounts of product. The reac-
tion also failed with other soft organometallic reagents based
the aryne precursor 1g with a methoxy group at the ortho
position afforded regioisomers in 85:15 ratio in which the
predominant product was that with the vinyl group from the
boronic acid attached ortho to the methoxy group (Table 1,
entry 7). In the case of benzyne precursor 1h, the reaction
gave a 1:1 mixture of regioisomers (Table 1, entry 8), as
expected for the reaction of the unsymmetrical 4-methylben-
zyne substrate.
ꢀ
on tin (PhC CSnBu3) and silicon (PhSiMe3). The boronic
This three-component assembly works well with both
acyclic and cyclic enones (Table 2). Propyl vinyl ketone (2b)
worked smoothly under the reaction conditions (Table 2,
entry 1). Cyclic enones (five-, six-, and seven-membered
rings) reacted equally efficiently to yield the expected
products in very good yields (Table 2, entries 2–4). Acrylates
acid acting as a proton source is the likely reason for this
observation (see below). The boronic acid was found to be
crucial for the success of this reaction. Alkenyl boronic acids
worked particularly well. Thus hexenylboronic acid afforded
the three-component product in excellent yield (Table 2,
entry 8). Of the other organoboronic acids tested, p-, o-, and
Table 2: Three-component coupling of benzyne with alkenes 2 and organoboronic acids 3.[a]
Entry
1
1
2
3
4
Yield [%][b]
94
Entry
7
1
2
3
4
Yield [%][b]
71
1a
2b
3a
1a
2h
3a
2
3
4
1a
1a
1a
2c
2d
2e
3a
3a
3a
84
81
77
8
1a
1a
1a
2a
2a
2c
3b
3c
3d
94
84
79
9
10
5
6
1a
1a
2 f
3a
3a
75
73
11
12
1a
1a
2a
2a
3e
3 f
67[c]
2g
60[c]
[a] Reaction conditions: aryne precursor 1 (0.30 mmol), enone 2 (0.45 mmol), boronic acid 3 (0.30 mmol), [Ni(cod)2] (0.030 mmol), PPh3
(0.060 mmol), and CsF (0.90 mmol) in CH3CN (1 mL) at 408C for 8 h. [b] Yields of isolated products. [c] P(p-C6H4F)3 was employed instead of PPh3.
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m-methoxybenzeneboronic acids (3c–e) gave the correspond-
ing products in 67–84% yield (Table 2, entries 9–11). Benze-
neboronic acid (3 f) provided product 4t in 60% yield
(Table 2, entry 12). In the case of boronic acids 3e and 3 f,
phosphine ligand P(p-C6H4F)3 was employed, as the reaction
did not proceed when PPh3 was used as the ligand.
The regioselectivity observed in the reaction of 1g (Table 1,
entry 7) can be rationalized by the formation of ortho-
metalated complex 5g on the basis of the coordination of the
methoxy group to nickel.[12]
A seven-membered ring nickel O-
enolate generated by the oxidative cyc-
A plausible mechanistic rationale for the present catalytic
reaction is shown in Scheme 1. The catalysis is likely initiated
by the reaction of Ni0 with the enone and the aryne to form a
nickelacycle 5. Protonation of the a carbon atom of the
lization of an enal and an alkyne with
Ni0 species containing a Z carbon–
carbon double bond is documented as
the intermediate for protonation during
the coupling reaction.[13] However, in
the present case, a seven-membered ring nickel enolate
intermediate from 5 can be ruled out, considering that the
seven-membered ring intermediate generated by a cyclic
enone such as 2-cyclopenten-1-one and an aryne with Ni0
would contain a strained E double bond in the seven-
membered ring.[14]
In summary, we have demonstrated a nickel-catalyzed
domino reaction of arynes, enones, and boronic acids. This
reaction represents the first example of the use of arynes in
nickel-catalyzed coupling reactions. The organoboronic acid
acts both as a proton source and as a carbon nucleophile.
Experimental Section
General Procedure: A round-bottomed side-arm flask containing
[Ni(cod)2] (0.030 mmol), PPh3 (0.060 mmol), CsF (0.90 mmol), and
boronic acid 3 (0.30 mmol) was evacuated and purged with nitrogen
gas. CH3CN (1.0 mL), alkene 2 (0.450 mmol), and aryne precursor 1
(0.30 mmol) were then added to the flask through syringes. The
reaction mixture was allowed to stir at 408C for 8 h. At the end of the
reaction, the reaction mixture was diluted with CH2Cl2 and filtered
through celite and silica gel. The filtrate was concentrated, and the
residue was purified through a silica-gel column with ethyl acetate/
hexane as eluent to give pure product 4.
Scheme 1. Proposed mechanism for the three-component coupling
reaction.
ketone moiety by the boronic acid and transmetalation of the
organic group onto the nickel center leads to 6. Subsequent
reductive elimination gives the desired coupling product and
regenerates the Ni0 catalyst. To verify this pathway, a
deuterated boronic acid, p-OMeC6H4B(OD)2, was carefully
prepared and employed. As expected, deuterium was incor-
porated at the a carbon atoms of the ketone product
(Scheme 2).[10] Protonation of 5 by the organoboronic acid
likely enhances electron density at the boron center and thus
the nucleophilicity of the carbon nucleophile to facilitate the
transmetalation and catalysis. Thus, the organoboronic acid
plays a dual role in the present catalytic process: it acts both as
a proton source and as a carbon nucleophile.[11] An alternative
pathway for the formation of 6 from 5 via a boron enolate 7
and subsequent protonation cannot be completely ruled out.
Received: March 10, 2007
Published online: June 20, 2007
Keywords: arynes · boronic acids · enones ·
.
multicomponent reactions · nickel
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Communications
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