Nickel-catalyzed borylative coupling of alkynes, enones, and bis(pinacolato)diboron as a route to substituted alkenyl boronates

Article abstract of DOI:10.1002/anie.200805293

(Chemical Equation Presented) Three-component coupling reactions of an alkyne, an enone, and a diboron reagent provide access to highly substituted alkenyl boronates in good to excellent yields (see scheme). The coupling is highly regio- and stereoselecti

Full text of DOI:10.1002/anie.200805293

Communications
DOI: 10.1002/anie.200805293
Multicomponent Reactions
Nickel-Catalyzed Borylative Coupling of Alkynes, Enones, and
Bis(pinacolato)diboron as a Route to Substituted Alkenyl Boronates**
Subramaniyan Mannathan, Masilamani Jeganmohan, and Chien-Hong Cheng*
Table 1: Three-component coupling of alkynes with ethyl vinyl ketone
(2a) and bis(pinacolato)diboron (3).[a]
Nickel-catalyzed sequential coupling of two different p com-
ponents with an organometallic reagent or a metal hydride is
a practical method for the one-pot assembly of three different
stable components with consecutive formation of two chem-
ical bonds.[1] In 1995, the Ikeda research group demonstrated
the intermolecular sequential coupling of alkynes, enones,
and organometallic reagents, such as organostannane, orga-
nozinc, and organoaluminum reagents.[2] In the meantime,
Montgomery and co-workers reported the intramolecular
sequential coupling of enynes with various organometallic
reagents.[3] Later, the sequential coupling of two different
p components and organometallic reagents or metal hydrides
was demonstrated.[4,5] Recently, we also described an inter-
molecular coupling of benzynes with activated alkenes and
organoboronic acids.[6] In these sequential coupling reactions
of two different p components, only organometallic reagents
and metal hydrides have been used as the terminating agents.
Our continuing interest in metal-catalyzed sequential
coupling reactions and the addition of dimetal reagents[7] to
carbon–carbon p components[8] prompted us to explore the
use of a diboron reagent as a terminating agent in coupling
reactions of alkynes and enones. Herein, we report a highly
regio- and stereoselective three-component coupling of
alkynes, alkenes, and bis(pinacolato)diboron (3) to afford
highly substituted alkenyl boronates in good to excellent
yields.[9] The alkenyl boronates formed in this way are useful
synthetic intermediates in various organic transformations.[10]
The treatment of 1-phenyl-1-propyne (1a) with ethyl vinyl
ketone (2a) and bis(pinacolato)diboron (3) in the presence of
[Ni(cod)2] (cod = 1,5-cyclooctadiene; 5 mol%) and PnBu3
(10 mol%) in a 3:1 mixture of toluene and methanol at
408C for 10 h gave the highly substituted alkenyl boronate 4a
in 85% yield (Table 1, entry 1). Control experiments revealed
that in the absence of either [Ni(cod)2] or PnBu3, no 4a was
obtained. The catalytic reaction is highly regioselective, with a
boron group of 3 adding very selectively to the phenyl-
Entry
Alkyne 1
Product 4
Yield [%][b]
1
2
1a: R2 =Me
1b: R2 =Et
4a
4b
85 (92)
80
3[c]
1c: R2 =(CH2)2OH
1d: R2 =CH2OMe
1e: R2 =CO2Me
4c/4c’ (82:18)
4d/4d’ (80:20)
4e/4e’ (98:2)
81
79
72
4[c]
5[c,d]
6[d]
7
1 f : R1 =R2 =Ph
1g: R1 =R2 =nPr
4 f
4g
72
55
À
substituted alkyne carbon atom and with C C bond forma-
tion occurring between the methyl-substituted alkyne carbon
8[e]
9[e]
1h: R1 =Ph
4h
4i
4j
78
79
75
1i : R1 =4-OMeC6H4
1j: R1 =pyridyl
10[e]
atom of 1a and the b carbon atom of vinyl ketone 2a. The
[a] Unless otherwise mentioned, reactions were carried out with the
alkyne 1 (1.5 mmol), 2a (1.0 mmol), 3 (1.5 mmol), [Ni(cod)2] (5 mol%),
and PnBu3 (10 mol%) in a 3:1 mixture of toluene and methanol (2 mL) at
408C for 10 h. [b] Yield of the isolated product; the yield in parenthesis
was determined by 1H NMR spectroscopic analysis with mesitylene as an
internal standard. [c] Two regioisomers of the product were formed: 4
(major) and 4’ (minor). [d] The reaction was carried out at 508C for 10 h
(entry 5) or at room temperature for 12 h (entry 6). [e] The reaction was
carried out in an 8:1 mixture of toluene and methanol (4.5 mL) at room
temperature for 2 h.
[*] S. Mannathan, Dr. M. Jeganmohan, Prof. Dr. C.-H. Cheng
Department of Chemistry, National Tsing Hua University
Hsinchu 30013 (Taiwan)
Fax: (+886)3572-4698
E-mail: chcheng@mx.nthu.edu.tw
Homepage: http://mx.nthu.edu.tw/%7Echcheng
[**] We thank the National Science Council of the Republic of China
(NSC 96-2113M-007-020-MY3) for support of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805293.
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Chemie
catalytic reaction is also highly stereoselective; the phenyl and
methyl groups in the product are cis to each other.
The present three-component coupling reaction was
extended successfully to various substituted enones
To optimize the present coupling reaction, we examined
the reaction of 1a with 2a and 3 in the presence of various
phosphine ligands and [Ni(cod)2] (5 mol%). The monoden-
tate phosphine ligands PPh3, P(2-furyl)3, PCy3 (Cy = cyclo-
hexyl), and PnBu3 (10 mol%), and the bidentate phosphine
ligands 1,2-bis(diphenylphosphanyl)ethane (dppe) and 1,3-
bis(diphenylphosphanyl)propane (dppp; 5 mol%) were
examined. With PnBu3, the most effective ligand, the reaction
afforded 4a in 92% yield. Other ligands were less effective
and gave 4a in 5–57% yield. A binary solvent system
comprising toluene and methanol (3:1) was also crucial for
the success of the reaction. In methanol alone, the product of
borylative coupling 4a was formed in only 50% yield, along
(Table 2). Methyl vinyl ketone (2b), n-propyl vinyl ketone
Table 2: Three-component coupling of alkyne 1a with various substi-
tuted enones and bis(pinacolato)diboron (3).[a]
Entry
Enone 2
Product 4
Yield [%][b]
1
2
3
2b: R3 =Me
2c: R3 =nPr
2d: R3 =Ph
4k
4l
4m
80
81
83
=
with the product of reductive coupling, (E)-PhCH CH(Me)-
(CH2)2COEt (5a), in 45% yield.[11] The formation of the
reductive-coupling product 5a was totally suppressed in the
3:1 toluene/methanol system. When the catalytic reaction was
performed in toluene only, neither 4a nor 5a was observed.
On the basis of these studies, we chose [Ni(cod)2] (5 mol%)
and PnBu3 (10 mol%) in a 3:1 mixture of toluene and
methanol as the standard conditions for the reactions in
Tables 1 and 2.
To explore the scope of the three-component reaction,
various alkynes were examined under the optimized reaction
conditions (Table 1). Thus, the treatment of 1-phenyl-1-
butyne (1b) with 2a and 3 also afforded a single isomeric
product 4b in 80% yield (Table 1, entry 2). Both 2-hydroxy-
ethyl-substituted phenylacetylene (1c) and the related sub-
strate 1d with a CH2OMe substituent gave regioisomeric
products: 4c/4c’ (82:18) and 4d/4d’ (80:20), respectively
(Table 1, entries 3 and 4). In terms of regio- and stereoselec-
tivity, the reactions to give the major isomers 4c and 4d were
equivalent to the formation of 4a. The transformation of
methyl phenylpropiolate (1e) also gave two regioisomers, 4e
4
5
2e
4n
78
69
2 f
4o
6
7
2g: n=1
2h: n=2
4p
4q
59
55
[a] Unless otherwise mentioned, reactions were carried out with 1a
(1.5 mmol), the enone 2 (1.0 mmol), 3 (1.5 mmol), [Ni(cod)2] (5 mol%),
and PnBu3 (10 mol%) in a 3:1 mixture of toluene and methanol (2 mL) at
408C for 10 h. [b] Yield of the isolated product.
À
and 4e’, in a 98:2 ratio and 72% combined yield with C C
bond formation occurring at the CO2Me-substituted alkyne
carbon atom of 1e (Table 1, entry 5). By contrast, in the
reported cobalt-catalyzed reductive coupling of 1e with
À
alkenes, C C bond formation occurs at the phenyl-substituted
alkyne carbon atom.[11] Under similar reaction conditions, the
symmetrical alkynes diphenyl acetylene (1 f) and 3-octyne
(1g) afforded 4 f and 4g in 72 and 55% yield, respectively, in a
completely stereoselective manner (Table 1, entries 6 and 7).
Terminal alkynes were also compatible with the present
reaction. Thus, phenyl acetylene (1h), 4-methoxyphenylace-
tylene (1i), and 3-ethynylpyridine (1j) were transformed into
the single regioisomeric products 4h, 4i, and 4j in 78, 79, and
75% yield, respectively (Table 1, entries 8–10). The use of an
8:1 solvent mixture of toluene and methanol is necessary for
high product yields. The catalytic reaction is highly regio- and
stereoselective, with a boron group of 3 adding at the
(2c), and phenyl vinyl ketone (2d) reacted efficiently with 1a
and 3 under the optimized reaction conditions to give the
corresponding coupling products 4k, 4l, and 4m in 80–83%
yield (Table 2, entries 1–3). Similarly, the a- and b-methyl-
substituted enones 2e and 2 f were converted into 4n and 4o
in 78 and 69% yield, respectively (Table 2, entries 4 and 5).
Cyclic enones were also good substrates for this reaction.
Thus, 2-cyclopentenone (2g) and 2-cyclohexenone (2h)
underwent coupling with 1a and 3 to give 4p and 4q in 59
and 55% yield, respectively (Table 2, entries 6 and 7). In
these two reactions, simple reductive-coupling products from
the corresponding enones 2 and 1a were also observed in 15
and 19% yield.[11]
À
substituted carbon atom, with C C bond formation occurring
at the unsubstituted carbon atom of the terminal alkyne
moiety, and with the boryl and -(CH2)2COEt groups cis to
each other in the product. In these reactions, homotrimeriza-
tion products of the terminal alkynes were also observed in
minor amounts.[12]
A possible catalytic reaction mechanism for this three-
component coupling reaction is shown in Scheme 1. Highly
chemoselective coordination of the alkyne 1 and enone 2 to
the Ni0 center, followed by a regioselective oxidative cyclo-
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Communications
ketone: The treatment of 4a with alkaline H2O2 in a 2:1
mixture of THF and ethanol at room temperature afforded
diketone 11 in 77% yield.[14b]
In conclusion, we have demonstrated a nickel-catalyzed
borylative coupling of alkynes with enones and a diboron
reagent to provide synthetically useful, highly substituted
alkenyl boronates in good to excellent yields. Dimetal
compounds have not been used previously as terminating
agents in sequential coupling reactions of p components in
the presence of a nickel catalyst. The utility of alkenyl
boronates in coupling reactions and functional-group trans-
formations was demonstrated. The extension of the method-
ology to the coupling of two different p components with
other dimetal reagents is in progress, as well as a detailed
mechanistic investigation.
Scheme 1. Proposed mechanism for the three-component coupling
reaction.
Experimental Section
metalation, yields a nickelacyclopentene intermediate 6.[11]
Selective protonation of 6 by MeOH then affords an alkenyl-
(methoxy)nickel intermediate 7,[11] which undergoes trans-
metalation with bis(pinacolato)diboron (3) to give the
alkenyl–nickel–boryl intermediate 8 and borate 9. Reductive
elimination of 8 affords the product 4 and regenerates the Ni0
catalyst for further catalytic cycles.
The proposed mechanism in Scheme 1 is supported by the
stoichiometric reaction of 1-phenyl-1-propyne (1a,
1.5 mmol), ethyl vinyl ketone (2a, 1.5 mmol), and [Ni(cod)2]
(1.0 mmol) in the presence of PnBu3 (2.0 mmol) in a 3:1
mixture of toluene and methanol (2 mL) at 408C for 10 h. We
obtained the double-protonation (reductive-coupling) prod-
General procedure: A round-bottomed side-arm flask containing
[Ni(cod)2] (0.050 mmol, 5 mol%) and bis(pinacolato)diboron (3,
1.5 mmol) was evacuated and purged with nitrogen gas three times.
Freshly distilled toluene (1.5 mL) and n-tributylphosphane
(0.100 mmol, 10 mol%) were added, and the mixture was stirred
until the solution became yellow.[11e] Enone 2 (1.0 mmol), the internal
alkyne 1 (1.5 mmol), and methanol (0.5 mL) were then added to the
reaction mixture, and the system was stirred at room temperature for
5 min and then at 408C for 10 h. The mixture was filtered through a
short pad of celite and washed with ethyl acetate/hexane (70:30 v/v).
The filtrate was concentrated, and the residue was purified by column
chromatography on silica gel with hexanes–ethyl acetate as the eluent
to afford the alkenyl boronate 4. For product 4e, the reaction was
carried out at 508C for 10 h, and for 4 f, the reaction was carried out at
room temperature for 12 h. For terminal alkynes 1h–j, the reactions
were carried out in an 8:1 mixture of toluene and methanol (4.5 mL)
at room temperature for 2 h.
=
uct (E)-PhCH CH(Me)(CH2)2COEt (5a) in 91% yield.
Although we were unable to isolate intermediate 7, the
formation of 5a strongly indicates that the reaction proceeds
via intermediates 6 and 7.
An alternative mechanism involving oxidative addition of
the diboron compound 3 to Ni0,[13a–b] coordinative insertion of
alkyne 1 into a nickel–boryl bond,[9] further insertion of the
alkene 2,[13c] and finally protonation by MeOH to give the
product 4 and borate 9 cannot be ruled out.
Two applications of alkenyl boronates 4 in coupling and
functional-group transformations are shown in Scheme 2. The
coupling of iodoarenes with alkenyl boronates 4 (4a, 4e,and
4h) in the presence of [Pd(dba)2] (dba = dibenzylideneace-
tone) and aqueous KOH in THF at 808C for 6 h gave the
corresponding products 10a–d in 87–91% yield.[14a] Further-
more, the boryl group in 4a can be oxidized readily to the
Received: October 29, 2008
Published online: February 11, 2009
Keywords: alkynes · boron · enones · multicomponent reactions ·
.
nickel
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