Harnessing C-H Borylation/Deborylation for Selective Deuteration, Synthesis of Boronate Esters, and Late Stage Functionalization

Article abstract of DOI:10.1021/acs.joc.5b01588

Ir-catalyzed deborylation can be used to selectively deuterate aromatic and heteroaromatic substrates. Combined with the selectivities of Ir-catalyzed C-H borylations, uniquely labeled compounds can be prepared. In addition, diborylation/deborylation reactions provide monoborylated regioisomers that complement those prepared by C-H borylation. Comparisons between Ir-catalyzed deborylations and Pd-catalyzed deborylations of diborylated indoles described by Movassaghi are made. The Ir-catalyzed process is more effective for deborylating aromatics and is generally more effective in the monodeborylation of diborylated thiophenes. These processes can be applied to complex molecules such as clopidogrel.

Full text of DOI:10.1021/acs.joc.5b01588

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Harnessing C–H Borylation/Deborylation for Selective Deuteration, Synthesis of
Boronate Esters, and Late Stage Functionalization
Venkata A Kallepalli, Kristin A. Gore, Feng Shi, Luis Sanchez, Ghayoor A. Chotana,
Susanne L. Miller, Robert E. Maleczka, Jr.,* and Milton R. Smith, III *
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Department of Chemistry, Michigan State University, 578 South Shaw Lane, East
Lansing, Michigan 48824-1322
Email: maleczka@chemistry.msu.edu, smithmil@msu.edu
Ir catalyst,
HBpin or B2pin2
Ir catalyst,
HBpin or B2pin2
S
S
Br
Br
Bpin
monoborylation
diborylation
complementary regiochemistry
and site-specific labeling
Ir or Pd catalyst,
Bpin proton or deuteron source
S
S
Br
Br
H/D
proto or
pinB
deuterodeborylation
pinB
Abstract: Ir-catalyzed deborylation can be used to selectively deuterate aromatic and
heteroaromatic substrates. Combined with the selectivities of Ir-catalyzed C–H
borylations, uniquely labeled compounds can be prepared. In addition,
diborylation/deborylation reactions provide monoborylated regioisomers that
complement those prepared by C–H borylation. Comparisons between Ir-catalyzed
deborylations and Pd-catalyzed deborylations of diborylated indoles described by
Movassaghi are made. The Ir-catalyzed process is more effective for deborylating
aromatics and is generally more effective in the monodeborylation of diborylated
thiophenes. These processes can be applied to complex molecules such as clopidogrel.
Introduction
Deuterium and tritium labeled compounds, including those labeled at specific
positions, are widely used as probes for spectroscopy, reaction mechanisms,
1
pharmacokinetics and enzymology. Recently, deuterated molecules have garnered
2
interest as a new class of drug candidates. As the need for specifically labeled
compounds grows, reliable methods for incorporating deuterium at specific positions
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becomes increasingly important. Traditional deuteration methods such as acid, base or
transition metal promoted H/D exchange methods can suffer from harsh conditions,
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incomplete deuterium incorporation, or poor functional group compatibility. Although
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some transition metal catalysts exhibit remarkable activities, there are still relatively few
examples of selective introduction of one deuterium in an aryl or heteroaryl ring. The
most common means of doing so is by metal-halogen exchange, followed by deuterolysis
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of the organometallic intermediate. More recently, alternatives like metal catalyzed
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deuterodecarboxylation have been developed. Both of these approaches require existing
functionality to be present. For C–H to C–D transformations, selective examples are
limited to ortho deuterations using stoichiometric or catalytic metal organometallic
3
,6-7
reagents.
Protolytic deborylations of organoboron compounds are known. For example,
benzylic organoboronates undergo stereospecific proto and deuterodeborylations in the
8
presence of CsF and H
2
O/D
2
O. It has also recently been shown that extremely electron
deficient aromatic and heteroaromatic boronic acids can be selectively deborylated in 0.2
9
M hydroxide solutions. Alternatively, electron rich boronic acids can be deborylated
1
0-11
using water or acetic acid as the proton source.
In these chemistries, the boronic ester
or acid can be used as for site-specific deuteration or as a blocking group that enables
regioselective bromination. These features are summarized in Scheme 1.
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Scheme 1. Previously reported base and acid mediated deborylations applied to
isotopic labelling and synthesis.
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Electron deficient boronic acids-base catalyzed9
GWE
(HO)2B
GWE
GWE
D
KOD, D O
2
GWE
Electron rich boronic acids-acid catalyzed10,11
H O or
2
AcOH
GDE
B(OH)2
GDE
H
DMSO, 100 °C
No general method under neutral conditions
Boronate blocked ortho bromination11
Br2
1. BCl3
MeO
Bpin
MeO
Bpin
CH Cl , r.t.
2. H O
2
2
2
Br
AcOH
dioxane
overall 56%
MeO
B(OH)2
MeO
1
00 °C, 24 h
Br
Br
In contrast, other boronic acids typically require prolonged reaction times for
1
2
deborylation. While their rates can be accelerated in highly acidic or basic aqueous
13-14
solutions and by metal-catalyzed processes,
many of the conditions employed for
deborylation are harsh, and virtually all examples involve boronic acids in aqueous
media.
Catalytic C-H activation/borylations of arenes typically install Bpin with
1
5
regioselectivities governed by sterics. In addition, borylations of arenes and
heterocycles occur under mild conditions and a number of important functional groups
are tolerated. If mild deborylation could be accomplished in organic solvents, subsequent
deuterodeborylation of these molecules would constitute a labeling method with good
functional group tolerance, and whose regioselectivity would complement existing
methods.
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A second application of the deborylation is more intriguing. Namely, certain
substrates, such as 2-substituted thiophenes, undergo selective sequential borylations
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beginning with the most reactive C–H bonds. If the deborylation rates mirror borylation
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rates, then a simple protocol for preparing complementary borylation regioisomers could
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7-19
be developed.
These possibilities are outlined in Scheme 2. We note that while this
work was in progress a diborylation/monodeborylation route to 7-borylated indoles was
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0-22
reported by Movassaghi and co-workers.
Scheme 2. Potential applications of C–H borylation/deborylation.
Isotopic labelling
R2
R1
R2
R1
R2
R1
C–H
borylation
deborylation
H
Bpin
S
D
Regioselective synthesis
C–H
borylation
C–H
borylation
R1
S
R1
Bpin
complementary
regioisomers
R1
S
deborylation
R1
S
O
Bpin
Bpin =
B
O
Bnip
Bnip
Results and Discussion
In the course of developing one-pot protocols for Ir-catalyzed C–H borylation and
2
3-25
subsequent elaboration of the resulting organoboronate intermediates,
we noticed that
significant quantities of starting substrates were sometimes present at the end of the
second reaction—even when the starting materials had been completely consumed during
C–H borylation. This indicated that the starting material arose from protolytic
deborylation. Moreover, given that Ir-catalyzed additions of aryl boron compounds are
2
6-27
known,
and deborylations have been implicated under the conditions of Ir-catalyzed
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18,28
borylations,
the deborylations we observed in one-pot reactions were likely Ir-
catalyzed.
The fact that pure boronic esters exposed to water under similar conditions did not
suffer this problem, and that the ligand used in the borylations, 1,2-
bis(dimethylphosphino)ethane (dmpe), failed to promote deborylation (Table 1, entry 2)
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also support an Ir catalyzed process. Indeed, screening of a number of Ir complexes
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(
Table 1) showed that (Ind)Ir(cod) (Ind = η -indenyl, cod = 1,5-cyclooctadiene),
[
Ir(OMe)(cod)]
2
, and [Ir(PCy
3
)(py)(cod)][PF
6
] (Crabtree’s catalyst, py = pyridine) in the
29-30
presence of D
2
O were very effective in promoting deborylation.
Some Ir species were
, the catalyst
less viable at catalyzing this reaction. For example, (dtbpy)Ir(coe)(BPin)
3
3
1
resting state during borylation, was a relatively poor promoter of deborylation, whereas
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IrCl
3
·3H
2
O and (η –C
6
H
6
)Ir(Bcat)
3
did not give detectable deuterated arene. It is
noteworthy that at 150 °C, the crude borylation mixtures are sufficiently active to
facilitate deuterodeborylation of arenes to afford reasonably pure compounds labeled at
the site of borylation (SI).
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a
Table 1. Catalyst screen for deuterodeborylation.
Cl
Cl
Cl
Cl
additive
solvent/D O 6:1,
2
1
50 °C, 30 min
Bpin
D
0
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0
additiveb
conversionc
entry
solvent
1
2
3
4
5
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8
9
Crude borylation mixture
dmpe
THF
THF
THF
DME
THF
DME
THF
THF
THF
DME
THF
>99%
<1%
95%
97%
98%
>99%
33%
<1%
<1%
47%
<1%
(Ind)Ir(cod)
(Ind)Ir(cod)
[Ir(OMe)(cod)]2
[Ir(PCy )(py)(cod)][PF ]
3
6
[IrCl(cod)2]
IrCl ·3H O
3
2
(C H )Ir(Bcat)
3
6
6
1
0
(dtbpy)Ir(coe)(Bpin)3
none
11
a
2
All reactions were run in 1 mmol scale in 0.5 mL D O (~23 equiv) and 3-4 mL
solvent, arbitrarily for 30 min. 2 mol% Ir in every case. GC area ratio calibrated with
corresponding non-deuterated compound.
b
c
We next sought lower temperature conditions for deborylation, as they would be
synthetically more appealing. Indeed, pure pinacolboronate esters undergo selective
deuterodeborylation in THF/D
2
O (6:1 by volume) at 80 °C in the presence of 2 mol %
[
Ir(µ-OMe)(cod)] , a catalyst loading that typically gave complete deborylation after 2 h.
2
Lower catalyst loadings are effective at longer reaction times. The results of
deuterodeborylations are given in Table 2. GC analyses indicated clean conversion to
products with lower yields in entries 3 and 4 resulting from loss on isolation. Isotopic
1
3
purity was determined from C NMR spectra by integrating the upfield triplet of the
deuterated C against the downfield resonance for the residual protonated isotopologue,
2
when detected. The site of deuteration was corroborated by H NMR spectroscopy. The
relative reactivities in deborylation mirror the reactivities of the parent arenes towards
borylation, with more electron deficient substrates being more reactive. No deborylation
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was observed when the substrates in entries 2 and 5 were subjected to Perrin’s and
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Aggarwal’s conditions, respectively.
a
Table 2. Selective deuterodeborylation reactions
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R2
R2
E
R1
E
R3
2 mol % [Ir(OMe)(cod)]2
R1
R3
THF/D O (6:1), 80 °C
2
E = C, N
Bpin
D
yieldb,
%
deuteration
time
entry
1
arene
Cl
product
Cl
Dc
Cl
Cl
Cl
Cl
Cl
Cl
Cl
80%,
98d
2
2
2
h
h
h
>
D
N
Bpin
N
Cl
Cl
2
3
4
5
6
82%,
96
D
D
Bpin
Bpin
F C
F C
Cl
3
3
65%,e
>
98
NC
Br
Cl
NC
Br
Cl
6
>
0%,
98
2 h
D
D
Bpin
Bpin
Me N
Me N
2
2
4.5 h
74%,
9
6
MeO
Cl
MeO
Cl
7
4%,
93
3
h
D
Bpin
a
b
c
All reactions were run with 2 mmol of organoboronate. Isolated yields. Determined
by integration of C NMR spectra; see SI for details for method of calculation. ~4% 4-
deuterated product was observed due to ~4% 4-borylated isomer in the starting material.
1
3
d
e
Owing to product volatility, solvent impurities were present.
A putative catalytic cycle is given in Scheme 3. A generic ligand set is given because
from Table 2 we have seen that Ir species without any added ligand are effective.
Transmetalation of an Ir hydroxide or alkoxide (vide infra) generates an Ir aryl
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intermediate. Deuterolysis of the incipient Ir-Ar bond affords the arene and regenerates
the Ir hydroxide/alkoxide. While the oxidation state is not defined in Scheme 3, Ir(I)
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6-27
complexes are typically implicated in transmetalations of aryl boron compounds.
This
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is consistent with the superior performance of Ir(I) complexes in Table 1. Deborylations
using conditions in Table 2 gave clear solutions, and catalysis was not inhibited when a
drop of Hg was added to the reaction mixtures, which supports deborylation by
homogeneous species.
Scheme 3. Proposed mechanism for deuterodeborylation.
Ar
D
IrLn OR
IrLn Ar
Ar BPin
deuterolysis
transmetalation
PinB OR
RO
R = H, CH
D
3
The fact that the relative reactivities in deborylation reactions parallel the reactivities
of the parent arenes towards borylation suggested that in cases where sequential
diborylation is observed, the products would deborylate selectively at the position that
was the first site of borylation. If this proved to be the case, the product of
diborylation/deborylation would be a different regioisomer of the product of direct C–H
borylation.
To test this hypothesis, deborylation of a number of diborylated heterocycles was
examined and the results are shown in Table 3. For these more reactive substrates milder
3
conditions were employed than those used in Table 1 and CH OH was used as the proton
source. For 9 of the 10 substrates, the site of monoborylation in the parent heterocycle is
indeed the site of deborylation in the diborylated compounds. The lone exception is 3-
cyanothiophene (entry 10), where monoborylation gives a mixture of 2 and 5-borylated
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compounds. In this case, the high selectivity for deborylation at the 3-position of the
diborylated product is the key to synthesizing isomerically pure 5-borylated product.
a
Table 3. Synthesis of monoborylated compounds via diborylation/deborylation.
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H
Bpin
monoborylation
diborylation
substrate
substrate
H
H
Bpin
H
1.5 mol% [Ir(OMe)(cod)]2
MeOH/CH Cl (2:1), 55-60 °C
substrate
substrate
2
2
pinB
entry
pinB
b
diborylated compound
product
time, yield
Bpin
H
Bpin
H
N
N
1
2
3
4
Bpin
0.75 h, 68%
CH3
CH3
Bpin
H
Bpin
H
N
N
1 h, 85%
1.75h, 83%
2 h, 58%
Bpin
CN
CN
Bpin
Bpin
H
N
H
N
Bpin
Br
Br
Bpin
H
Bpin
H
N
N
Bpin
NHBoc
NHBoc
CO Me
CO Me
2
2
Boc
N
Boc
N
N
S
S
S
N
5
4h, 49%
pinB
NC
pinB
Bpin
S
Bpin
Bpin
Bpin
NC
6c
5.5 h, 75%
10 h, 80%
pinB
pinB
S
Br
Br
7c
pinB
pinB
S
H C
H C
3
3
8c
5h, 72%
pinB
Cl
pinB
Cl
S
S
S
Bpin
Bpin
9c
0.5 h, 60%
5 h, 58%
pinB
Bpin
pinB
S
Bpin
1
0d
NC
NC
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a
Except as where noted reactions were carried out with pure diborylated starting
b
c
materials. Time refers to the deborylation step. One-pot synthesis from starting
thiophene. Monoborylation of 3-cyanothiophene catalyzed by [IrOMe(cod)]
gives a 1.1:1 ratio of 2- and 5-borylated isomers.
d
2
/dtbpy
Several of the results in Table 3 merit comment. For the indole substrates,
diborylation/deborylation affords the 7-borylated products, which have previously been
prepared by a relay-directed reaction of N–silylated indoles, which are in turn prepared in
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0
3
2
a Ru-catalyzed reaction from the parent indole and a disilane. After Ir-catalyzed C–H
borylation, the silane deprotection yields the 7-borylated product.
Diborylation/deborylation obviates the need for N-protection/deprotection. Entries 4 and
utilize Boc protected compounds and demonstrate that, as is the case for Ir-catalyzed
5
C–H borylation, Boc protecting groups are compatible with Ir-catalyzed deborylation.
Diborylation/deborylation of 2-halogenated thiophenes provide unique halogenated
building blocks. Synthesis of these compounds by lithiation would not be feasible
because halogenated heteroaryl lithium compounds undergo “ halogen dance ”
33
rearrangements. The fact that 3- or 5-borylated isomers of 2-halogenated thiophenes can
be accessed is a testament to the mild conditions of these Ir-catalyzed processes. We note
that reaction times for Table 3, entry 1 were particularly sensitive to the quality of the
MeOH used in the deborylation, with lower grade reagent requiring substantially longer
reaction times.
In Movassaghi and co-worker’s recent report, a mechanism involving indole
2
0
protonation is proposed with no role invoked for the metal. Three procedures were
described in their paper. In the first (condition A), diborylation of 3-substituted indoles is
carried out with 5.0 equiv HBpin catalyzed by 2.5 mol % [Ir(OMe)(cod)]
2
and 5 mol %
Cl and
dtbpy in THF. After diborylation is completed, the reaction is diluted with CH
2
2
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trifluoroacetic acid (TFA) is added at 0 °C. The reaction is allowed to warm to 23 °C and
quenched when the monoborylated product is maximized. In the second procedure
(
condition B), N-2-(1H-Indol-3-yl)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide was
diborylated under Ir-catalyzed conditions. The crude product was purified by flash
chromatography. The pure material was then dissolved in CH Cl and deborylation was
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2
carried out with TFA. In the third set of conditions (condition C), diborylation is carried
out under Ir-catalyzed conditions. Afterwards, volatile materials are removed, the crude
2
mixture is dissolved in acetic acid, and 5 mol % Pd(OAc) is added to effect
deborylation. It is important to note that metal (Ir and/or Pd) is present during the
deborylation.
To assess the role of the metal, we carried out a set of experiments. First we repeated
Movassaghi and co-worker’s synthesis of 7-borylated 3-methylindole using condition A,
and obtained similar results. Next, we attempted metal-free deborylation of pure 2,7-
2 2
diborylated 3-methylindole with TFA in CH Cl . After the same reaction time as the
procedure with conditions A called for, an aliquot was taken and volatile materials were
1
removed. In contrast to the case for condition A, H NMR spectra revealed a complex
mixture with multiple resonances in the aromatic region. Next, we compared
deborylations of isolated 2,7-diborylated 3-methylindole with acetic acid catalyzed by
2 2
either 2.5 mol % [Ir(OMe)(cod)] or 5 mol % Pd(OAc) . After 8 h at 30 °C, aliquots from
1
the reactions were analyzed by H NMR spectroscopy by integrating the NH resonances
that are resolved and shifted downfield from the NH resonance of 3-methylindole. For the
Ir-catalyzed reaction the ratio of 7-borylated to 2,7-diborylated species was 75:25. For the
Pd-catalyzed reaction, a third species was observed with an NH resonance at δ 9.38 ppm.
1
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2
2
2
2
2
2
2
2
3
3
3
3
3
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1
2
This product increased when the Pd(OAc) loading was increased. In the H NMR
spectrum, the NH chemical shift is consistent with an indole whose NH is flanked by one
or two Bpin groups and the splitting pattern of the C6 ring protons is similar to that for
the diborylated indole. LC/MS spectra revealed molecular ion at m/z = 513.064, which is
consistent with a homocoupled bisindole. In conjunction with the NMR data, we assign
this byproduct to structure 1 (eq 1). Attempts to separate 1 from the indole products were
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
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unsuccessful. At a 5% loading of Pd(OAc)
2
, deborylation with acetic acid at 30 °C for 8
h, the ratio of 7-borylated, 2,7-diborylated, to the homocoupled bisindole species was
9
5:2:3 (average of three runs). This suggests that the first step in the deborylation
0
reaction is homocoupling of the indole to generate Pd . For Pd-catalyzed deborylation of
the crude diborylated indole that results from Ir-catalyzed C–H borylation, only traces of
1
the homocoupled bisindole are found in H NMR spectra. This is an added advantage of
the one-pot transformation.
Pd0 + 2 pinBOAc +
Bpin
H
N
2
Bpin + Pd(OAc)2
Bpin
(1)
H C
3
H
N
CH3
N
H
CH3
Bpin
1
To complete the comparison of Pd and Ir-catalyzed chemistries, deborylation of the
diborylated product of 3-methylindole was carried out with 3 mol % Pd(OAc) in
MeOH/CH Cl (2:1) at 60 °C for 3 h. Conversion to 7-borylated 3-methylindole (17%)
2
2
2
and along with 3% 3-methylindole shows that under these conditions Pd is less efficient
than Ir at facilitating deborylation. The superior performance of the Ir-catalyzed reactions
under these conditions makes them better suited for molecules with acid sensitive groups.
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Pd-catalyzed deborylations of the diborylated thiophenes in entries 6, 8, and 10 of
Table 3 were carried out in acetic acid with 5 mol % Pd(OAc)
Movassaghi’s conditions, and with 3 mol % Pd(OAc) in MeOH/CH
to compare to Ir catalyzed reactions in Table 3. The results are shown in Table 4. While
the reactions in MeOH/CH Cl gave the highest conversions for the Pd-catalyzed
2
at 30 °C, to compare to
2
2
Cl (2:1) at 55 °C,
2
10
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2
2
reactions, they were less efficient and in the case of the diborylated product of 3-
cyanothiophene, less selective than the corresponding deborylations with Ir (Table 3).
Table 4. Pd-catalyzed deborylation of diborylated thiophenes
entry
1
reactant
S
Pd(OAc) loading, T,
product
(% conversion)
2
solvent, time
S
NC
Bpin
Bpin
Bpin
NC
pinB
pinB
5
mol %, 30 °C,
AcOH, 23 h
1
1%
3mol %, 55 °C,
1
5%
MeOH/CH Cl , 5.5 h
2
2
S
pinB
NC
S
S
pinB
NC
Bpin
2a
NC
5
mol %, 30 °C,
AcOH, 23 h
8%
7%
14%
42%
3mol %, 55 °C,
MeOH/CH Cl , 5 h
2
2
S
S
H C
H C
3
3
3
pinB
pinB
5
mol %, 30 °C,
AcOH, 23 h
5
9%
9%
3
mol %, 55 °C,
3
MeOH/CH Cl , 5.5 h
2
2
a
The diborylated thiophene rapidly deborylates to the 5-borylated product when
washed with saturated NaHCO solutions.
3
The conditions for C-H activation/borylation are sufficiently mild for late stage of
advanced molecules like pharmaceuticals. This is illustrated in Scheme 4 where
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1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
clopidogrel (2), the active ingredient of Plavix, is selectively borylated at the 5-position
of its thiophene ring to afford (3). Deuterodeborylation of borylated clopidogrel confirms
the site of borylation and provides a probe for the stereospecificity of the borylation (and
deborylation) reactions. As shown in Scheme 4, Ir-catalyzed deuterodeborylation can be
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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4
5
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
achieved at 55 °C in 2:1 CD
3 3
OD/CDCl with 92% deuteration at the 5-position of the
thiophene ring, confirming the site of borylation. Moreover, the 5-deuterated clopidogrel
3
4
showed no loss of optical rotation when compared to unlabeled clopidogrel. Thus, both
the borylation and deborylation proceed with a high degree of stereospecificity. This is
significant as synthesis of borylated clopidogrel by ortholithiation and subsequent
3
5
trapping with boron electrophiles gives racemic product.
To demonstrate the potential for diborylation/deborylation in complex substrates, we
return again to clopidogrel (Scheme 5). With a moderate excess of HBpin, clopidogrel is
smoothly borylated at the thiophene and arene rings affording diborylated isomers 4a,b
due to competitive borylation at the 4 and 5-positions of the arene ring. This isomer
mixture undergoes regioselective deborylation at the thiophene moiety to produce the
monoborylated isomers 5a,b in Scheme 5 in excellent yield. The results in Scheme 4 and
5
further demonstrate the potential for Ir-catalyzed borylations and deborylations in the
2
8
late stage functionalization of complex molecules.
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Scheme 4. Borylation/deuterodeborylation of clopidogrel.
Bpin
S
1
.5 equiv HBpin
S
1
.5 mol% [Ir(OMe)(COD)]
3 mol% dtbpy
2
MeO C
N
2
MeO C
N
2
MTBE, r.t., 1.25 h
Cl
Cl
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59
60
2
3
clopidogrel,
5
6% yield
API in Plavix™
Bpin
S
D
S
3
mol% [Ir(OMe)(COD)]
CD OD/CDCl (2:1),
2
MeO C
N
MeO C
N
2
2
3
3
5
5 °C, 2.5 h
Cl
Cl
2
-d1
8
1% yield
2 % D-incorporation
no change in optical rotation
9
Scheme 5. Diborylation/deborylation of clopidogrel.
Diborylation
Bpin
S
3
.0 equiv HBpin
S
3
mol% [IrOMe(cod)]2
6 mol% dtbpy
MeO C
N
2
MeO C
N
2
Cl
MTBE, r.t., 30 h
Cl
Bpin
4
a,b
7
7% yield,
Deborylation
Cl
1
:1 isomer ratio
CO Me
2
3
mol% [IrOMe(cod)]2
N
Bpin
S
MeOH/CH Cl , 55 °C, 5 h
Bpin
2
2
Cl
CO Me
Cl
CO Me
2
2
N
N
+
S
S
Bpin
Bpin 5a
5b
80% yield, 1:1 isomer ratio
Conclusions
In summary, we have shown that Ir-catalyzed deborylation can be utilized to
isotopically label unactivated C–H positions of arenes selectively. In addition,
deborylation can be coupled to diborylation to prepare monoborylated compounds where
the regioselectivities complement those found for monoborylation of the parent
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2
2
2
2
2
2
2
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5
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substrates. The Ir-catalyzed deborylations of 2-borylated indoles are slower than Pd-
catalyzed reactions reported by Movassaghi, but are superior for deborylations of arenes
and thiophenes. In contrast to Brønsted acid and base mediated deborylations, the Ir-
catalyzed deborylations are not limited by substrate electronics. The mild conditions of
Ir-catalyzed borylations and deborylations make applications to complex substrates
0
1
2
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0
3
6
possible, where other methods for deborylation would result in unwanted side reactions.
Experimental Section
5
2 2
Pinacolborane (HBPin) and B pin were generously supplied by BoroPharm, Inc. (η -
4
37
4
indenyl)(η -1,5-cycloodtadiene)iridium ((Ind)Ir(cod)), Bis(η -1,5-cyclooctadiene)-di-
3
8
31
6
µ-methoxy-diiridium(I) ([Ir(OMe)(cod)]
2
),
(dtbpy)Ir(coe)(Bpin)
3
,
and (η -
3
9
6 6 3
C H )Ir(Bcat)
were prepared per the literature procedures. 4,4′-Di-t-butyl-2,2′-
bipyridine (dtbpy) was purchased from Aldrich. IrCl
3
•(H
2
x
O) was purchased from
–
Pressure Chemical Co. and [Ir((PCy
3
)(py)(cod)][PF
6
] was purchased from Strem
Chemicals, Inc. Diborylated N-Boc-7-azaindole and diborylated N-Boc-L-tryptophan
4
0
methyl were prepared according to the literature procedure. All substrates were purified
by column chromatography or passing through a plug of alumina. Pinacolborane (HBPin)
was distilled before use. n-Hexane, cyclohexane and MTBE were refluxed over sodium,
2 2
distilled, and degassed. Tetrahydrofuran and CH Cl were obtained from a dry still
packed with activated alumina and degassed before use. Silica gel was purchased from
EMD™ (230-400 Mesh).
All reactions were monitored by GC-FID (column type: Fused silica 30m × 0.25mm
ID coating CP-SIL 8 CB). GC-FID method: 70 °C, 2 min.; 20 °C/min, 9 min.; 250 °C, 10
or 20 min.; All reported yields are for isolated materials unless otherwise stated.
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H and C NMR spectra were recorded at 300.11 and 75.47 MHz, respectively, or
4
99.74 and 125.67 MHz, respectively, and referenced to residual solvent signals (7.24
1
1
ppm and 77.0 ppm for CDCl
3
, respectively. B spectra were recorded at 96.29 MHz and
10
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were referenced to neat BF
3
•Et O as the external standard. All coupling constants are
2
apparent J values measured at the indicated field strengths. All 2-dimensional
experiments were run using z-axis pulse field gradients. GC-MS data were obtained using
fused silica 30m × 0.25mm ID columns coated with CP-SIL 8 CB. Melting points were
measured on a capillary melting apparatus and are uncorrected. Optical rotations were
recorded at the sodium D line.
General Procedure for C–H Borylation with diphosphine ligands. In the glove
box, arene, HBpin (1.5-2.5 equiv), (Ind)Ir(cod) (2 mol%), and dmpe/dppe (2 mol%) were
transferred into an air-free flask equipped with a stirrer bar in the following order: HBpin
with Ir calatyst, followed by ligand, followed by arene. 0.5-2 mL (per mmol of arene)
solvent (cyclohexane, n-hexane, heptane, or octane) could be used to help dissolution and
transfer. The flask was sealed and brought out of the glove box and placed in an oil bath
heated to 150 °C (for (Ind)Ir(cod)/dmpe) or 100 °C (for (Ind)Ir(cod)/dppe) until the
reaction was judged complete by GC-FID. (Note: in the cases of multiple borylations
2
and borylations of sluggish substrates, periodic cooling and purging of the H gas help to
maintain an effective rate of reaction.) At that time the reaction was allowed to cool to
room temperature. Upon stirring, the residue was quenched by dropwise addition of
MeOH until gas evolution ceased. The mixture was concentrated by a gentle nitrogen
flow and the resultant syrup was passed through a silica plug (10-15 cm long, 2 cm wide
2 2 2 2
for 1-2 mmol scale, CH Cl or hexanes/CH Cl ) to give the desired boronic ester.
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2
2
2
2
2
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3
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4
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4
4
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5
5
5
5
5
5
5
5
5
6
2
General procedure for borylation with [Ir(OMe)(cod)] and dtbpy. Two separate
test tubes were charged with [Ir(OMe)(cod)]
2
and dtbpy. Excess HBPin was added to the
pin was used as the borylating agent, HBPin
3 x Ir mol%) was used to generate active catalyst. n-Hexane or cyclohexane or MTBE (1
[
Ir(OMe)(cod)]
2
test tube. In cases where B
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
mL) was added to the dtbpy containing test tube in order to dissolve the dtbpy. The dtbpy
solution was then mixed with the [Ir(OMe)(cod)] and HBPin mixture. After mixing for
2
one minute, the resulting solution was transferred to Schlenk flask equipped with a
magnetic stirring bar. Additional n-hexane or cyclohexane or MTBE (2 × 1 mL) was used
to wash the test tubes and the washings were transferred to the Schlenk flask. Substrate (1
mmol, 1 equiv.) was added to the Schlenk flask. The flask was stoppered, brought out of
the glove box, and attached to the Schlenk line in a fume hood. The Schlenk flask was
2
placed under N and the reaction was carried out at the specified temperature. The
reaction was monitored by GC-FID/MS. After completion of the reaction, the volatile
materials were removed on a rotary evaporator. The crude material was purified by
column chromatography or dissolved in CH
General Procedure for the Borylation of Arenes. In a glovebox, in an air-free flask,
Ir(OMe)COD] (1 mol %), dtbpy (2 mol %), HBPin (1.8 equiv.), and the substrate (11
2 2
Cl and passed through a plug of silica.
[
2
mmol) were combined neat or in cyclohexane. The flask was sealed, brought out of the
dry box, and heated to a temperature depending on the substrate until GC/MS indicated a
complete reaction. The reaction was pumped down to obtain the crude product, which
was purified by column chromatography (CH
General Procedure for Preparation of Deuterated Aromatics via C–H
Borylation/Deuteration with D O. A borylation reaction with 2 mmol arene was set up
2 2
Cl ) to afford the pure product.
2
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and monitored by GC-FID until judged complete. Solvent for this borylation, if any, was
removed by a gentle nitrogen flow. The residue was placed under high vacuum for a few
hours and the flask was back filled with nitrogen. To the reaction were added 0.5 mL
10
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D
2
O and 3-4 mL dry THF or DME. The flask was resealed and heated in an oil bath to
150 °C until the reaction was judged complete by GC-FID. Upon completion, the
mixture was poured into water and extracted with pentane (or CH Cl if the product has
low solubility in pentane), dried over MgSO , filtered, and evaporated. Column
chromatography (pentane or CH Cl ) afforded the product.
2
2
4
2
2
For deuteration of isolated boronic acids/esters, 2 mmol aryl boronic acid/ester and
the Ir catalyst (0.02 mmol, 2 mol %) were dissolved in 3-4 mL THF or DME in the glove
box and transferred into an air-free flask equipped with a stirrer bar. The flask was
2
sealed and brought out of the dry box and charged with 0.5 mL D O. It was resealed and
heated in an oil bath to 150 °C until the reaction was judged complete by GC-FID, and
worked up as described in the general procedure.
General Procedure for the Deuteration of Aryl Boronic Esters with D
glovebox, in an air-free flask, [Ir(OMe)(cod)] (2 mol %) and the aryl boronic ester (2
mmol) were combined in THF (3 mL). The flask was sealed and brought out of the box
where it was charged with D O (0.5 mL). The flask was resealed and heated at 80 °C
until the reaction was judged to be complete by GC/MS. When the reaction was
complete, it was poured into water and extracted with CH Cl , Et O, or pentane, dried
over MgSO , filtered, and concentrated. Purification by Kugelrohr distillation,
sublimation, or column chromatography afforded the pure product.
2
O. In the
2
2
2
2
2
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General procedure for deborylation with MeOH. A Schlenk flask equipped with a
magnetic stirring bar and condenser was charged with substrate (1.0 mmol, 1.0 equiv)
2
and [Ir(OMe)(cod)] (10 mg, 0.015 mmol, 3 mol% Ir). The Schlenk flask was then
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0
evacuated and backfilled with nitrogen (this sequence was carried out two times). Solvent
mixture (methanol/dichloromethane 2:1, 5 mL) was added to the Schlenk flask and
flushed under nitrogen twice as mentioned previously. The Schlenk flask was placed
2
under N and the reaction was carried out at the specified temperature. The reaction was
monitored by GC-FID/MS. After completion of the reaction, the volatile materials were
removed on a rotary evaporator. The crude material was purified by column
2 2
chromatography or dissolved in CH Cl and passed through a plug of silica.
General Procedure for one-pot diborylation/deborylation. The Ir-catalyst was
generated as follows: in a glove box, two separate test tubes were charged with
[
2
Ir(OMe)(cod)] (10 mg, 0.015 mmol, 3 mol% Ir) and dtbpy (8 mg, 0.03 mmol, 3 mol%).
2
Excess HBPin (2.5 to 3 equiv.) was added to the [Ir(OMe)(cod)] test tube. n-Hexane (1
t
mL) was added to the d bpy containing test tube in order to dissolve the dtbpy. The dtbpy
2
solution was then mixed with the [Ir(OMe)(cod)] and HBPin mixture. After mixing for
one minute, the resulting solution was transferred to Schlenk flask equipped with a
magnetic stirring bar. Additional n-hexane (2 × 1 mL) was used to wash the test tubes
and the washings were transferred to the Schlenk flask. Substituted thiophene (1 mmol, 1
equiv.) was added to the Schlenk flask. The reaction was stirred at room temperature and
was monitored by GC-FID/MS. After completion of the reaction, the volatile materials
were removed and 5 mL of CH
3 2 2
OH/CH Cl mixture (2:1) was added and heated at 55 °C.
The reaction was monitored by GC-FID/MS and after completion of the reaction, the
2
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volatile materials were removed on a rotary evaporator. The crude material was purified
by column chromatography or dissolved in CH
Small amounts of impurities, if present, were removed by crystallization.
,2-Dichlorobenzene-4-d. The borylation step was carried out neat with 295 mg 1,2-
dichlorobenzene (2 mmol) and 365 mg HBpin (2.85 mmol, 1.4 equiv), 16.6 mg
Ind)Ir(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) at 150 °C for
.5 h. The crude borylation mixture was pumped down under high vacuum and charged
with 0.5 mL D O and 3 mL THF. The deuteration step was then carried out at 150 °C for
0 min and worked up as described in the general procedure, after which the crude
2 2
Cl and passed through a plug of silica.
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54
55
56
57
58
59
60
1
(
3
2
3
material was purified with a silica gel chromatography (pentane) to afford 220 mg of the
1
deuterated compound (74%) as a colorless oil. H NMR (300 MHz, CDCl
3
): d 7.41-7.44
2
13
(
m, 2 H), 7.16-7.20 (m, 1 H); H NMR (76.75 MHz, pentane): d 7.21; C NMR (125
MHz, CDCl ): d 132.6, 130.5, 130.4, 127.6, 127.4 (t, JC-D = 25 Hz); IR (neat): 3063,
3
-
1
+
1
7
564, 1455, 1385, 1125, 1034, 901, 835, 731, 648 cm ; LRMS (EI): m/e 147 (M ), 112,
+
6. HRMS (EI) m/e calcd for [C
Synthesis of 5-Bpin-1,2,3-trichlorobenzene. The reaction was carried out neat
with 1,2,3-trichlorobenzene (11 mmol, 2.00 g), [Ir(OMe)(cod)] (1 mol %, 0.11 mmol, 73
6 3 2
H DCl ] 146.9753, found 146.9759.
4
1
2
mg), dtbpy (2 mol %, 0.22 mmol, 59 mg), and HBPin (19.8 mmol, 2.5 g). The reaction
stirred at 80 °C for 2 h. The crude product was purified as outlined in the general
1
procedure to afford the pure product (3.07 g, 91%) as a white solid; mp 94-97 °C. H
1
3
NMR (500 MHz, CDCl
3
): δ 7.25 (s, 2H), 1.34 (s, 12H); C NMR (125 MHz, CDCl
3
): δ
1
1
1
34.4, 134.1, 133.9, 84.7, 24.8; B NMR (160 MHz, CDCl
3
): δ 30.1; FT-IR (KBr): 2989,
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-1
2
931, 1583, 1533, 1450, 1370, 1342, 1147, 1121, 965, 882, 847, 799, 703, 673, 555 cm ;
-
-
3 3
HRMS (ESI) m/z Calcd for C12H15BCl O [M+ OH] 323.0182, found 323.0185.
1
,2,3-Trichlorobenzene-5-d. The borylation step was carried out neat with 364 mg
,2,3-trichlorobenzene (2 mmol) and 450 mg HBpin (3.6 mmol, 1.8 equiv), 16.6 mg
(Ind)Ir(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) at 150 °C for
.25 h. The crude borylation mixture was pumped down under high vacuum and charged
with 0.5 mL D O and 3 mL THF. The deuteration step was then carried out at 150 °C for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
2
60 min and worked up as described in the general procedure, after which the crude
material was purified with a silica gel chromatography (pentane) to afford 343 mg of the
deuterated compound (94%) as a white solid; mp 52-53 °C (53-55 °C for commercial
1
2
non-deuterated compound). H NMR (500 MHz, CDCl
3
): d 7.36 (t, JH-D = 1.1 Hz); H
13
NMR (76.75 MHz, pentane): d 7.14; C NMR (125 MHz, CDCl
3
): d 134.3, 131.6, 128.6,
1
27.2 (t, JC-D = 25 Hz); IR (neat): 3071, 1553, 1412, 1385, 1196, 1159, 899, 768, 666
-
1
+
cm ; LRMS (EI): m/e 181 (M ), 146, 110. Anal. Calcd for C
9.06.
1,2,3-Trichlorobenzene-5-d (Alternative Procedure). The deuteration was carried
out in THF and D O as outlined in the general procedure with 5-Bpin-1,2,3-
trichlorobenzene (2 mmol, 614 mg) and [Ir(OMe)(cod)] (2 mol %, 0.04 mmol, 26.4
mg). The reaction was heated at 80 °C for 2 h. When the reaction was complete, it was
poured into water and 1 M NaOH. The product was extracted into CH Cl , dried over
MgSO , and concentrated. The crude product was purified by passing it through a short
silica column (CHCl ) to afford the deuterated compound as a white solid (292 mg,
0%); mp 52-54 °C. Approximately 3-4 % of the isolated deuterium compound was
6 2 3
H DCl : C, 39.50. Found C,
3
2
2
2
2
4
3
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,2,3-trichlorobenzene-4-d as determined by H NMR and confirmed by H NMR. Due to
spectral overlap, deconvolution of the spectra was necessary to extract accurate
integration. There was also approximately 3-4 % of 4-Bpin-1,2,3-trichlorobenzene
10
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14
15
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49
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59
60
1
observed in the isolated borylated starting material. H NMR (500 MHz, CDCl
3
): δ 7.36
2
13
(apparent t, JH-D = 1.0 Hz, 2H); H NMR (76.75 MHz, CH
2
Cl
2
): δ 7.18; C NMR (125
3
MHz, CDCl
3
): δ 134.3 (t, JC-D = 1.76 Hz), 131.5, 128.6, 127.2 (t, JC-D = 25 Hz); LRMS
+
+
(
EI): m/z 181 (M ); HRMS (EI): m/z calculated for [C
6
H
2
DCl
3
] 180.9363, found
1
3
180.9365. Percent D incorporation (based on quantitative C NMR): >98.1%
23
Synthesis of 4-Bpin-2,6-dichloropyridine. The reaction was carried out in
cyclohexane (20 mL) with 2,6-dichloropyridine (11 mmol, 1.63 g), [Ir(OMe)(cod)]
mol %, 0.11 mmol, 73 mg), dtbpy (2 mol %, 0.22 mmol, 59 mg), and HBPin (19.8 mmol,
.5 g). The reaction stirred at 80 °C for 1 h. The crude product was purified as outlined in
the general procedure to afford the pure product (2.65 g, 88%) as a white solid; mp 114-
17 °C. Spectral data matched the reported data.
,6-Dichloropyridene-4-d. The borylation step was carried out with 300 mg 2,6-
dichloropyridene (2 mmol) and 450 mg HBpin (3.6 mmol, 1.8 equiv), 16.6 mg
Ind)Ir(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) in 1 mL
2
(1
2
1
2
(
heptane at 150 °C for 3.25 h. After removal of heptane by a gentle nitrogen flow, the
crude borylation mixture was pumped down under high vacuum and charged with 0.5 mL
D
2
O and 3 mL THF. The deuteration step was then carried out at 150 °C for 60 min and
worked up as described in the general procedure, after which the crude material was
purified with a silica gel chromatography (CH Cl ) to afford 273 mg of the deuterated
compound (92%) as a white solid; 84-86 °C (86-88.5 °C for commercial non-deuterated
2
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6
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2
compound). H NMR (500 MHz, CDCl
3
): d 7.25 (t, JH-D = 1.1 Hz); H NMR (76.75
): d 7.65; C NMR (125 MHz, CDCl ): d 150.6, 140.4 (t, JC-D = 25 Hz),
22.7; IR (neat): 3050, 2269, 1559, 1547, 1373, 1136, 986, 901, 739, 702 cm ; LRMS
1
3
MHz, CH
2
Cl
2
3
-
1
1
0
1
2
3
4
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8
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(
EI): m/e 148 (M ), 113. Anal. Calcd for C
N, 8.80.
,6-dichloropyridine-4-d (Alternative Procedure). The deuteration was carried out
in THF and D O as outlined in the general procedure with 4-Bpin-2,6-dichloropyridine (2
mmol, 496 mg) and [Ir(OMe)(cod)] (2 mol %, 0.04 mmol, 26.4 mg). The reaction was
heated at 80 °C for 2 h. When the reaction was complete, it was poured into water, and
the product was extracted into Et O, dried over MgSO , and concentrated. The crude
5 2 2
H DNCl : C, 40.31; N, 9.40. Found C, 40.34;
2
2
2
2
4
product was purified by sublimation (0.08 mm Hg/ 45 °C) to afford the deuterated
1
compound as a white solid (244 mg, 82%); mp 85-88 °C. H NMR (500 MHz, CD
2
2
Cl ): δ
2
13
7
.36 (t. JH-D = 1.0 Hz, 2H); H NMR (76.75 MHz, CH
2
Cl
2
): δ 7.61; C NMR (125 MHz,
3
CDCl
3
): δ 150.6 (t, JC-D = 1.71 Hz), 140.4 (t, JC-D = 25 Hz), 122.8; LRMS (EI): m/z 148
+
+
(
5 3 2
M ); HRMS (ESI+): m/z calculated for [C H DCl N] 148.9783, found 148.9792.
1
3
Percent D incorporation (based on quantitative C NMR): 96.3%
Synthesis of 5-Bpin-3-chlorobenzotrifluoride. The reaction was carried out neat
2
with 3-chlorobenzotrifluoride (11 mmol, 1.98 g), [Ir(OMe)(cod)] (1 mol %, 0.11 mmol,
73 mg), dtbpy (2 mol %, 0.22 mmol, 59 mg), and HBPin (19.8 mmol, 2.5 g). The reaction
stirred at 80 °C for 1 h. The crude product was purified as outlined in the general
1
procedure to afford the pure product (3.10 g, 92%) as a clear, colorless oil. H NMR (500
1
3
MHz, CDCl
MHz, CDCl
3
): δ 7.91 (d, 2H, J = 8.2 Hz), 7.65 (s, 1H), 1.33 (s, 12H); C NMR (125
2
3
3
): δ 137.9, 136.9, 134.5, 131.7 (q, JC-F = 33 Hz), 129.4 (q, JC-F = 3.8 Hz),
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27.9 (q, JC-F = 3.9 Hz), 123.4 (q, JC-F = 272 Hz), 84.6, 24.8; B NMR (160 MHz,
3
CDCl ): δ 30.1; FT-IR (KBr): 2982, 2933, 2873, 1611, 1367, 1296, 1172, 1140, 965, 887,
-
1
-
-
8
47, 823, 724, 706, 685 cm ; HRMS (ESI) m/z Calcd for C13
23.0836, found 323.0835.
3-Chlorobenzotrifluoride-5-d. The borylation step was carried out with 363 mg 3-
chlorobenzotrifluoride (2 mmol) and 450 mg HBpin (3.6 mmol, 1.8 equiv), 16.7 mg
Ind)Ir(cod) (0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) in 2 mL
3 3
H16BClF O [M+ OH]
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59
60
3
(
cyclohexane at 150 °C for 3 h. After removal of cyclohexane by a gentle nitrogen flow,
the crude borylation mixture was pumped down under high vacuum and charged with 0.5
2
mL D O and 3 mL THF. The deuteration step was then carried out at 150 °C for 90 min
and worked up as described in the general procedure, after which the crude material was
purified with a silica gel chromatography (pentane) to afford 244 mg material containing
2
39 mg of the deuterated compound (66%) and 5 mg pentane. Continuing evaporation
1
afforded pure deuterated compound (some loss of product occurred) as a colorless oil. H
2
NMR (300 MHz, CDCl
3
): d 7.60 (br, 1 H), 7.50-7.51 (br, 2 H); H NMR (76.75 MHz,
1
3
pentane): d 7.45; C NMR (125 MHz, CDCl
29.9 (t, JC-D = 25 Hz), 125.7 (q, JC-F = 4 Hz), 123.3 (q, JC-F = 4 Hz), 123.3 (q, JC-F = 272
Hz); IR (pentane solution film): 3087, 1576, 1426, 1310, 1175, 1134, 1103, 1161, 887,
3
): d 135.0, 132.3 (q, JC-F = 34 Hz), 131.9,
1
-
1
+
708, 677 cm ; LRMS (EI): m/e 181 (M ), 162, 146. HRMS (EI): m/e calcd for
+
[C
7
H
3
DClF
3
-Cl] 146.0328, found 146.0330.
3
-Chlorobenzotrifluoride-5-d (Alternative Procedure). The deuteration was
carried out in THF and D O as outlined in the general procedure with 5-Bpin-3-
chlorobenzotrifluoride (2 mmol, 615 mg) and [Ir(OMe)(cod)] (2 mol %, 0.04 mmol,
2
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6.4 mg). The reaction was heated at 80 °C for 2 h. When the reaction was complete, it
was poured into water and 1 M NaOH. The product was extracted into Et
MgSO , and concentrated. The crude product was purified by passing it through a short
silica column (CHCl ) to afford the deuterated compound as a clear oil (236 mg, 65%).
THF (2.2 mg) and Et
2
O, dried over
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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0
1
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4
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0
1
2
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4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
3
1
2
O were observed in the C NMR and H NMR spectra
respectively. But, owing to the volatility of the compound, it could not be removed,
1
because of the risk of loss of the product. H NMR (500 MHz, CDCl
3
): δ 7.60 (br s, 1H),
2
13
7.51 (d, J = 7.2 Hz, 2H); H NMR (76.75 MHz, CH
2
Cl
2
): δ 7.42; C NMR (125 MHz,
3
2
3
CDCl
3
): δ 134.9 (t, JC-D = 1.7 Hz), 132.3 (dq, JC-F = 33 Hz, JC-D = 1.3 Hz), 131.9 (q,
4
3
3
1
J
C-F = 1.2 Hz), 129.9 (t, JC-D = 25 Hz), 125.7 (q, JC-F = 4 Hz), 123.33 (q, JC-F = 272.5
3
+
Hz), 123.32 (q, JC-F = 3.9 Hz); LRMS (EI): m/z 181 (M ). Percent D incorporation
13
(based on quantitative C NMR): 98.1%
4
2
Synthesis of 5-Bpin-3-bromobenzonitrile. The reaction was carried out neat with
3
-brmobenzonitrile (11 mmol, 2.00 g), [Ir(OMe)(cod)] (1 mol %, 0.11 mmol, 73 mg),
2
dtbpy (2 mol %, 0.22 mmol, 59 mg), and HBPin (19.8 mmol, 2.5 g). The reaction stirred
at 50 °C for 2.5 h. The crude product was purified as outlined in the general procedure to
afford the pure product (3.04 g, 90%) as a white solid; mp 83-86 °C. Spectral data
matched the reported data.
3-Bromobenzonitrile-5-d. The borylation step was carried out with 364 mg 3-
bromobenzonitrile (2 mmol) and 400 mg HBpin (3.1 mmol, 1.55 equiv), 20.0 mg
t
[Ir(OMe)(cod)]
2
(0.03 mmol, 1.5 mol%) and 16.0 mg d bpy (0.06 mmol, 3 mol%) in 2
mL heptane at room temperature for 6 h. After removal of heptane by a gentle nitrogen
flow, the crude borylation mixture was pumped down under high vacuum and charged
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with 0.5 mL D
2
O and 3 mL THF. The deuteration step was then carried out at 150 °C for
2
h and worked up as described in the general procedure, after which the crude material
was purified with a silica gel chromatography (CH Cl ), followed by a sublimation at 45-
0 °C under 0.1 mmHg to afford 257 mg of the deuterated compound (70%) as a white
2
2
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
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41
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44
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50
51
52
53
54
55
56
57
58
59
60
5
1
solid; mp 37-39 °C (38-40 °C for commercial non-deuterated compound). H NMR (500
2
MHz, CDCl
NMR (76.75 MHz, CH
130.3 (t, JC-D = 25 Hz), 122.8, 117.2, 114.2; IR (neat): 3075, 2234, 1553, 1429, 1406,
3
): d 7.78 (apparent t, J = 1.6 Hz, 1 H), 7.73 (br, 1 H), 7.59 (br, 1 H); H
1
3
2
2 3
Cl ): d 7.39; C NMR (125 MHz, CDCl ): d 136.0, 134.7, 130.5,
-1
+
1
186, 909, 882, 785, 675 cm ; LRMS (EI): m/e 182 (M ), 103. Anal. Calcd for
DNBr: C, 45.94; N, 7.65. Found C, 45.70; N, 7.53.
3-Bromobenzonitrile-5-d (Alternative Procedure). The deuteration was carried out
in THF and D O as outlined in the general procedure with 5-Bpin-3-bromobenzonitrile (2
mmol, 616 mg) and [Ir(OMe)(cod)] (2 mol %, 0.04 mmol, 26.4 mg). The reaction was
heated at 80 °C for 2 h. When the reaction was complete, it was poured into water and 1
M NaOH. The product was extracted into CH Cl , dried over MgSO , and concentrated.
7 3
C H
2
2
2
2
4
The crude product was purified by sublimation (0.15 mm Hg/ 50 °C) to afford the
1
deuterated compound as a white solid (219 mg, 60%). H NMR (500 MHz, CDCl
3
): δ
): δ
2
7
.75 (t. J = 1.8 Hz, 1H), 7.71 (br, 1H), 7.57 (br, 1H); H NMR (76.75 MHz, CH
2
Cl
2
1
3
7.38; C NMR (125 MHz, CDCl
3
): δ 136.0, 134.7, 130.6, 130.3 (t, JC-D = 25 Hz), 122.9
3
3
+
(
t, JC-D = 1.5 Hz), 114.2 (t, JC-D = 1.4 Hz) ; LRMS (EI): m/z 182 (M ); HRMS (EI): m/z
+
calculated for [C
7
H
3
DBrN] 181.9596, found 181.9590. Percent D incorporation (based
1
3
on quantitative C NMR): >98.1%
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Synthesis of 5-Bpin-3-chloro-N,N-dimethylaniline. The reaction was carried out
neat with 3-chloro-N,N-dimethylaniline (11 mmol, 1.71 g), [Ir(OMe)(cod)]
2
(1 mol %,
0
.11 mmol, 73 mg), dtbpy (2 mol %, 0.22 mmol, 59 mg), and HBPin (19.8 mmol, 2.5 g).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The reaction stirred at 80 °C for 16 h. The crude product was purified as outlined in the
general procedure to afford the pure product (2.44 g, 79%) as a white solid; mp 128-131
1
°
C. H NMR (500 MHz, CDCl
3
): δ 7.12 (s, 1H), 7.02 (d, 1H, J = 2.49 Hz) 6.77 (t, 1H, J =
1
3
2
.21 Hz), 2.97 (s, 6 H), 1.31 (s, 12H); C NMR (125 MHz, CDCl
3
): δ 151.1, 134.8,
): δ 30.52; FT-IR
KBr): 2974, 2926, 2809, 1601, 1562, 1432, 1372, 1325, 1304, 1152, 1110, 997, 964,
1
1
122.1, 116.5, 114.9, 83.9, 40.5, 24.9; B NMR (160 MHz, CDCl
3
(
-
1
+
8
2
76, 847, 813, 703 cm ; HRMS (ESI) m/z Calcd for C14H21BClNO H [M+H] 282.1435,
found 282.1447.
-Chloro-N,N-dimethylaniline-5-d. The borylation step was carried out with 312 mg
3
3
5
-chloro-N,N-dimethylaniline (2 mmol). The borylation step was carried out neat with
12 mg HBpin (4 mmol, 2 equiv), 16.6 mg (Ind)Ir(cod) (0.04 mmol, 2 mol%) and 6.0 mg
dmpe (0.04 mmol, 2 mol%) at 150 °C for 18 h. The crude borylation mixture was
pumped down under high vacuum and charged with 0.5 mL D O and 3 mL DME. 102
mg Ac O (1 mmol, 0.5 equiv) was also added at this time. The deuteration step was then
carried out at 150 °C for 2 h and cooled to room temperature. It was basified with 5%
NaOH to pH > 10 before being extracted with CH Cl . After drying and concentration,
2
2
2
2
2 2
the crude material was purified with a silica gel chromatography (pentane/CH Cl 3:1) to
1
afford 292 mg of the deuterated compound (93%) as a colorless oil. H NMR (500 MHz,
2
CDCl
3
): d 6.68 (br, 2 H), 6.58 (br, 1 H), 2.93 (s, 6 H); H NMR (76.75 MHz, pentane): d
13
7
3
.14; C NMR (125 MHz, CDCl ): d 151.5, 134.9, 129.6 (t, JC-D = 24 Hz), 116.1, 112.2,
2
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9
8
10.4, 40.3; IR (neat): 3085, 2892, 2807, 2272, 1593, 154, 1491, 1439, 1227, 1113, 986,
-
1
+
8 9
72, 675 cm ; LRMS (EI): m/e 155 ([M-H] ). Anal. Calcd for C H DNCl: C, 61.35; N,
.94. Found C, 61.09; N, 8.86.
10
11
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55
56
57
58
59
60
3
-Chloro-N,N-dimethylaniline-5-d (Alternative Procedure). The deuteration was
carried out in THF and D O as outlined in the general procedure with 5-Bpin-3-chloro-
N,N-dimethylaniline (2 mmol, 563 mg) and [Ir(OMe)(cod)] (2 mol %, 0.04 mmol, 26.4
mg). The reaction was heated at 80 °C for 4.5 h. When the reaction was complete, it was
poured into water and 1 M NaOH. The product was extracted into Et O, dried over
MgSO , and concentrated. The crude product was purified by Kugelrohr distillation (20
2
2
2
4
mm Hg/ 120 °C) to afford the deuterated compound as a clear, colorless oil (231 mg,
1
74%). H NMR (500 MHz, CDCl
3
): δ 6.67-6.65 (m, 2H), 6.56 (br s, 1H), 2.93 (s, 6 H);
2
13
H NMR (76.75 MHz, CH
2
Cl
2
): δ 7.14; C NMR (125 MHz, CDCl
3
): δ 151.5, 134.9 (t,
3
J
C-D = 1.8 Hz), 129.7 (t, JC-D = 25 Hz), 116.0, 112.2, 110.4, 40.3; LRMS (EI): m/z [M-
+
+
+
H] 155; HRMS (ESI+): m/z calculated for [M+H] [C
8
H
10DClN] 157.0643, found
13
1
57.0645. Percent D incorporation (based on quantitative C NMR): 95.9%
4
3
Synthesis of 5-Bpin-3-chloroanisole. The reaction was carried out neat with 3-
chloro-N,N-dimethylaniline (11 mmol, 1.56 g), [Ir(OMe)(cod)] (1 mol %, 0.11 mmol, 73
2
mg), dtbpy (2 mol %, 0.22 mmol, 59 mg), and HBPin (19.8 mmol, 2.5 g). The reaction
stirred at 80 °C for 16 h. The crude product was purified as outlined in the general
procedure to afford the pure product (2.24 g, 76%) as a clear, colorless oil. Spectral data
matched the reported data.
3
-Chloroanisole-5-d. The borylation step was carried out neat with 288 mg 3-
chloroanisole (2 mmol) and 400 mg HBpin (3.1 mmol, 1.55 equiv), 16.6 mg (Ind)Ir(cod)
2
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5
5
5
5
6
(
0.04 mmol, 2 mol%) and 6.0 mg dmpe (0.04 mmol, 2 mol%) at 150 °C for 12 h. The
crude borylation mixture was pumped down under high vacuum and charged with 0.5 mL
O and 3 mL THF. The deuteration step was then carried out at 150 °C for 1 h and
worked up as described in the general procedure, after which the crude material was
D
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 2
purified with a silica gel chromatography (CH Cl ), to afford 258 mg of the deuterated
1
compound (90%) as a colorless oil. H NMR (300 MHz, CDCl
3
): d 6.91 (br, 1 H), 6.88 (t,
2
J = 2.2 Hz, 1 H), 6.77 (br, 1 H), 3.78 (s, 3 H); H NMR (76.75 MHz, pentane): d 7.20;
1
3
C NMR (125 MHz, CDCl
3
): d 160.3, 134.9, 129.9 (t, JC-D = 24 Hz), 120.7, 114.3,
1
1
12.4, 55.3; IR (neat): 3083, 3007, 2963, 2940, 2834, 1593, 1574, 1458, 1258, 1237,
-
1
+
7 6
044, 679 cm ; LRMS (EI): m/e 143 (M ). Anal. Calcd for C H DClO: C, 58.55. Found
C, 58.61.
-Chloroanisole-5-d (Alternative Procedure). The deuteration was carried out in
THF and D O as outlined in the general procedure with 5-Bpin-3-chloroanisole (5 mmol,
.34 g), [Ir(OMe)(cod)] (2 mol %, 0.1 mmol, 66.4 mg), and D O (1.25 mL). The
reaction was heated at 80 °C for 3 h. When the reaction was complete, it was poured into
water. The product was extracted into pentane, dried over MgSO , and concentrated. The
3
2
1
2
2
4
crude product was purified by Kugelrohr distillation (25 mm Hg/ 90 °C) to afford the
1
deuterated compound as a clear, colorless oil (212 mg, 74%). H NMR (500 MHz,
2
CDCl
3
): δ 6.91 (br, 1H), 6.88 (t, J = 1.9 Hz, 1H), 6.77 (br, 1H), 3.78 (s, 3H); H NMR
13
3
(76.75 MHz, CH
2
Cl
2
): δ 7.20; C NMR (125 MHz, CDCl
3
): δ 160.3, 134.9 (t, JC-D = 1.8
+
Hz), 129.9 (t, JC-D = 25 Hz), 120.7, 114.3, 112.4, 55.4; LRMS (EI): m/z 143 (M ); HRMS
+
(EI): m/z calculated for [C
7
H
6
DClO] 143.0248, found 143.0245. Percent D incorporation
13
(based on quantitative C NMR): 93.0%
3
0
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