Chemoselective coupling of 1,1-bis[(pinacolato)boryl]alkanes for the transition-metal-frec borylation of aryl and vinyl halides: A combined experimental and theoretical investigation

Article abstract of DOI:10.1021/jacs.6b11757

A new transition-metal-frec borylation of aryl and vinyl halides using l,l-bis[(pinacolato)boryl]alkanes as boron sources is described. In this transformation one of the boron groups from 1,1-bis[(pinacolato)boryl]alkanes is selectively transferred to aryl and vinyl halides in the presence of sodium tert-butoxide as the only activator to form organoboronate esters. Under the developed borylation conditions, a broad range of organohalides are borylated with excellent chemo-selectivity and functional group compatibility, thus offering a rare example of a transition-metal-frec borylation protocol. Experimental and theoretical studies have becn performed to elucidate the reaction mechanism, revealing the unusual formation of Lewis acid/base adduct betwecn organohalides and α-borylcarbanion, generated in situ from the reaction of l,l-bis[(pinacolato)boryl]alkanes with an alkoxide base, to facilitate the borylation reactions.

Full text of DOI:10.1021/jacs.6b11757

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Article
Chemoselective Coupling of 1,1-Bis[(pinacolato)boryl]alkanes
for the Transition-Metal-Free Borylation of Aryl and Vinyl
Halides: A Combined Experimental and Theoretical Investigation
Yeosan Lee, Seung-yeol Baek, Jinyoung Park, Seoung-Tae Kim, Samat
Tussupbayev, Jeongho Kim, Mu-Hyun Baik, and Seung Hwan Cho
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11757 • Publication Date (Web): 14 Dec 2016
Downloaded from http://pubs.acs.org on December 15, 2016
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Chemoselective Coupling of 1,1ꢀBis[(pinacolato)boryl]alkanes for the
TransitionꢀMetalꢀFree Borylation of Aryl and Vinyl Halides: A
Combined Experimental and Theoretical Investigation
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Yeosan Lee,†,ǁ Seungꢀyeol Baek,‡,§,ǁ Jinyoung Park,† SeoungꢀTae Kim,‡,§ Samat Tussupbayev, §,‡
Jeongho Kim,† MuꢀHyun Baik*,§,‡ and Seung Hwan Cho*,†
†Department of Chemistry and Division of Advanced Nuclear Engineering, Pohang University of Science and Technology
(POSTECH), Pohang, 37673, Republic of Korea
‡Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of
Korea
§Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, 34141, Republic of Korea
Supporting Information Placeholder
ABSTRACT: A new transitionꢀmetalꢀfree borylation of aryl and vinyl halides using 1,1ꢀbis[(pinacolato)boryl]alkanes as boron sources is
described. In this transformation one of the boron groups from 1,1ꢀbis[(pinacolato)boryl]alkanes is selectively transferred to aryl and vinyl
halides in the presence of sodium tertꢀbutoxide as the only activator to form organoboronate esters. Under the developed borylation
conditions, a broad range of organohalides are borylated with excellent chemoselectivity and functional group compatibility, thus offering
a rare example of a transitionꢀmetalꢀfree borylation protocol. Experimental and theoretical studies have been performed to elucidate the
reaction mechanism, revealing the unusual formation of Lewis acid/base adduct between organohalides and αꢀborylcarbanion, generated
inꢀsitu from the reaction of 1,1ꢀbis[(pinacolato)boryl]alkanes with an alkoxide base, facilitate the borylation reactions.
Scheme 1. Chemoselective Coupling of Aryl and Vinyl
Introduction
(pseudo)Halides with 1,1ꢀBis[(pinacolato)boryl]alkanes
1,1ꢀBisborylalkanes have recently emerged as new class of
coupling reagents in organic synthesis.1,2 Prompted by the seminal
report by Endo and Shibata on the palladiumꢀcatalyzed
chemoselective crossꢀcoupling of aryl halides with 1,1ꢀ
bis[(pinacolato)boryl]alkanes,2 several considerable efforts were
made for the utilization of 1,1ꢀbis[(pinacolato)boryl]alkanes in a
variety of chemoꢀ and enantioselective transformations.3ꢀ6 For
example, Morken3a,b and Hall3c independently developed an
elegant
palladium/chiral
phosphine
system
for
the
enantioselective coupling of aryl3a,3c and vinyl3b halides with 1,1ꢀ
bis[(pinacolato)boryl]alkanes to afford chiral secondary
alkylboronate esters. Wang and coꢀworkers reported that vinyl
bromides and 1,1ꢀdibromoalkenes could react with 1,1ꢀ
bis[(pinacolato)boryl]alkanes in the presence of a palladium
catalyst, providing 1,4ꢀdienes and allenes.3d Fu and Xiao
described that aryl triflates could work as facile electrophiles in
boronꢀcontaining groups into organic molecules. While such
compounds are typically prepared by the reaction of
organometallic nucleophiles, such as Grignard or organolithium
reagents, with boron electrophiles,7 recent efforts have focused on
the catalytic borylation of aryl (pseudo)halides8 or simple arenes.9
Electrophilic borylations are also well documented.10 Despite
these splendid advances, transitionꢀmetalꢀfree borylation is in
high demand because of its low cost and convenience, and several
examples have been reported using diboron compounds such as
B2pin2 or B2(OH)4.11 Therefore, finding new reagents for the
borylation of aryl and vinyl halides remains an important
challenge. In particular, reagents that enable new synthetic
methodologies with increased selectivity and efficiency in the
construction of target boron compounds are highly sought after.
chemoselective
bis[(pinacolato)boryl]alkanes.3e While these studies illustrate the
unique reactivity and selectivity of 1,1ꢀ
crossꢀcouplings
with
1,1ꢀ
bis[(pinacolato)boryl]alkanes in the coupling with aryl
(pseudo)halides, they typically involve the formation of a C–C
bond (Scheme 1a). The formation of a C–B bond with aryl and
vinyl halides employing 1,1ꢀbis[(pinacolato)boryl]alkanes as a
boron source has thus far been elusive.
Organoboronate esters are highly versatile building blocks in
organic synthesis and methods for their preparation continue to
inspire organic chemists.7 Consequently, extensive efforts have
been made to develop efficient strategies for the installation of
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Table 1. Evaluation of Reaction Conditions for the Borylation of Aryl Iodides with 1,1ꢀBis[(pinacolato)boryl]alkanesa
1
2
3
4
5
6
7
8
9
R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
entry
1
base
solvent
toluene
temp (°C)
120
120
120
120
120
120
120
120
120
120
100
80
Yield (%)b
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
F
LiOtBu
NaOtBu
KOtBu
LiOMe
NaOMe
KOMe
KF
6
70
10
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12
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16
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60
2
toluene
3
toluene
<1
4
toluene
<1
5
toluene
50
6
toluene
<1
7
toluene
<1
8
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
ꢀ
THF
71
9
1,4ꢀdioxane
toluene/THF
toluene/THF
toluene/THF
toluene/THF
toluene/THF
toluene/THF
toluene/THF
70
91(85)d
10c
11c
12c
13c
14c
15c
16c
80
5
120
120
120
80
75
<1
NaOtBu
NaOtBu
90
90(73)d
F
aReaction Conditions: A1 or A2 (0.2 mmol), B1 or B2 (2.0 equiv), base (2.0 equiv) and solvent (2.0 mL) at indicated temperature for 6 h.
bGC yield of C1 or C2 using dodecane as an internal standard. A 1:1 mixture of toluene/THF was used as the solvent. dYield in
c
parentheses indicates the isolated yield.
In this context, Ito previously showed that silylboron reagents
may be used to achieve similar transformations12a,b and a
mechanism based on DFT calculations was proposed.12c
reaction temperature resulted in a decrease in the yield (entries 11
and 12). The treatment of 1,1ꢀbis[(pinacolato)boryl]ethane (R2 =
Me) instead of B1 also afforded the borylated product C1 (entry
13) in slightly lower yield of 75%, suggesting that substituted 1,1ꢀ
diboryl compound could also be used as a boron source in the
current process. No conversion was observed in the absence of a
base (entry 15). Notably, the borylation of 4ꢀfluoroꢀ1ꢀiodobenzene
(A2) as a substrate afforded the desired borylated product C2 in a
good yield even at 80 °C with nearly equal efficiency to the
reaction performed at 120 °C (entries 16 and 17), suggesting that
the reaction is influenced by the electronic properties of aryl
iodides we conducted. It is interesting to note that the borylated
products C1 and C2 were formed as the only reaction product
Herein, we report the transitionꢀmetalꢀfree borylation of aryl
and
vinyl
halides
using
commercially
available
bis[(pinacolato)boryl]methane as a new class of boron transfer
reagents (Scheme 1b).13 Our protocol significantly enriches the
growing
class
of
useful
reactions
of
1,1ꢀ
bis[(pinacolato)boryl]alkanes, representing the first example for
the formation of C–B bond of aryl halides using 1,1ꢀ
bis[(pinacolato)boryl]alkanes. Mechanistically, these new
reactions constitute an interesting platform for discovering how
the general Lewis acid/base characteristics of aryl halides and 1,1ꢀ
bis[(pinacolato)boryl]alkanes can be exploited to carry out a
demanding reaction in a controlled and specific manner.
Scheme 2. First Part of the Mechanism for the Borylation of
4ꢀIodoanisole
Results and Discussion
Reaction Development. In line with our recent efforts utilizing
1,1ꢀbis[(pinacolato)boryl]alkanes in organic synthesis,6 we
hypothesized initially that 1,1ꢀbis[(pinacolato)boryl]alkanes may
be suitable reagents for the transfer of boron to aryl and vinyl
halides with unusual chemoselectivity. Interestingly, the reaction
of 4ꢀiodoanisole (A1) with bis[(pinacolato)boryl]methane (B1) in
the presence of LiOtBu in toluene at 120 °C proceeded to form 4ꢀ
methoxyphenyl boronate ester C1 in 6% yield (Table 1, entry 1),
as determined by gas chromatography (GC) analysis. Using
NaOtBu as a base (entry 2) significantly increased the yield of C1
to 70%, whereas other alkoxide and fluoride bases (entries 3–7)
gave decreased yields compared with that achieved with NaOtBu.
Solvent screening (entries 8–10) revealed that an equal mixture of
toluene/THF provided the highest yield (entry 10). Lowering the
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∆G(sol)
1
2
3
4
5
6
7
kcal mol-1
O
H2C
B
B1C-TS'
(44.25)
O
50
MeO
MeO
I
Na
Na Ar
B1G-TS
40
30
(26.35)
tBuO Bpin
B1C-TS
(33.13)
Na
I
O
O
B
B1D-TS
(27.75)
Na
Ar
B1E-TS
(24.17)
CH2
pinB
Bpin
B1E
(17.33)
8
*
B1I'-TS
9
B1A-TS
(15.86)
20
10
(19.83)
B1D
(20.80)
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*
B1G
(16.68)
Na
Ar
B1C
(13.56)
B1B
(10.67)
*
I
Bpin
*
B1F
(-2.21)
tBuO Bpin
0
B1
(0.00)
pinB CH2 Na
B1A
(-1.66)
C1
(-3.35)
B1H
(-2.67)
B1I'
-4.63
pinB
Bpin
-10
-60
-70
O
O
OtBu
Bpin
Na
MeO
B
pinB
B1D'
-57.44
B1D'
-57.44
Na
I
Ar
Bpin
Figure 1. Energy profile for the transitionꢀmetalꢀfree borylation of 4ꢀiodoanisole (A1) with bis[(pinacolato)boryl]methane (B1).
Transition states marked by * were not explicitly located.
and no alkylation products, D1 or D2, were detected under
optimized conditions.
RꢀC6H5 ꢀ RꢀC6H4ꢀ + H+, where R = OMe, F, CF3, NO2 (1)
pinBꢀCH3 ꢀ pinBꢀCH2ꢀ + H+
(2)
Theoretical Studies. Scheme 2 summarizes the initial phase of
our proposed mechanism and Figure 1 shows the DFT calculated
reaction free energy profile using 4ꢀiodoanisole (A1) and
bis[(pinacolato)boryl]methane (B1) as the borylating agent. The
reaction starts with the activation of B1 furnished by the tertꢀ
Table 2. Gasꢀ and Aqueousꢀphase Free Energies of the
Deprotonation Reaction (1) and (2) in kcal/mol
ꢁrG (gas) ꢁrG (water)a
butoxide anion attacking one of the boryl moieties in
a
nucleophilic fashion. The reactant complex B1A at a relative free
energy of ꢀ1.7 kcal/mol undergoes B–C bond cleavage to form the
sodium αꢀborylcarbanion B1B, liberating the tertꢀbutoxyboronate
ester. This process is 12.3 kcal/mol uphill traversing the transition
state B1AꢀTS associated with a barrier of 17.5 kcal/mol.
Therefore, the initialization step is energetically reasonable and it
should be rapid under normal reaction conditions. To push the
reaction forward, B1B may react with aryl iodide to afford a
weakly bound Lewis acid/base adduct B1C, which was located at
MeO–C6H5
F–C6H5
396.8
392.4
385.9
378.4
70.9
68.4
67.3
53.9
F3C–C6H5
pinB–CH3
aAbsolute aqueous solvation free energy of the proton was taken
equal to −265.9 kcal/mol.16
13.6 kcal/mol. The adduct B1C shows
a linear C–I–C
arrangement, as illustrated in Figure 2. Formally, the
borylcarbanion acts as a Lewis base to bind to the iodide which
serves as the complementary Lewis acid. This binding motif is
reminiscent of what is known as an “ateꢀcomplex” of iodine.15 In
a typical ateꢀcomplex, such as lithiumbis(pentafluorophenyl)
iodinate,15d the C–I–C fragment is symmetric and C–I bonds are
relatively short (~2.3 Å). B1C is notably different, because the
iodine atom is flanked by two very different functional groups;
namely, a para methoxyꢀaryl and an αꢀborylcarbanion fragment.
The αꢀborylcarbanion is a much weaker base than the methoxyꢀ
aryl carbanion, as the electron withdrawing boryl fragment
stabilizes the anionic charge. To compare the strengths of the
basicities and to establish a gauge, we evaluated the the gasꢀphase
free energies of the proton abstraction reactions (1) and (2).
As summarized in Table 2, our calculations show that the
methoxylꢀaryl carbanion is indeed the strongest Brønsted base
with the deprotonation of its conjugate acid requiring 396.8
kcal/mol. As anticipated, the αꢀborylcarbanion is a much weaker
base and the deprotonation of borylmethane is nearly 19 kcal/mol
Figure 2. DFTꢀoptimized geometry of B1C with selected
distances in Å. Nonꢀessential hydrogen atoms were omitted
for clarity.
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easier at 378.4 kcal/mol in gas phase.17 Interestingly, this
kinetically, the computed energy differences are too small to be
1
2
3
4
5
6
7
8
deprotonation energy is much smaller than that of an aryl carrying
highly electronꢀwithdrawing groups like –F or –CF3, for which we
calculated deprotonation energies of 392.4 and 385.9 kcal/mol. As
a result of these notable difference in the electronꢀdonating nature
of the two carbanions, the intermediate B1C is not a classical ateꢀ
complex and displays significantly different C–I bonds. One of
the C–I distances is close to the sum of covalent radii (2.162 Å
),while the other is significantly longer 3.126 Å and the negative
charge is additionally stabilized by the sodium cation, as
illustrated in Figure 2. If the sodium cation is removed these
bonds become 2.289 and 2.622 Å, respectively.
physically meaningful. Finally, both B1F and B1H may release
Na[H2C– Bpin] or NaOtBu, respectively, to yield the borylation
product C1.18
Scheme 3. Second Part of the Mechanism for the
Borylation of 4ꢀIodoanisole
pinB
Bpin
Na
Ar
Na
Ar
Na Ar
pinB Bpin
B1
Ar Bpin
9
pinB
B1E
(Ar = p-anisole)
Bpin
pinB
Bpin
C1
B1B
B1E-TS
B1F
10
11
12
13
14
15
16
17
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19
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22
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25
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The nucleophilic substitution at iodine in Path A proceeds via
the transition state B1CꢀTS, which was located at 33.1 kcal/mol,
to form the iodomethyl boronate ester B1D. The C–I–C fragment
is again not symmetric in B1CꢀTS with the newly forming C–I
bond being 2.312 Å long, as shown in Figure 3, and the rupturing
bond being at 2.925 Å. The sodium has moved and bridges the
arylꢀanion and the Bpin moiety. In Path B, the electrophilic attack
of the carbanion by the Arꢀgroup must traverse B1CꢀTS' to give
B1D'. Our calculations suggest that the C–C coupling product
B1D' is 78.2 kcal/mol lower in energy than B1D, i.e. the
formation of B1D' is thermodynamically much more preferable.
But the resting state B1A must overcome a barrier of 45.9
kcal/mol to form B1D', whereas only 34.7 kcal/mol is required to
reach B1D. Hence, in spite of the great stability of B1D' its
formation is kinetically impossible and forming the
thermodynamically less favorable Lewis acid/base pair B1D is the
only reaction viable, as illustrated in solid black lines in Figure 1.
Na
Ar
Na
Ar
tBuO Bpin
Na Ar
Na Ar
Ar Bpin
I
Bpin
tBuO Bpin
tBuO Bpin
B1G-TS
tBuO Bpin
B1H
B1D
C1
NaOtBu
B1G
Na Ar
Na Ar
I Bpin
Na
I
Na Ar
Bpin
I
Bpin
I
Ar
Bpin
B1D-TS
B1I'
B1I'-TS
B1D'
In one possible side reaction C–C coupling may occur after
B1D is formed as a result of the reaction between ICH2Bpin and
NaAr. Here, the arylꢀanion may attack the boron atom of
ICH2Bpin directly to give intermediate B1I', which is 25.4
kcal/mol lower in energy than B1D. The following C–C coupling
to generate B1D' proceeds via B1I'ꢀTS at a relative free energy of
19.8 kcal/mol, thus giving a barrier of 24.5 kcal/mol. This barrier
is much higher than that for the formation of the monoborate
species B1F and B1H, but is reasonable for the given reaction
condition. Therefore, the reaction pathway affording the undesired
product B1D' has the potential to become one of the unproductive
side reactions. But at any given time during the course of the
reaction, the concentration of free ICH2Bpin is negligible
compared to the overwhelming abundance of both B1 and tBuO–
Bpin. Thus, the only way this side reaction can occur is within the
product complex B1D caught in a solvent cage. Experimentally,
there is no evidence for this reaction taking place, in good
agreement with our interpretation of the calculated reaction
energy profiles. This is
exceptionally great thermodynamic driving force, mentioned
above.
a remarkable finding, given the
A more detailed analysis of the relative energies reveals that the
higher barrier for the C–C coupling step associated with B1Cꢀ
TS', a nucleophilic aromatic substitution, is due to a strong
electrostatic repulsion between the πꢀcloud of aryl moiety, the
anionic methyleneꢀcarbanion and the anionic iodide leaving
group. At 2.627 Å, the C–I bond is not yet fully broken and at
2.670 Å the C–C bond is not yet formed in the transition state
B1CꢀTS' (Figure 3). The electronꢀdonating nature of the methoxy
group in the para position compounds the electrostatic penalty.
Our calculations show that the energy of B1CꢀTS' can be
significantly lowered by ~6 and ~10 kcal/mol if the methoxy
group in the para position is replaced by electronꢀwithdrawing –F
or –CF3 groups, respectively (see supporting information).
Therefore, the kinetic challenge associated with Path B, which is
ultimately responsible for the chemoselectivity described above,
stems from the fact that the transition state is early and the aryl
fragment is too electronꢀrich to provide a viable reaction partner
for the incoming carbanion. This mechanistic insight and the
magnitude of change in the transition state energy as a function of
the electron density of the arylꢀiodide is a potentially powerful
handle for controlling the reaction. A more detailed study of how
to control the reaction mechanism by functionalizing the arylꢀ
Figure 3. DFTꢀoptimized geometries of B1CꢀTS and B1Cꢀ
TS’ with selected distances in Å. Nonꢀessential hydrogen
atoms were omitted for clarity.
The NaAr moiety formed transiently in intermediate B1D is
highly reactive and will readily engage an equivalent of
bis[(pinacolato)boryl]methane B1 or tertꢀbutoxyboronate ester,
both present in large excess quantities in solution, as illustrated in
Scheme 3. The anionic Ar– fragment can attack the Lewis acidic
boron in B1 or tBuO–Bpin via B1EꢀTS and B1GꢀTS,
respectively, to give the Ar–borate species B1F or B1H. Both
reaction steps have very low barriers, which is not surprising for a
reaction where Ar–, a strong and hard Lewis base, attacks strong
and hard Lewis acids. Whereas our calculations indicate that the
formation of monoborate species B1F is slightly preferred
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iodide moiety is in progress in our laboratories and will be
reported elsewhere in due course.
radical scavenger 9,10ꢀdihydroanthracene (DHA), the product C1
1
2
3
4
5
6
7
8
was formed in slightly lower yield along with detectable amounts
of anisole (Scheme 4b). To understand how the anisole was
formed under the reaction conditions, we performed a control
experiment by subjecting 9,10ꢀhydroanthracene to inꢀsitu
generated sodium aryl anion. It was found that the corresponding
arene was formed in nearly quantitative yield,14 implying that
benzylic CꢀH bonds of 9,10ꢀdihidroanthracene is deprotonated by
the aryl anion species to yield anisole.22 Because a recent radicalꢀ
mediated borylation reaction have shown that the reaction was
completely inhibited in the presence of excess amount of 9,10ꢀ
9
dihydroanthracene, we could eliminate
involving aryl radical intermediates with a fair level of certainty.23
key component of our proposed mechanism is the
a reaction pathway
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20
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22
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A
involvement of the aryl anion in the reaction path A, as discussed
above. In search of an experimental support for this notion, we
performed competition experiments using B1 and electronically
different paraꢀsubstituted aryl iodides, as outlined in Scheme 5.
When an equimolar mixture of A4/A5/A6 (0.2 mmol each) was
heated at 120 °C in toluene/THF in the presence of 2.5
equivalents each of B1 (0.5 mmol) and NaOtBu (0.5 mmol) in a
single vessel, the electronꢀdeficient aryl iodide (A6) underwent
borylation more rapidly than the electronically neutral (A4) and
electronꢀrich (A5) aryl iodides. Whereas this observation does not
prove that the aryl anion is really involved, it is very consistent
with the calculated reaction pathway discussed above and
supports our proposal that an aryl anion species is involved as a
key intermediate in our borylation protocol.
Figure 4. Comparison of initial rates in the presence of
various transitionꢀmetal catalysts
Experimental Mechanistic Studies. To challenge and possibly
find support for the computed reaction mechanism, several
experiments were conducted. First, we used inductively coupled
plasma atomic emission spectroscopy (ICPꢀAES)14 to ensure that
there is no trace amounts of transitionꢀmetal contaminants in
NaOtBu, which may possibly be responsible for the reactivity. We
confirmed that no transition metal impurities could be detected.
Moreover, no acceleration of the reaction rate was observed when
catalytic amounts of several transition metals were deliberately
employed in the reaction, thus ruling out the possibility of a
transitionꢀmetalꢀmediated mechanism (Figure 4).19
Scheme 5. Intermolecular Competition Experiment
I
Bpin
NaOtBu (2.5 equiv)
pinB
Bpin
+
toluene/THF
120 oC, 6 h
R
R
B1
(2.5 equiv)
R = H, A4
C4, 20%
C5, 12%
R = Me, A5
Scheme 4. Probe for an Aryl Radical Mechanism
A6
R = CF3,
C6
, 61%
(each 1.0 equiv)
a)
B1
(2.0 equiv)
NaOtBu (2.0 equiv)
+
Scope of Borylation of Aryl Iodides. On the basis of this
mechanistic understanding, the substrate scope of our borylation
reaction was investigated, as enumerated in Table 3. Because the
mechanism suggests that the borylation reaction should be highly
dependent on the electronic nature of aryl iodides, as it is directly
involved in the rate determining step, and we were able to
qualitative confirm this dependence in our experiments, we
explored the scope by fineꢀtuning the reaction temperature while
varying the nature of the aryl iodides. The borylation of aryl
iodides containing electronically neutral (C4) and donating (C5,
C7–C8) substituents at the para position provided the desired
products in good yields at 120 °C. Interestingly, aryl iodides
bearing a CF3 (C6 and C18) group borylated readily even at 50
°C. Furthermore, 1ꢀchloro and 1ꢀbromoꢀ4ꢀiodobenzene were
successfully reacted with B1 at 80 °C, conveniently leaving the
chloro and bromo groups intact (C9 and C10) for further
elaboration. Substrates containing ester (C11) and amide (C12)
reacted in good to moderate yields at 80 °C. Protected alcohol
(C13 and C14) and masked ketone (C15) groups are also
tolerated. The presence of substituents at the meta (C16ꢀC18) and
ortho (C19) positions of the aryl rings has little impact upon
reaction efficiency. Moreover, aryl iodides containing two
additional substituents were suitable for the borylation, and
provided the corresponding boronate esters (C20ꢀC28) in good to
excellent yields. The protocol developed here could also be
applied to sterically demanding substrates, which were
exceedingly difficult to access by previously known catalytic
borylation protocols.8 The reaction of 1,3ꢀdimethylꢀ(C29), 1ꢀ
toluene/THF
120 oC, 6 h
Bpin
I
R
A3
R = Bpin, C3', <1%
C3, 85%
R = H, C3'', <1%
b)
DHA (5.0 equiv)
B1 (2.0 equiv)
NaOtBu (2.0 equiv)
I
Bpin
H
+
toluene/THF
120 oC, 6 h
MeO
MeO
MeO
C1
, 54%
(GC yield)
30%
(GC yield)
A1
Given the propensity of aryl iodides to undergo homolytic bond
cleavage leading to radical species,20 we sought to exclude such
alternative mechanism. Unfortunately, density functional theory is
notoriously unreliable for modeling radical pathways and, thus,
we did not attempt to calculate the radical pathway. Instead, we
chose to test for such a possibility experimentally. When an aryl
iodide containing a pendant olefin (A3) was subjected to the
standard reaction conditions, the arylboronate ester C3 was
formed in 85% isolated yield; however, formation of the cyclized
product C3' or C3'' were not detected by crude 1HꢀNMR and GCꢀ
MS analysis (Scheme 4a).21 In addition, when the reaction of A1
with B1 was performed in the presence of 5.0 equivalent of the
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Table 3. Borylation of (Hetero)Aryl and Vinyl Iodides with Bis[(pinacolato)boryl]methanea,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction Conditions: A (0.2 mmol), B1 (2.0 equiv), NaOtBu (2.0 equiv), and toluene/THF (2.0 mL, 1:1) at indicated temperature for 6 h.
bYield of isolated product is given. 1HꢀNMR yield using dibromomethane as an internal standard is shown in parentheses. cRuns at 120 °C.
dRuns at 80 °C. eRuns at 50 °C. f1,4ꢀDioxane was used as a solvent instead of toluene/THF.
ethylꢀ3ꢀmethylꢀ(C30), and 1,3,5ꢀtrimethylꢀ(C31) substituted aryl
iodides afforded the corresponding borylated products in good
yields. Notably, substrates having at least one halide group in the
aryl ring underwent borylation at temperatures ranging from 50 to
80°C, whereas alkylꢀsubstituted aryl iodides required high
temperature (120 °C) to afford satisfactory product yields. 1ꢀ
Iodonaphthalene was also found to be an effective substrate for
the borylation reaction forming the borylated products C32 in
good to moderate yields. We were pleased to observe that
heteoaryl iodides could also be utilized as efficient
substratesunder the present borylation conditions. Electron
deficient heteroaryl iodides such as 3ꢀiodopyridine and 3ꢀ
iodoquinoline reacted with B1 at 50 oC to provide the desired
products C33 and C34 in moderate yields. Moreover, 8ꢀIodoꢀNꢀ
methylꢀindole and 3ꢀiododibenzothiophene were also viable
substrates and products C35 and C36 were obtained in
o
satisfactory yields at elevated temperature (120 C). Finally, we
were able to apply the developed borylation protocol to transꢀ
Figure 5. Comparison of free energy varying electronic nature of
vinyl iodides when 1,4ꢀdioxane was used as the solvent to obtain
aryl iodides. Transition states marked by * were not explicitly
a single stereoisomer of the borylated products C37 and C38 in
located.
moderate yields.
affect the mechanism significantly: the conversion of B1A to B1D
Substituent Effects and Scope of Borylation of Aryl
via the transition state B1CꢀTS is still rateꢀlimiting step. The free
Bromides. The theoretical studies described above shed light on
energy barrier for the formation of B1CꢀTS from A1 was 34.8
why electron deficient aryl iodides facilitated the borylation
kcal/mol since the formation of A2ꢀB1CꢀTS from A2 and A6ꢀ
reaction under mild conditions. In order to rationalize these
B1CꢀTS from A6 was found to be lower in energy than B1CꢀTS
electronic effects, the complete free energy pathway profiles for
by 1.6 kcal/mol and 2.9 kcal/mol, respectively. This findings are
three representative aryl iodides (A1, A2 and A6) were calculated
in excellent agreement with the experimental results (Table 1 and
and summarized in Figure 5.14 The change of substituent does not
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Journal of the American Chemical Society
2) that aryl iodides bearing electron withdrawing substituents
1,1ꢀbis[(pinacolato)boryl]ethane (B2) was more effective
1
2
3
4
5
6
7
8
underwent the borylation under relatively mild conditions. To
test whether this borylation process occurs with aryl bromides in a
similar fashion, we performed DFT calculations using 1ꢀbromoꢀ4ꢀ
(trifluoromethyl)benzene (E1) as a model substrate (Figure 6).
These calculations suggest that E1ꢀB1CꢀTS located at 32.9
kcal/mol is the highest energy transition state, implying that this
reaction may be feasible at high temperatures.14
borylation reagent than B1 to form C6 (55%), which may be
attributed to making the carbon that undergoes C–Br formation
more electronꢀrich. By using these modified reaction conditions,
the reactions of aryl bromides bearing electron withdrawing
substituent such as 1ꢀbromoꢀ4ꢀ chloroꢀbenzene (E2), 1ꢀbromoꢀ3ꢀ
(trifluoromethyl)benzene
(E3)
and
4ꢀbromoꢀ2ꢀchloroꢀ1ꢀ
methylbenzene (E4) with B1 or B2 afforded the products C9, C18
and C23 in low to moderate yields. It should be noted that B2
gives higher yields when reacting with aryl bromides. As
anticipated, electronically rich (E5) and neutral (E6) aryl
bromides exhibited low reactivity (C1 and C4).
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Conclusion
In summary, we developed a transitionꢀmetalꢀfree borylation of
aryl
and
vinyl
halides
employing
1,1ꢀ
bis[(pinacolato)boryl]alkanes as the boron source. This
operationally simple reaction proceeds chemoselectively, thus
transferring
bis[(pinacolato)boryl]alkanes to aryl or vinyl halides to form
diverse organoboronate esters with high functional group
tolerance. Combining theoretical and experimental studies, we
were able to understand how aryl halides and αꢀborylcarbanion,
one
boron
group
from
1,1ꢀ
generated
inꢀsitu
by
combination
of
1,1ꢀ
bis[(pinacolato)boryl]alkanes and NaOtBu, are able to generate
sodium aryl anion species, which can subsequently undergo C–B
bond formation reactions. This work constitutes the first example
for the formation of C–B bond of aryl halides using 1,1ꢀ
bis[(pinacolato)boryl]alkanes as boron source with integrated
theoretical and experimental studies. We believe that the present
transitionꢀmetalꢀfree borylation protocol will provide a powerful
tool for the preparation of synthetically useful organoboron
compounds with uncommon chemoselective coupling of 1,1ꢀ
bis[(pinacolato)boryl]alkanes.
Figure 6. Comparison of free energy for the borylation of 1ꢀiodoꢀ
4ꢀ(trifluoromethyl)benzene
(A6)
and
1ꢀbromoꢀ4ꢀ
(trifluoromethyl)benzene (E1) with B1. Transition states marked
by * were not explicitly located.
With this result in mind, we reinvestigated the reaction
parameters
for
the
borylation
using
1ꢀbromoꢀ4ꢀ
(trifluoromethyl)benzene E1 and B1 as model substrates, which
were initially not found to be viable substrates. After extensive reꢀ
optimization,14 we found that E1 undergoes borylation in the
presence of an excess amount of B1 (3.0 equiv) and THF as the
ASSOCIATED CONTENT
Supporting Information
Experimental procedure and characterization of compounds (1H
and 13CꢀNMR spectra), kinetic profiles, Cartesian coordinates of
DFTꢀoptimized structures, benchmark calculations and
computational details. This material is available free of charge via
the Internet at http://pubs.acs.org.
o
solvent at elevated temperature (120 C) with prolonged reaction
time (12 h) to afford the corresponding borylated product C6 in
37% 1HꢀNMR yield (Table 4). Further Investigation showed that
Table 4. Borylation of Aryl Bromides with 1,1ꢀ
Bis[(pinacolato)boryl]alkanes a,b
AUTHOR INFORMATION
Corresponding Author
*seunghwan@postech.ac.kr
*mbaik2805@kaist.ac.kr
Author Contributions
ǁ
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Science, ICT & Future Planning
(NRFꢀ2015R1C1A1A02036326). M.ꢀH.B. acknowledges support
from the Institute for Basic Science (IBSꢀR10ꢀD1) in Korea. J.
Park thanks the National Research Foundation of Korea (NRF) for
the global Ph.D. fellowship (NRFꢀ2016H1A2A1908616).
aReaction Conditions: aryl bromide (E, 0.2 mmol), B1 or B2 (3.0
equiv), NaOtBu (2.0 equiv), and THF (2.0 mL) at 120 oC for 12 h.
b1HꢀNMR yield using dibromomethane as an internal standard is
given.
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9
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12
13
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13. The bis[(pinacolato)boryl]methane is commercially available
from Aldrich (catalog number 794287) and TCI (catalog number
B4103).
14. See the Supporting Information for details.
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17. Note that we use gas phase free energies to obtain a direct and
most immediate measure of the intrinsic deprotonation energy. These
are not to be confused with solution phase deprotonation energies.
The solvation energy of a proton is ~260 kcal/mol in water and the
solvation energies of the carbanions will also be ~50ꢀ100 kcal/mol.
Thus, the solution phase free energy of deprotonation will be much
smaller in absolute number. Here, we are interested in assessing the
electronic energy, as it will be the most direct measure for how the
anionic fragments will behave as binding partners.
18. During the course of the reaction, we detected (CH2Bpin)2 and
tBuOCH2Bpin, which are presumably formed by the reaction between
(iodomethyl)boronate ester (ICH2Bpin) and αꢀborylcarbanion (B1B)
or alkoxide anion, by GCꢀMS.
19. The alkylated product D1 was solely obtained in the presence
of Pd(OAc)2 as a catalyst. For related works, see Refs 2 and 3.
20. For selected examples of aryl radical generation from aryl
iodides in the presence of alkoxide base: (a) Shirakawa, E.; Itoh, K.;
Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 15537. (b)
Qiu, Y.; Liu, Y.; Yang, K.; Hong, W.; Li, Z.; Wang, Z.; Yao, Z.;
Jiang, S. Org. Lett. 2011, 13, 3556. (c) Wei, W.; Dong, X.; Nie, S.;
Chen, Y.; Zhang, X.; Yan, M. Org. Lett. 2013, 15, 6018. (d) Chen, Y.;
Zhang, X.; Yuan, H.; Wei, W.; Yan, M. Chem. Commun. 2013, 49,
10974. (e) Drapeau, M. P.; Fabre, I.; Grimoud, L.; Ciofini, I.;
Ollevier, T.; Taillefer, M. Angew. Chem., Int. Ed. 2015, 54, 10587. (f)
Barham, J. P.; Coulthard, G.; Emery, K. J.; Doni, E.; Cumine, F.;
Nocera, G.; John, M. P.; Berlouis, L. E. A.; McGuire, T.; Tuttle, T.;
Murphy, J. A. J. Am. Chem. Soc., 2016, 138, 7402.
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21. Annunziata, A.; Galli, C.; Marinelli, M.; Pau, T. Eur. J. Org.
Chem. 2001, 1323.
22. We carried out the borylation reaction of 4ꢀiodoanisole (A1)
with B1 in the presence of 1.0 equivalent of tertꢀbutanol as a proton
source. As anticipated, detectable amounts of anisole (19%),
presumably captured by tertꢀbutanol, was formed along with the
desired borylated product (20%) in 60% conversion of A1. This result
provides a supportive evidence that aryl anion is likely involved as a
reactive species in the reaction. For details, see the Supporting
Information.
23. Bose, S. K.; Fucke, K.; Liu, L.; Steel, P. G.; Marder, T. B.
Angew. Chem., Int. Ed. 2014, 53, 1799.
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