Highly selective methods for synthesis of internal (α-) vinylboronates through efficient NHC-Cu-catalyzed hydroboration of terminal alkynes. Utility in chemical synthesis and mechanistic basis for selectivity

Article abstract of DOI:10.1021/ja2007643

Cu-catalyzed methods for site-selective hydroboration of terminal alkynes, where the internal or α-vinylboronate is generated predominantly (up to >98%) are presented. Reactions are catalyzed by 1-5 mol % of N-heterocyclic carbene (NHC) complexes of copper, easily prepared from N-aryl-substituted commercially available imidazolinium salts, and proceed in the presence of commercially available bis(pinacolato)diboron [B₂(pin)₂] and 1.1 equiv of MeOH at -50 to -15 °C in 3-24 h. Propargyl alcohol and amine and the derived benzyl, tert-butyl, or silyl ethers as well as various amides are particularly effective substrates; also suitable are a wide range of aryl-substituted terminal alkynes, where higher α-selectivity is achieved with substrates that bear an electron-withdrawing substituent. α-Selective Cu-catalyzed hydroborations are amenable to gram-scale procedures (1 mol % catalyst loading). Mechanistic studies are presented, indicating that α selectivity arises from the structural and electronic attributes of the NHC ligands and the alkyne substrates. Consistent with suggested hypotheses, catalytic reactions with a Cu complex, derived from an N-adamantyl-substituted imidazolinium salt, afford high β selectivity with the same class of substrates and under similar conditions.

Full text of DOI:10.1021/ja2007643

ARTICLE
pubs.acs.org/JACS
Highly Selective Methods for Synthesis of Internal (r-) Vinylboronates
through Efficient NHCꢀCu-Catalyzed Hydroboration of Terminal
Alkynes. Utility in Chemical Synthesis and Mechanistic
Basis for Selectivity
Hwanjong Jang, Adil R. Zhugralin, Yunmi Lee, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S Supporting Information
b
ABSTRACT: Cu-catalyzed methods for site-selective hydro-
boration of terminal alkynes, where the internal or R-vinylboro-
nate is generated predominantly (up to >98%) are presented.
Reactions are catalyzed by 1ꢀ5 mol % of N-heterocyclic
carbene (NHC) complexes of copper, easily prepared from
N-aryl-substituted commercially available imidazolinium salts,
and proceed in the presence of commercially available bis-
(pinacolato)diboron [B2(pin)2] and 1.1 equiv of MeOH at ꢀ50 to ꢀ15 °C in 3ꢀ24 h. Propargyl alcohol and amine and the derived
benzyl, tert-butyl, or silyl ethers as well as various amides are particularly effective substrates; also suitable are a wide range of aryl-
substituted terminal alkynes, where higher R-selectivity is achieved with substrates that bear an electron-withdrawing substituent. R-
Selective Cu-catalyzed hydroborations are amenable to gram-scale procedures (1 mol % catalyst loading). Mechanistic studies are
presented, indicating that R selectivity arises from the structural and electronic attributes of the NHC ligands and the alkyne
substrates. Consistent with suggested hypotheses, catalytic reactions with a Cu complex, derived from an N-adamantyl-substituted
imidazolinium salt, afford high β selectivity with the same class of substrates and under similar conditions.
’ INTRODUCTION
adventitious elimination reactions. Selective hydroboration of a
terminal alkyne, especially one that is catalytic, would constitute
one of the most direct routes for synthesis of an R-vinylboronate;
such procedures, however, particularly the catalytic variants, have
not been previously disclosed.5,6
Vinylboron reagents, and vinyl(pinacolato)borons in particu-
lar, are employed in a range of CꢀC bond-forming reactions,
including the widely utilized catalytic cross-coupling processes,1,2
and are thus considered highly valuable entities in chemical
synthesis. Whereas terminal or β-vinyl(pinacolato)borons can be
prepared by a number of procedures, access to internal or R-
vinylboronates is significantly more limited and the existing
approaches involve stepwise and relatively demanding proce-
dures. R-Vinylboronates may be synthesized by a three-step, two-
vessel process that includes initial preparation of an R-vinyl
halide, which is converted to the derived R-vinyllithiums and
subsequently treated with isopropoxy(pinacolato)boron.3 Alter-
natively, Pd-catalyzed cross-coupling in the presence of bis-
(pinacolato)diboron might be used to generate an internal
vinylꢀboron bond;1e formation of the requisite R-vinyl halides,
however, requires strongly acidic conditions. R-Bromo alkenes,
precursors to the aforementioned vinylmetals, can be obtained
by reaction of an alkyne with BBr3 and subsequent protonation of
the terminal CꢀB bond with 15ꢀ20 equiv of HOAc, or through
hydroiodination (HI generated in situ by reaction of TMSI with
water).4 As a result, R-vinylboron reagents that bear an acid-
sensitive moiety cannot be utilized in the latter approach.
Conversion of R-vinylhalides that carry an allylic CꢀN or
CꢀO bond adjacent to the derived R-vinylmetals (such as
vinylaluminums)7 is usually not feasible because of facile and
Herein, we present a catalytic method for converting terminal
alkynes to a variety of R-vinylboronates with high site selectivity
(upto>98:2) andinupto95%yieldofthepureisomer(Scheme1).
Reactions are performed with bis(pinacolato)diboron [(B2(pin)2;
1] and are efficiently catalyzed by N-heterocyclic carbene (NHC)
complexes of Cu(I) obtained from N-aryl-substituted imida-
zolinium salts, which, similar to 1, are commercially available.
Terminal propargyl and R-amino alkynes, and their protected
derivatives, as well as an assortment of aryl alkynes serve as
effective starting materials; the earlier class of substrates cannot
be utilized in the recently outlined Ni-catalyzed hydroalumina-
tion/boronate trap procedure.7 We demonstrate that by altering
the electronic attributes of the NHCꢀCu complex, site selectivity
can be controlled to the degree that either R- or β-vinylboronates
are obtained in useful yields (Scheme 1); with catalysts
derived from N-adamantyl-substituted imidazolinium salts,
vinylboronates are obtained in up to >98% β-selectivity
(vs strong preference for the R isomer with N-aryl-substituted
Received: January 25, 2011
Published: April 28, 2011
r
2011 American Chemical Society
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Scheme 1. Control of Site Selectivity in Cu-Catalyzed
Hydroborations of Terminal Alkynesa
Table 1. Screening of Various NHCꢀCu Complexesa
a B2(pin)2 = bis(pinacolato)diboron.
Scheme 2. Preliminary Observations
a Reactions performed under N2 atmosphere. b Conversion (based on
1 as the limiting reagent) and site selectivity ((2%) were determined by
1
analysis of 400 MHz H NMR spectra of product mixtures prior to
purification. Mes =2,4,6-Me3-C6H2; Ad = adamantyl; Ar = 2,6-(i-Pr)2-
C6H3.
NHCꢀCu (compare entries 3 and 4), bis(adamantyl)-based com-
plex 9 delivers 84% of the β product isomer 4a. In contrast, Cu
complex 10 (entry 5), which bears a more sterically demanding
2,6-(i-Pr)2-phenyl (vs 2,4,6-(Me)3-phenyl or Mes), promotes
transformation with 82:18 R:β selectivity.
NHCꢀCu complexes). We present a rationale for the unex-
pected R-selectivities and the dependence of selectivity on steric
and electronic attributes of substrates and the NHCꢀCu
complexes.
c. R-Selective Hydroborations of Propargyl Alcohols, Amines
and Derivatives with NHCꢀCu Complex 6. When reactions
were subsequently performed at lower temperature in order to
improve selectivity, hydroborations with complex 6 remained
reasonably efficient whereas those performed in the presence of
the more discriminating 10 become too sluggish. For example,
>98% conversion to 3a is observed when 6 is used [thf, ꢀ50 °C, 5.0
mol % CuꢀNHC complex, 5.0 mol % NaOt-Bu], affording 3a in
84% yield (entry 1, Table 2); in contrast, there is <10% 3a
generated with 10 under the same conditions. As shown in
Table 2, in addition to 3a, R-vinylboronates bearing a benzyloxy
(3b, entry 2), a tert-butyldimethylsiloxy (3c, entry 3) or the
parent hydroxyl group (3d, entry 4) can be isolated in
84:16ꢀ93:7 R:β selectivity and 76ꢀ82% yield in >98% purity
after routine silica gel chromatography.
Cu-catalyzed additions to propargyl amine (entry 5, Table 2)
proceeds with similar R selectivity compared to the correspond-
ing alcohol and ethers (entries 1ꢀ4, Table 2); attempts to purify
11a, however, did not result in isolation of the desired product in
appreciable yield.9 When the derived amides are used (entries
6ꢀ8, Table 2), R-vinylboronates form with substantially higher
preference (g95% R) and in 73ꢀ93% yield after purification.
Two additional points are worthy of note: (1) The reaction with
the parent alcohol (entry 4) does not require the use of MeOH,
suggesting that the hydroxyl group remains available through the
’ RESULTS AND DISCUSSION
1. NHCꢀCu-Catalyzed r-Selective Hydroboration of
Terminal Alkynes Derived from Propargyl Alcohol and
Amine. a. Initial Observations. A key finding, which served as
the foundation for the present investigations, emerged in the
course of our studies regarding NHCꢀCu-catalyzed double
hydroboration of terminal alkynes, furnishing enantiomerically
enriched diboronates.8 Whereas CuꢀB addition to propargyl
ether 2, catalyzed by the NHCꢀCu complex derived from 5
and protonation of the resulting CuꢀC (with MeOH), gen-
erates 4a preferentially (3a:4a = 11:89), in the presence of
monodentate NHCꢀCu complex 6, reaction proceeds with
the opposite sense of selectivity, furnishing 3a as the major
isomer (3a:4a = 83:17, Scheme 2).
b. Examination of Various NHCꢀCu Complexes. To explore
further the aforementioned preference for generation of the
R-vinylboronate, we examined the ability of a select number of
monodentate NHCꢀCu complexes to promote formation of 3a.
As the data summarized in Table 1 illustrate, reactions catalyzed by
7ꢀ9(entries2ꢀ4) give rise to larger amounts of the β-vinylboronate
(vs entry 1). Although less efficient than the cyclohexyl-containing
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Table 2. r-Selective NHCꢀCu-Catalyzed Hydroborations of
Terminal Alkynes Bearing an Allylic O- or N-Based
Substituenta
Table 3. r-Selective NHCꢀCu-Catalyzed Hydroborations of
Aryl-Substituted Terminal Alkynesa
entry
aryl
conv (%)b
R:βb
yield of pure R (%)c
1
Ph
94
98
79
81
54
76
78
>98
64
86
53
85
79
89
69
61
89
88:12
94:6
78
87
72
73
35
51
ndd
78
52
67
45
73
70
71
61
ndd
ndd
2
o-FC6H4
3
o-ClC6H4
91:9
4
o-BrC6H4
91:9
5
o-CF3C6H4
o-MeC6H4
o-MeOC6H4
m-FC6H4
83:17
70:30
41:59
94:6
6
7
8
9
m-CF3C6H4
m-MeOC6H4
p-FC6H4
89:11
79:21
87:13
91:9
10
11
12
13
14
15
16
17
p-BrC6H4
p-CF3C6H4
p-NO2C6H4
p-MeO2CC6H4
2-pyridyl
96:4
91:9
92:8
90:10
78:22
3-thienyl
aꢀc See Table 2. d nd = not determined because of complication in isolation.
high purity (<2% contamination with the β isomer) from the
terminal alkynes in 35ꢀ87% yield. Several features of this class of
transformations are noteworthy:
a Reactions performed under N2 atmosphere. b Conversion and site
selectivity ((2%) were determined by analysis of 400 MHz 1H NMR
c
(1) High selectivity in reactions with aryl-substituted alkynes
requires the less active but more discriminating 2,6-(i-
Pr)2phenyl-substituted NHCꢀCu complex 10 (vs mesi-
tyl-substituted 6; see Table 1). As illustrated in Table 3,
reactions proceed to useful levels of conversion when
performed at ꢀ15 °C, affording R-vinylboronates in high
selectivity.
spectra of product mixtures prior to purification. Yields of isolated R
isomer products ((5%). d MeOH was not used in this transformation;
reaction quenched by addition of 4.0 N HCl in dioxane/MeOH. e Yield
of isolated material not determined because of product instability to
purification procedures.
course of the reaction to serve as the proton source (vs rapid
conversion to the derived boronic ester by reaction with 1 prior to
CuꢀB addition). In contrast, hydroboration with propargyl amine
requires the presence of MeOH, indicating that an amine is either
not sufficiently acidic to protonate the vinylcopper intermediate
or the resulting NHCꢀCu-amide does not readily react with 1 to
cause catalyst turnover.10 (2) The products formed in reactions
shown in Table 2 cannot be accessed by the previously mentioned
Ni-catalyzed hydroalumination/methoxy(pinacolato)boron trap,
presumably because of facile and adventitious elimination.7 The
alternative approach involving a vinyllithium (vinyl halide metal/
halogen exchange/treatment with a boron-based electrophile)
would suffer from the aforementioned complications with neigh-
boring heteroatom substituents and require initial site-selective
preparation of an R-vinyl halide (see above for associated
drawbacks).11
(2) Although, in many cases, site selectivities shown in Table 3
do not vary to a significant degree, a brief analysis of
variations as a result of the electronic attributes of the aryl
groups is warranted. Electron-withdrawing aryl substitu-
ents, such as those that attract electrons through σ-bond
framework as well as those that do so through resonance,
generally give rise to higher R selectivity. Reactions of
alkynes bearing an o-F and a p-F unit proceed with 94%
and 87% R selectivity, respectively (entries 2 and 11,
Table 3); with the electronegative halogen more proximal
to the alkyne, R:β ratio is improved, underscoring the
significance of the inductive effect. As another example,
the reaction in entry 9, involving m-trifluoromethylphe-
nylacetylene, is less discriminating (89% R) than that
shown in entry 13, where the same substituent resides at
the para position (96% R); in the latter case, stronger
electron withdrawal is likely due to aryl πfσ*CꢀF donation.
However, the influence of inductive effects is not always
straightforward. For instance, as expected, with the less
electronegative bromide (vs fluoride), somewhat lower R-
selectivity is observed in reactions with alkynes that carry the
2. NHCꢀCu-Catalyzed r-Selective Hydroboration of Aryl-
and Heteroaryl-Substituted Terminal Alkynes. Terminal aryl
alkynes (entries 1ꢀ15, Table 3), including those containing a
heterocyclic substituent (entries 16 and 17, Table 3), undergo
Cu-catalyzed hydroboration in up to 96:4 R selectivity. Various
types of R-vinylboronates can thus be obtained directly and in
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halogen at the ortho position (91% vs 94% R, respectively;
entries 2 and 4, Table 3); however, an alkyne with an p-Br
unit is slightly more selective than one that contains an F
atom at the same site (91% vs 87%R, respectively; entries 11
and 12, Table 3).
latter conditions, substrates are consumed entirely but
desired products are not obtained (<5%).
(2) In cases where the substrate bears a functional group that
can be concomitantly reduced by dibal-H, such as those
shown in entries 14 and 15 of Table 3, the NHCꢀCu-
catalyzed hydroboration is the protocol of choice.
The negative impact of π-donor aryl units on R selectivity is
manifested in the transformations shown in entries 7 and 10
of Table 3, involving the less discriminating reactions with
substrates that contain a methoxy-substituted aryl groups
(41:59 and 79:21 R:β for o- and m-MeO-phenylacetylene,
respectively).12 When p-methoxyphenylacetylene serves as
the substrate (not shown, but the same conditions as in
Table 3), only 62% R-selectivity is observed even when
NHCꢀCu complex 10 is used (58% conv). In contrast,
reactions with alkynes that bear a p-NO2 or p-carboxylic
ester are significantly more R-selective (91ꢀ92% R; entries
14 and 15). The importance of electronic effects is further
underlined by comparison of the data in entries 6 and 7: the
smaller o-methoxy substituent leads to a preference for the
β-vinylboronate (41:59 R:β) compared to the alkyne that
carries an o-methylphenyl unit (70:30 R:β). Similar to the
aforementioned inductive effects, changes in selectivities in
CuꢀB additions to aryl alkynes that bear a π-acceptor
group are, at times, difficult to explain. As an example, there
is a relatively small difference in selectivity between reaction
of phenylacetylene (89% R; entry 1, Table 3) and p-
nitrophenylacetylene (91% R; entry 14, Table 3). Consider-
ing that π-acceptor groups are typically expected to exert a
stronger influence, it is curious that highest R-selectivity is
observed in the case of an alkyne with a p-trifluoromethyl
unit. It should be noted that, despite the recondite variations
in selectivity, the data in Table 3 does point to the general
trend that donor groups favor β selectivity and higher
percentage of R-vinylboronates are formed with electron-
withdrawing substituents.
The catalytic hydroalumination protocol is preferred in certain
cases. Higher R-selectivities are achieved through the Ni(dppp)-
catalyzed hydroalumination/CꢀB formation when aryl alkynes
are used7 (95:5 to >98:2 R selectivity vs findings in Table 3). Ni-
catalyzed hydrometalation is particularly effective with alkyl-
substituted alkynes. For example, with homopropargyl alcohol
(see eq 3, below), reaction in the presence of 6 affords 61% of
the β-vinylboronate (ꢀ50 °C, toluene, 20 h, 81% conv); in
contrast, there is 95% R-selectivity in the reaction of the same
substrate with dibal-H, and 3 mol % Ni(dppp)Cl2 [pure R-
vinylboronate is isolated in 82% yield after treatment with
methoxy(pinacolato)boron].7
4. The Utility of Cu-Catalyzed r-Selective Alkyne Hydro-
boration. a. Cu-Catalyzed Alkyne Hydroboration on Gram Scale.
The present protocols are easy to perform; in addition to bis-
(pinacolato)diboron, the imidazolinium and imidazolium salts are
air stable and commercially available, and the NHCꢀCu complexes
can be easily prepared.13 The Cu-catalyzed processes are amenable to
gram scale procedures; the example shown in eq 1 is illustrative. Only
1.0 mol % of the readily accessible NHCꢀCu complex and 1.1 equiv
of B2(pin)2 suffice, affording vinylboronate 11b in 91% yield after
purification with exclusive R selectivity (>98% R).
(3) Steric effects play a notable role as well. For example,
o-trifluoromethylphenylacetylene (entry 5) undergoes
catalytic hydroboration to afford the R isomer with 83%
selectivity, whereas the transformation with the substrate
bearing a p-trifluoromethyl unit proceeds with 96:4 R:β
selectivity (entry 13). Presumably, the stronger inductive
effect of the more proximal o-CF3 group is counter-
balanced by the steric repulsion generated due to formation
of a CꢀB bond involving a relatively sizable (pinacolato)-
boron substituent at the benzylic site (repulsion between
B(pin) and o-CF3Ph). Mechanistic discussions and the signi-
ficance of electronic and steric factors are provided below.
b. An Efficient Route for Conversion of Terminal Alkynes to
Methyl Ketones. As stated above, the most significant utility of R-
vinylboronates accessed through the NHCꢀCu-catalyzed meth-
od relates to various metal-catalyzed cross-coupling reactions.1
Additionally, the present protocol offers a convenient route
for the conversion of terminal alkynes to the corresponding methyl
ketones, in a net transformation that is analogous to the Pd-catalyzed
Wacker oxidations performed with alkenes.14 The example presented
in Scheme 3 is illustrative. Catalytic hydroboration of the terminal
alkyne that resides within enyne 13 proceeds to afford 14 in 95% yield
after purification with >98% R selectivity and with exceptional
chemoselectivity (<2% reaction of the alkene). Subsequent oxidation
delivers methyl ketone 15 in 82% yield. The Cu-catalyzed hydro-
boration and the follow-up oxidation may be performed in a single
vessel, without isolation or purification of the R-vinylboronate 14,
affording 15 in 69% yield after purification.
c. Synthesis of Cyclic Vinylboronates through Sequential Cu-
Catalyzed Hydroboration/Ru-Catalyzed Ring-Closing Metathesis.
The availability of R-selective catalytic hydroboration of alkynes can
be utilized toward preparation of cyclic vinylboronates that would
otherwise be less easily accessible.15 The example shown in
Scheme 4 is illustrative. R-Vinylboronate 17, obtained in 88% yield
and >98% site selectivity through Cu-catalyzed hydroboration of
enyne 16, is converted to cyclic vinylboronate 19 in 71% yield by
ring-closing metathesis promoted by 5 mol % Ru carbene 18.16
3. Complementarity of the Cu-Catalyzed Hydroboration
with Ni-Catalyzed Hydroalumination/Boronate Trap Proto-
cols to Access r-Vinylboronates. A comparison of the meth-
ods outlined above with the recently reported Ni-catalyzed
alkyne hydroalumination/CꢀB bond formation [addition of
methoxy(pinacolato)boron] developed in these laboratories7 is
warranted. Overall, the Ni(dppp)- and NHCꢀCu-catalyzed proto-
cols are complementary in connection with R-vinylboronate
synthesis. The advantages of the present approach are two-fold:
(1) In contrast to the Cu-catalyzed hydroboration, with propar-
gyl alcohol, propargyl amine and the related derivatives
serving as the substrate (see Table 2), the Ni-catalyzed
reactions are ineffective, presumably because of adventitious
elimination of the intermediate vinylaluminum. Under the
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Scheme 3. Site- and Chemoselective NHCꢀCu-Catalyzed
Hydroboration of an Enyne. Conversion of a Terminal Alkyne
to a Methyl Ketone
Table 4. β-Selective NHCꢀCu-Catalyzed Hydroborations of
Terminal Alkynes Promoted by NHCꢀCu Complex 9a
Scheme 4. Synthesis of Cyclic Vinylboronates
aꢀb See Table 2. c Yields of isolated β isomer products ((5%). d MeOH
was not used in this transformation; reaction quenched by addition of
4.0 N HCl in dioxane/MeOH.
we judged that establishing the generality of such Cu-catalyzed
processes would be valuable for two reasons: (1) The trends in
reactivity and selectivity might be useful for establishing the
origins of R-selective variants promoted by NHC complexes 6
and 10 (detailed below). (2) The catalytic transformations
described in this study represent more than a hydroboration
process; protonation of the intermediate vinylcopper is only
one of several possible modes of functionalization. Catalytic
reactions that place a (pinacolato)boron at the terminal (β)
carbon and a CuꢀNHC at the internal site of a terminal alkyne
may be trapped by other classes of electrophiles, allowing access
to a range of valuable organic molecules. Investigations along
these lines are in progress.
It should be noted that synthesis of 19 through alternative proce-
dures, such as Pd-catalyzed cross-coupling with B2(pin)2 (1),17
would require a vinyl halide or an enol triflate substrate, selective
synthesis of which might prove to be less than straightforward.
5. β-Selective NHCꢀCu-Catalyzed Hydroborations of
Terminal Alkynes. Several strategies have been developed for
synthesis of terminal vinyl(pinacolato)borons. β-Selective hydro-
borations of terminal alkynes by reaction with catecholborane,18
di(isocamphenyl)borane,19 pinacolatoborane,20 or di(isopropylpre-
nyl)borane21 have been reported. There are methods for synthesis of
β-vinylboronates through Rh-catalyzed dehydrogenative boryla-
tion.22 Boron hydride additions to terminal alkynes promoted by
Rh, Ir,23 Ti,24 or Zr25 complexes have been disclosed as well.
Reactions of vinylmetal reagents with B-based electrophiles is
another strategy for accessing terminal vinylboronates.26 The afore-
mentioned Pd-catalyzed cross-coupling with enol triflates or
halides17 and Ru-catalyzed cross-metathesis27 are catalytic protocols
that can furnish β-vinylboronates from alkene-containing substrates.
Initial screening of representative NHCꢀCu complexes (cf.
Table 1) indicated that when N-adamantyl-substituted 9 is used,
high β selectivity is observed in the reaction with tert-butylpro-
pargyl ether 2 (84% β at 22 °C). Although a number of β-selec-
tive alkyne hydroborations have been previously reported,18ꢀ27
A variety of terminal alkynes undergo β-selective reactions at
ambient temperature within 12 h to afford the desired vinylboro-
nates after purification in up to 88% yield and >98% selectivity
(Table 4). Appreciable site selectivities (81ꢀ89% β) are observed
in transformations with alkyl-substituted acetylenes (entries 1ꢀ3,
Table 4) and substrates derived from propargyl alcohol and amine
(73ꢀ88% β, entries 4ꢀ7), allowing the corresponding β-vinylboro-
nates to be isolated in 56ꢀ80% yield. β selectivities are higher when
arylacetylenes are employed as substrates (93% to >98% β, entries
8ꢀ14).
6. Chemoselectivity of NHCꢀCu-Catalyzed Hydrobora-
tion of Terminal Alkynes. As was described previously,28 olefins
that do not bear an aryl or a (pinacolato)boron substituent do
not undergo NHCꢀCu-catalyzed hydroboration; in contrast,
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Scheme 5. Chemoselectivity in NHCꢀCu-Catalyzed Hydroboration Reactions
and as illustrated above, alkynes bearing an alkyl unit can serve as
effective substrates. Such difference in reactivity is manifested in
the complete chemoselectivity observed in the reaction of enyne
13, illustrated in Scheme 3. A more competitive scenario involves
transformations of alkynyl substrates in the presence of alkenes
that do participate in NHCꢀCu-catalyzed hydroborations.28ꢀ30
As summarized in Scheme 5, regardless of whether Cu complex 6
or 9 is used, transformation with a terminal alkyne appears to be
significantly more efficient than styrene, R- or β-methylstyrene,28a
R-vinylboronate,28b an allylic carbonate,29 or an R,β-unsaturated
carboxylic ester.30 These findings bode well for applications where
site-selective functionalization of a polyfunctional substrate is
required.
7. Mechanistic Basis for Site Selectivity in NHCꢀCu-Cata-
lyzed Hydroboration of Terminal Alkynes. The original ob-
servation regarding the preference for formation of R-
vinylboronates with monodentate NHCꢀCu catalysts was
somewhat unexpected, since Cu-catalyzed processes involving
other substrate classes, including those promoted by NHC-based
complexes, exhibit preference for the formation of β isomers.
Indeed, NHCꢀCu-mediated reactions of mono-31 and NHCꢀ
Cu-catalyzed processes with disubstituted styrenes32 afford β-
boryl products exclusively.33 To elucidate the origins of the
unusual R-selectivities, we first set out to identify factors that
govern site selectivity in NHCꢀCu-catalyzed CꢀB bond for-
mation. These initial investigations are summarized below,
followed by a scheme proposed to account for the origin of
selectivity in R- as well as β-selective catalytic hydroborations.
The studies detailed below will illustrate that site selectivity in
CuꢀB additions to alkynes depends not only on the steric and
electronic attributes of the NHC ligands, but also on the steric
and electronic characteristics of the alkyne substrates; it is as a
result of subtle balance involving all the aforementioned factors that
site selectivity is determined. Two additional points regarding our
mechanistic investigations should be noted: (1) Our studies
suggest that, unlike reactions with alkenes, in transformations
promoted by aryl-substituted NHCs and involving substrates
derived from propargyl alcohol and amine as well as aryl alkynes,
Cu complex association with the substrate molecule may be
product-determining. (2) Although similar to processes with
olefins, it appears that, overall, the alkyne serves as the electro-
philic component, factors involving donation of electrons from
the acetylene π-cloud to the available low energy orbitals of the
transition metal must also be considered.
a. The Identity of the Product-Determining Event. As the first
step toward developing a plausible mechanistic model, we set out
to ascertain that the identity of the hydroboration reactions is not
due to thermodynamic difference between the two CuꢀB addition
products; rather it is either the coordination or the insertion step
that determines the identity of the predominant isomer. As
shown in Scheme 6, crossover experiments point to the CuꢀB
addition to an alkyne as being irreversible.34 It is therefore likely
that the identity of the major vinylboronate isomer is not due to
rapid protonation of the CꢀCu bond of one of the two
intermediate isomers (e.g., 21 in Scheme 6) by the proton source
(MeOH in the catalytic processes).35 Consistent with the latter
findings, computational investigation of the mechanism indicate
that formation of insertion products 21 and 22 is strongly exoergic
(ΔG° between ꢀ36.4 and ꢀ43.8 kcal/mol); the reverse reaction is
thus not likely to occur.13 Furthermore, and importantly, com-
putational studies of substrate coordination to copper, involving
an aryl-substituted alkyne, and the subsequent insertion step
indicates that catalystꢀsubstrate association is product-determining.13
b. Correlation of Electron-Donating Ability of the NHC
Ligands to Site Selectivity. At this juncture, we sought to
elucidate factors that cause reactions performed in the presence
of alkyl-substituted NHCꢀCu complexes (8 and 9) to afford
β-vinylboronates predominantly but favor generation of the R
isomers with aryl-substituted NHC (6 or 10; Table 1). We thus
examined the correlation between R:β ratios and the electronic
characteristics of the NHC ligands; the results of these studies are
depicted in Figure 1. Since the electron-donating ability of an
NHC is inversely proportional to Tolman electronic parameter
(TEP), the data are presented with inverted TEP values.36 The
analysis illustrated in Figure 1 points to an inverse correlation
between R:β product ratios and the ability of the carbene ligands
to serve as two-electron donors. That is, the more Lewis basic
NHCꢀCu complex (i.e., alkyl-substituted NHCs) promote
preferential formation of the β-vinylboronates, whereas R prod-
ucts are preferred with catalysts that carry the less donating
variants (i.e., Ar-substituted NHC ligands).
c. Correlation of Electronic Attributes of Alkyne Substituents
to R Selectivity in Reactions with NHCꢀCu Complexes 6 or 10.
Analysis of the data presented in Tables 2ꢀ4 underscores the
sensitivity of the product distribution to electronic characteristics
of the substrates and the NHC ligands used in generating the Cu-
based catalysts. We therefore investigated the effect of the
electronic attributes of the aryl alkyne substrates on the level
and direction of site selectivity. We limited our analysis to the
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Scheme 6. Crossover Experiment To Investigate the Reversibility of the CuꢀB Addition Step in the Related NHCꢀCu-Catalyzed
Processesa
a Product ratios were determined by analysis of the 400 MHz 1H NMR spectra of the unpurified product mixtures.
Figure 2. Correlation of R:β vinylboronate ratios to substituent con-
stants (σ). Values in parentheses correpond to 95% confidence interval.
Figure 1. Correlation of R:β vinylboronate ratios to inverse Tolman
electronic parameters (TEP) for various NHC ligands. Values in parenth-
eses are the 95% confidence interval; numbers correpond to the NHCs
(cf. Table 1) of the Ni complexes for which measurements were made.
the β isomer, and log(R:β)H corresponds to R:β ratio generated
through NHCꢀCu-catalyzed reaction of phenylacetylene. The
resulting Hammett plot is illustrated in Figure 2.
data for CuꢀB additions promoted by N-aryl-containing com-
plexes 6 or 10, since the high selectivities with aryl-substituted
alkynes obtained through transformations with adamantyl-sub-
stituted Cu complex 9 (g93% β; Table 4, entries 8ꢀ14) do not
permit for extraction of significantly meaningful ratios.
The stereoelectronic effects of aryl-alkyne substituents were
gauged through the use of a Hammett equation.37 Although, detailed
kinetic studies have not been performed, ratios of R and β products
represent the data for a competition experiment. Subtraction of the
Hammett equation derived for β-vinylboronates from that which
corresponds to the formation of R product isomers furnishes an
equation that relates electronic properties of the aryl substituents to
site selectivity. As shown in eq 2:
The positive value obtained for FR ꢀ Fβ (i.e., FR > Fβ; see
Figure 2) arises from preferential formation of R-vinylboronates
in reactions of alkynes containing an electron-withdrawing substi-
tuent [Table 3; see discussion above (Section 2), regarding the
influence of electronic factors on R selectivity].38 Furthermore,
the experimentally determined FR = þ1.55 translates to Fβ = þ0.74
based on the equation shown in Figure 2. The above considerations
suggest that, overall, andregardless of the trend in site selectivity, an
alkyne serves as the electrophilic entity in NHCꢀCu-catalyzed
additions. Nonetheless, such an effect should be viewed as the net
outcome of different substrateꢀcatalyst interactions (electron
reorganization or electrostatic as well as charge transfer or
covalent);39 that is, associations that represent electron flow
from the alkyne to the NHCꢀCu complex, such as donation
from the alkyne π cloud to the low-lying Cu s orbital (see
Scheme 8), should also be considered.40 Accordingly, we turned
to identifying additional electronic parameters, particularly those
that correspond to the overlap of frontier orbitals (i.e., covalent
logðR:βÞ ¼ σðFR ꢀ FβÞ þ logðR:βÞH
ð2Þ
where R:β is a product molar ratio, FR is the reaction constant for a
pathway that results in the formation of the R-vinylboronate, Fβ
corresponds to the constant relating to a transformation that affords
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Scheme 7. Electronic and Steric Effects Influence the Sense and Level of Selectivity in NHCꢀCu-Catalyzed CuꢀB Additions to
Terminal Alkynes
interactions) and which can influence product distribution. We
calculated local softness indices for the alkyne’s two carbon
atoms in the substrates shown in Table 3.41 The softness index of
an atom provides an estimate of the degree to which bond
formation involving the said atom has advanced in a transition
state (e.g., sR = softness index at CR);42 nucleophilic or electro-
philic softness index (e.g., sꢀ or sþ) can serve as qualitative
measurement of the HOMO or LUMO coefficient,39 respec-
an attribute. The aforementioned considerations suggest that the
incipient Cu CR is longer than Cu Cβ, but to varying
3 3 3
3 3 3
ꢀ
degrees: elevated sRꢀ:sβ ratios (i.e., larger electron density at
the CR) indicate that Cu CR is relatively more advanced
3 3 3
(shorter) and bond formation at both carbon atoms is similarly
developed in the corresponding transition states. Comparison of
R:β ratios to sRþ:sβþ values gives an inverse correlation as well,
albeit with a low coefficient of determination (R2 = 0.0657).13
The significance of the above findings, vis-ꢀa-vis the suggested
model for the selectivity trends, is described above (Scheme 7).
d. Proposed Mechanistic Scenarios Accounting for the Ob-
served Site Selectivities. Plausible pathways for the generation of
R-vinylboronates in reactions performed with NHCꢀCu 6 or 10
derived from N-aryl-substituted imidazolinium salts (via
IfICfIV) as well as β-vinylboronates, generated in transforma-
tions with complex 9 (via IVfIVCfIVV), are illustrated in
Scheme 7.43 In the case of less electron-donating N-aryl-sub-
stituted NHCꢀCu complexes and terminal alkynes with an
electron-withdrawing group, the mode of coordination repre-
sented by I is favored (vs II), where steric repulsion between the
alkyne substituent (G) and the large NAr moieties of the NHC
are destabilizing elements. The size of the NAr unit accounts for
the faster rate but lower selectivity observed with 6 compared to
ꢀ
tively, at that particular atom. Thus, sRꢀ:sβ estimates the
contribution of CuꢀCR and CuꢀCβ bond formations to the
overall energy of the transition state for alkyne coordination to
an NHCꢀCu complex, where the substrate serves as the
electron donor.
In all cases, we find that sR:sβ < 1,13 indicating that an
asynchronous coordination transition state is operative wherein
the CuꢀCR bond is less advanced than the CuꢀCβ bond. The
log(R:β) values were plotted versus sRꢀ:sβꢀ, as illustrated in
Figure 3, allowing us to identify a correlation between the
experimental R:β and calculated sRꢀ:sβꢀ ratios. These measure-
ments imply that CRꢀB bond formation is more favored (higher
R selectivity is observed) in reactions which involve alkynes
possessing increased electron density at their CR and that can
proceed via transition states that more easily accommodate such
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above, Cβ is softer (possesses a larger HOMO coefficient), a
more advanced Cu Cβ bond can be expected in the transition
3 3 3
state (I) leading to metallacyclopropene IC. As depicted in
Schemes 7 and 8 (I and A, respectively), the net result is a
relatively symmetric transition state, because with an electron-
withdrawing substituent (G = CH2OR, CH2NR2 or aryl), there is
enhanced electron density at CR, which causes more similar
HOMO coefficients at the two alkynyl carbons (softness index
ratios closer to unity). The proposed scenario may be considered
from a different vantage point: as Cβ is “softer”, dissipation or
accumulation of electron density at CR and Cβ is not equivalent;
electronic alteration, regardless of its origin, is stronger at the
alkyne’s β carbon. The influence of a substrate’s electronic
attributes is therefore more pronounced at the Cβ, engendering
a stronger lack of electron density at the β carbon with an
electron-withdrawing alkyne substituent; this leads to a similar
level of electron density at the two carbon sites and a relatively
symmetric transition state (I).
ꢀ
Figure 3. Correlation of R:β vinylboronate product to sRꢀ:sβ
The presence of electron-donating alkyne substituents trans-
late to diminution in R selectivities (Tables 2 and 3). Increased
electron density at Cβ may result in a higher HOMO coefficient
ratios. Values in parentheses correpond to 95% confidence interval.
at this site and a relatively less advanced Cu CR, as depicted in
IIA (Scheme 7); such electronic variation, originating from the
3 3 3
Scheme 8. Interactions Involving Cu and Alkyne Frontier
Orbitalsa
alkyne substituent, leads to a longer Cu CR and amelioration
3 3 3
of the steric factors in I, responsible for preferential generation of
R-vinylboronates. Reduced R selectivities are thus observed with
methoxy-substituted phenylacetylenes (41:59 and 79:21 R:β
with o- and m-methoxy substitution, respectively; entries 7 and
10, Table 3).
The above considerations offer an explanation for the low
R selectivity in catalytic addition to o-tolyl alkyne (70:30
R:β; entry 6, Table 3); in comparison, it is likely due to the
aforementioned electronic effects that reaction with the alkyne
bearing the electron-withdrawing o-trifluoromethylphenyl group,
despite the larger substituent (CF3 vs Me), leads to a stronger
preference for the derived R isomer (83:17 R:β in entry 5, Table 3
vs 70:30 in entry 6). To challenge the validity and/or establish
further evidence in support of the proposed scenario, we carried
out the additional transformations depicted in eq 3. In contrast to
processes with propargyl alcohol and derivatives (entries 1ꢀ4,
Table 2), reactions of homopropargyl alcohol (30, eq 3) and
bis(homopropargyl) alcohol (31, eq 3) are substantially less
selective (39:61 R:β and 45:55 R:β, respectively, vs 93:7 R:β
obtained for propargyl alcohol; Table 2, entry 4).46 Thus, by the
same token, reactions of propargyl ethers in entries 1ꢀ3 of Table 2
(84:16ꢀ89:11) are less selective than the propargyl amides
illustrated in entries 6ꢀ8 of the same table (>95:5); the more
electron-withdrawing amides exert a stronger electronic influence
than a tert-butyl, benzyl, or a silyl ether.47
a Ar = 2,4,6-Me3C6H2 or 2,6-(i-Pr)2C6H3; Ad = adamantyl.
10 (Mes vs (i-Pr)2Ph-substituted NHC; see entries 1 and 5 of
Table 1). The transformation may proceed via metallacyclopropene
IC,44 which is subsequently converted to (pinacolato)boron-sub-
stituted vinylcopper IV; in situ protonation of IV affords the R-
vinylboronate product, regenerating NHCꢀCuꢀOMe complex
28, which can initiate additional catalytic cycles.
Based on the DewarꢀChattꢀDuncanson model,45 and as
mentioned previously, coordination of an alkyne to a Cu atom
involves donation of electron density from the π CtC (A or D,
Scheme 8) as well as back-donation from the transition metal to
the alkyne π* (B or C, Scheme 8) in various degrees of
significance. We emphasize such dual interaction through depic-
tion of the intermediacy of metallacyclopropenes IC and IVC
(Scheme 7).44 In the case of complex I, involving a relatively less
electron-donating NHC (vs the more Lewis basic adamantyl-
substituted variant), π-donation from the alkyne to the Cu
s-orbital plays a more dominant role (A, Scheme 8 vs B, involving
donation from Cu d-orbital to the alkyne π*). Since, as described
When the more electron-donating alkyl-substituted NHCꢀCu
complex 9 is used, mode of coordination IV may become favored
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Scheme 9. β-Selective Reactions of Alkyl-Substituted Alkyne
offer an explanation for the β selectivity observed with Cu
complexes derived from NHCs that contain an N-alkyl (entries
1ꢀ3, Table 4) or an N-aryl group, represented by the processes
with Complex 6a
shown in Scheme 9. Our calculations (NHCꢀCu alkyne
3 3 3
coordination product-determining)13 as well as experimental
findings, however, indicate that a similar scenario likely does
not apply to reactions of aryl alkynes illustrated in Table 4 and
should not be used to explain the higher β selectivity observed
with this substrate class. Accordingly, in contrast to the related
reactions involving aryl-substituted olefins, where CuꢀBadditionto
the alkene is believed to be product-determining,28a,51 there is little
difference in the rate of reaction between a substrate that bears an
electron-withdrawing or donating unit (entry 12 vs 14, Table 4).
Subtle structural modifications within the substrate regarding
the position of electron-withdrawing substituents, which in
certain cases are relatively distal to the alkyne, can have a notable
impact on site selectivity (e.g., 32 or 34 vs 35, 32 vs 37 vs 38;
Scheme 9). If CuꢀB addition to the alkyne were consistently the
step that determines product identity, the presence of the
electronegative substituents would lead to a preference for β-
vinylboronate generation, since accumulation charge density at
the R position would be more stabilized, favoring CuꢀCR bond
formation (β selectivity). In contrast, however, the presence of
electron withdrawing units result in diminution of β selectivity
(Scheme 9); such variations can be explained by the mechanistic
picture presented above in connection with increased stability of
the developing electron density at the CR site.
a Reactions performed under N2 atmosphere. Conversion (based on 1 as the
limiting reagent) and site selectivity ((2%) were determined by analysis of
400 MHz 1H NMR spectra of product mixtures prior to purification.
(Scheme 7, right column); β-vinylboronate products might
therefore be generated via metallacyclopropene IVC and vinyl-
copper intermediate IVV. A number of electronic and steric
principles might serve to establish a rationale for the preference
for the above mode of reaction. One critical factor is the
departure from linearity48 of NHCꢀCuꢀB(pin)49 imposed by
the more strongly donating NHC ligand (vs I with NAr
substituted variant). Such distortion would likely be due to the
relatively strong trans-influence imposed by the heterocyclic
carbene,48,50 leading to the formation of an available coordina-
tion site that is anti to the heterocyclic ligand. As a result, and as
shown in III and IV (Scheme 7), the alkyne substrate approaches
the NHCꢀCuꢀB(pin) from an angle that positions it more
distal to the NHC (labeled as “anti-to-NHC” vs IꢀII labeled as
“syn-to-NHC”). Electronic factors can be called upon to explain
the preference for reaction through IV (vs III). In the case of a
more strongly electron-donating NHC (i.e., Cu complex 9), as
illustrated by C in Scheme 8, an alkyne serves as a π-acceptor.
Accordingly, mode of alkyneꢀcatalyst association IV (Scheme 7),
where the softer Cβ (larger LUMO) is positioned anti to the
heterocyclic ligand (more effective hyperconjugation), becomes
favorable. Since the Cβ has a larger LUMO coefficient than the
CR (but to varying levels; see below), β selectivity is rendered less
sensitive to the electronic attributes of the alkyne substituent
compared to reactions with NAr-substituted Cu complexes 6 or
10 (compare the data in Table 4 vs Tables 2 and 3 and eq 3).
Furthermore, the lower selectivity with propargyl alcohol, amines,
and derivatives (73ꢀ88% β in entries 4ꢀ7, Table 4), contrary to
those observed in additions to aryl acetylenes (93 to >98% β in
entries 8ꢀ14, Table 4), are likely connected to the more dominant
electronic influence of the resonance-based effects of the aryl
substituents versus the inductive effects by the former set.
’ CONCLUSIONS
The present investigations introduce hydroboration reactions
of a range of terminal alkynes promoted by easily accessible
NHCꢀCu complexes and a commercially available B-containing
reagent to afford R-vinylboronates in up to >98% site selectivity.
The catalytic method should prove to be of value in chemical
synthesis, since the Cu-catalyzed reactions are amenable to gram-
scale processes and because the majority of previously reported
protocols deliver the alternative terminally boron-substituted β-
vinylboronates either exclusively or in high selectivity (>90%).
The catalytic reactions selectively deliver intermediates that arise
from the addition of NHCꢀCu and (pinacolato)boron across
terminal alkynes, and because the CꢀCu, as well as the CꢀB
bond, can be used in subsequent bond-forming processes, the
implications of the transformations described herein extend
beyond hydroboration.
Mechanistic studies suggest that the unusual R selectivities
arise from steric and electronic effects that originate from the
NHC ligands of the Cu-based catalysts and the substituents of
terminal alkyne substrates. Theoretical investigations reported
previously imply that the rate- and product-determining step in
NHCꢀCu-catalyzed CuꢀB additions to alkenes might involve
alkene insertion into a CuꢀB bond.51 However, the unusual
selectivity patterns observed in CuꢀB additions to terminal
alkynes might best be accounted for through a mechanistic
regime where the rate- and product-determining step is alkyne
coordination to a NHCꢀCuꢀB(pin) complex. The investiga-
tions presented above illustrate that, by altering the electronic
nature of the latter transition metal system, considerable varia-
tions in site selectivity can be achieved such that the more
difficult-to-access R-vinylboronates or the alternative β-vinylboro-
nates are generated in up to >98% R or β selectivity.
It is possible that in reactions of alkyl-substituted alkynes
(those that do not contain an electron-withdrawing unit proximal
to the triple bond), regardless of the nature of the NHCꢀCu
complex, the CuꢀB insertion step (vs Cuꢀalkyne coordination)
serves as the product-determining step. Such a hypothesis does
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Development of catalytic CuꢀB additions to other classes of
alkynes and alkenes, alternative protocols for functionalization of
the resulting organometallic products, and further mechanistic
investigations are in progress.52
(7) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10961–10963.
(8) Lee, Y.; Jang, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2009,
131, 18234–18235.
(9) See the Supporting Information for a 400 MHz 1H NMR
spectrum of the product mixture prior to purification attempts.
(10) It may be suggested that propargyl alcohol and amine are first
converted to the corresponding boronate ester or amide, and it is such
entities that undergo Cu-catalyzed net hydroboration. However, such a
scenario would require the consumption of an equivalent of bis-
(pinacolato)diboron (1), likely through reaction of NHCꢀCuꢀOMe
with 1 to generate NHCꢀCuꢀB(pin), which subsequently reacts with
an alcohol or amine to deliver the aforementioned derivatives. Since only
1 equiv of 1 is used in all reactions and g83% conversion is observed,
such a pathway can occur, at best, to only a minor extent.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data for substrates and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(11) For an example of vinyl halide conversion to a vinyllithium
followed by (pinacolato)-isopropoxyboron utilized in the course of a
natural product total synthesis, see: Murelli, R. P.; Cheung, A. K.;
Snapper, M. L. J. Org. Chem. 2007, 72, 1545–1552.
Corresponding Author
amir.hoveyda@bc.edu
(12) Reaction with p-methoxyphenylacetylene under identical con-
ditions gives rise to 58% conversion and 62:38 R:β selectivity (pure R-
vinylboronate is isolated in 33% yield after silica gel chromatography).
(13) See the Supporting Information for details.
(14) (a) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel,
A. Angew. Chem., Int. Ed. Engl. 1962, 1, 80–88. (b) Muzart, J. Tetrahedron
2007, 63, 7505–7521.
’ ACKNOWLEDGMENT
The NSF (CHE-0715138) provided financial support. We are
grateful to Professor Amnon Stanger (Technion, Haifa) for
helpful discussions and Professor Cristina Nevado (University
of Z€urich) for informing us about the dialkylborane-catalyzed
hydroboration reactions of terminal alkynes. We are grateful to
Frontier Scientific for generous gifts of bis(pinacolato)diboron.
Mass spectrometry facilities at Boston College are supported by
the NSF (DBI-0619576). We thank Boston College Research
Services for providing access to computational facilities.
(15) For a method for synthesis of cyclic vinylboronates through the
use of β-borylallylsilanes, prepared by Pd-catalyzed BꢀSi additions to
allenes, see: (a) Suginome, M.; Ohmori, Y.; Ito, Y. J. Am. Chem. Soc.
2001, 123, 4601–4602. For synthesis of cyclic vinylboronates through
Pd-catalyzed CꢀH borylation, see: (b) Olsson, V. J.; Szabꢁo, K. J. Angew.
Chem., Int. Ed. 2007, 46, 6891–6893. (c) Selander, N.; Willy, B.; Szabꢁo,
K. J. Angew. Chem., Int. Ed. 2010, 49, 4051–4053. Cyclic vinylboronates
have also been prepared through Ni-catalyzed borylation processes that
involve CꢀO activation: (d) Huang, K.; Yu, D.-G.; Zheng, S.-F.; Wu,
Z.-H.; Shi, Z.-J. Chem.ꢀEur. J. 2011, 17, 786–791.
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(6) Alkyl-substituted R-vinylboronates can be accessed through
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(32) (a) See ref 28a. The NHCꢀCu-catalyzed reactions of the
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(33) NHCꢀCu-catalyzed reactions of B2(pin)2 (with MeOH pre-
sent) with alkyl,aryl-substituted internal alkynes afford β-boryl products;
high efficiency is observed with methyl-substituted substrates. See: Kim,
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(34) It may be argued that CuꢀB addition might be reversible but
the NHCꢀCu-boronate remains coordinated to the same alkyne
substrate. Although evidence to address such a possibility is not yet
available, the fact that the presence of a large excess of a second, and
nearly identical, alkyne (e.g., 23 in Scheme 6) does not lead to significant
cross-over, suggests otherwise.
(35) Although initial studies suggest that the CuꢀB addition step
is the product-determining step, kinetic measurements indicate that
reaction of MeOH with the derived vinylꢀcopper intermediate is
energetically significant as well. Thus, kH/kD values of 2.7 and 3.6
have been measured for reactions of terminal alkyne 2 (cf. Table 1
and entry 1, Table 2) and 5-chloro-1-pentyne (Scheme 6) performed
in the presence of NHCꢀCu complex 10 (see Table 1). See the
Supporting Information for details.
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observed site selectivities. The presence of MeOH in the mixture
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were such byproducts observed, leading us to put forward the modes
of CuꢀB addition illustrated in Scheme 7. For an example of a Cu-
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(46) Catalytic hydroborations can be performed with nearly similar
efficiency and selectivity in tetrahydrofuran or toluene.
(47) Attempts to examine transformations of allylic esters, such as an
acetate or a tosylate, were thwarted by substrate instability or generation
of complex product mixtures.
(48) For computational studies regarding the connection between
substrate coordination to distortion of d10 metal complexes [Cu(I),
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is due to the bending in LꢀCuꢀL0 systems, is diminished with the more
strongly donating ligands. For examples of distortion from linearity in an
NHCꢀmetalꢀligand bond and related discussions, see: (b) Poater, A.;
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(49) The near-linear nature of an NHCꢀCuꢀB(pin) is supported
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X-ray structure data regarding a planar bent Cu(I) complex, see:
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(38) It is unclear, however, whether the presence of an electron-
withdrawing group within the alkyne substrate results in an increase in
reaction rate.
(39) For a discussion of various effects involved in interactions
between two molecules, see: Ess, D. H.; Jones, G. O.; Houk, K. N.
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(40) For a general discussion of secondary orbital interactions and
their significance in predicting selectivity, see: Ginsburg, D. Tetrahedron
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(50) The (pinacolato)boron ligand can impose a strong trans
influence as well, as illustrated in a number of previous reports. See:
(a) Zhu, J.; Lin, Z.; Marder, T. B. Inorg. Chem. 2005, 44, 9384–9390.
(b) Zhao, H.; Lin, Z.; Marder, T. B. J. Am. Chem. Soc. 2006,
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ever, is a constant structural feature in all the systems under investiga-
tion; it is the variation in the electronic and steric attributes caused by
the change in the identity of the NHC ligand that gives rise to the
observed differences in site selectivity. Accordingly, our discussions
are focused on the impact caused by the latter component of the
catalyst structure.
(41) The local softness parameters were calculated from Hirshfeld
population analyses (HPA) of the optimized structures of aryl alkynes as
described in the Supporting Information, following a finite difference
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(51) Dang, L.; Zhao, H.; Lin, Z.; Marder, T. B. Organometallics 2007,
26, 2824–2832.
(52) The basis for β-selective reactions promoted by chiral sulfo-
nate-based bidentate NHCꢀCu complexes (cf. 5 in Scheme 2) will be
the subject of a separate investigation and report. Such bidentate
carbenes, in contrast to the monodentate systems examined here, give
rise to NHC-based cuprates (vs NHCꢀCu) complexes, and their
substrate association and reactivity are therefore governed by different
steric and electronic requirements.
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