A Boron Protecting Group Strategy for 1,2-Azaborines

Article abstract of DOI:10.1021/jacs.7b09491

Upon reaction with either molecular oxygen or di-tert-butylperoxide in the presence of a simple copper(I) salt and an alcohol, a range of 1,2-azaborines readily exchange B-alkyl or B-aryl moieties for B-alkoxide fragments. This transformation allows alkyl and aryl groups to serve for the first time as removable protecting groups for the boron position of 1,2-azaborines during reactions that are not compatible with the easily modifiable B-alkoxide moiety. This reaction can be applied to synthesize a previously inaccessible BN isostere of ethylbenzene, a compound of interest in biomedical research. A sequence of epoxide ring opening using N-deprotonated 1,2-azaborines followed by an intramolecular version of the boron deprotection reaction can be applied to access the first examples of BN isosteres of dihydrobenzofurans and benzofurans, classes of compounds that are important to medicinal chemistry and natural product synthesis.

Full text of DOI:10.1021/jacs.7b09491

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Article
A Boron Protecting Group Strategy for 1,2-Azaborines
Andrew William Baggett, and Shih-Yuan Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09491 • Publication Date (Web): 02 Oct 2017
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A Boron Protecting Group Strategy for 1,2-Azaborines
Andrew W. Baggett,†and Shih-Yuan Liu*
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Department of Chemistry, Boston College, Chestnut Hill, Massachusetts 02467-3860, United States
ABSTRACT: Upon reaction with either molecular oxygen or di-tert-butylperoxide in the presence of a simple copper (I) salt and an alcohol,
a range of 1,2-azaborines readily exchange B-alkyl or B-aryl moieties for B-alkoxide fragments. This transformation allows alkyl and aryl
groups to serve for the first time as removable protecting groups for the boron position of 1,2-azaborines during reactions that are not com-
patible with the easily modifiable B-alkoxide moiety. This reaction can be applied to synthesize a previously inaccessible BN isostere of
ethylbenzene, a compound of interest in biomedical research. A sequence of epoxide ring opening using N-deprotonated 1,2-azaborines fol-
lowed by an intramolecular version of the boron deprotection reaction can be applied to access the first examples of BN isosteres of dihydro-
benzofurans and benzofurans, classes of compounds that are important to medicinal chemistry and natural product synthesis.
1. INTRODUCTION
BN/CC isosterism of classic organic arenes1 has emerged as a vi-
able strategy to expand structural diversity of arenes and produce
molecules with applications in biomedical research2 and materials
science.1c,1d,3 In order to access a broad range of monocyclic 1,2-
dihydro-1,2-azaborine substrates (abbreviated 1,2-azaborines), our
group primarily utilizes late-stage functionalization strategies to
diversify an assembled 1,2-azaborine core that is generated from a
modified ring-closing metathesis route4 pioneered by Ashe.5 De-
spite recent advances including late-stage functionalization of 1,2-
azaborines at the C3 position via an EAS (electrophilic aromatic
substitution)/Negishi coupling sequence6 and at the C6 position
via a C-H borylation/Suzuki coupling sequence (Figure 1),7 the
development of applications of these heterocycles is still hampered
by the lack of further viable functionalization strategies.
Scheme 1. Removal of B-alkyl or B-aryl groups from azaborines
R1
R1
Well-Established Routes
N
B
N
B
(1)
(2)
No Established General
Protocol
R2
X
X = Cl, OR, H
R2 = Alkyl, Aryl
Relatively Harsh
Synthetic Step
(e.g., Suzuki Coupling)
R6
R6
FG
This work:
R1
R2
R1 Mild Boron Oxidation
R1
N
N
B
N
B
B
R2
O-R
R = aryl, alkyl
R2 = aryl, alkyl
R2 = aryl, alkyl
[Nu] Incompatible With
Harsh Synthetic Step
[H-]
R6
R6
R1
H
N
Access to Simple
'Parental' Structures
if R1 = H
N
B
B
H
Nu
In contrast to the abundance of available transformations of B-
alkoxy, B-Cl, or B-H azaborines into B-alkyl or B-aryl azaborines,
previous examples13 of the reverse transformation are restricted to
polycyclic azaborines and are narrow in scope (Scheme 1, eq. 1).
The development of a more general transformation for monocyclic
azaborines—and perhaps for boron-containing heteroarenes of any
type—is highly desirable because it would enable alkyl or aryl
groups to serve as removable boron protecting groups during reac-
tion sequences requiring synthetic steps incompatible with
azaborines bearing labile substituents at boron (Scheme 1, eq. 2).
We envisioned that a reasonable strategy to carry out this transfor-
mation would involve oxidative conversion of a B-alkyl or B-aryl
azaborine to a versatile B-alkoxy azaborine.14 Conversion of alkyl
boranes to alkyl boronates through the use of hydrogen peroxide
reagents15 is a cornerstone transformation in the synthesis of alco-
hols from alkenes,16 but application of similar conditions to
azaborine substrates results in decomposition of the aromatic het-
erocycles.
Figure 1. Ring position labeling of 1,2-azaborines.
Manipulation of the boron position of azaborines forms the core
of our synthetic efforts as the nature of the boron substituent great-
ly influences properties of azaborines such as solubility, volatility,
stability towards air and moisture,8 reactivity towards nucleophiles,
and stability during the course of relatively harsh transformations
such as Suzuki coupling. For example, C6-B(pin) azaborines bear-
ing alkyl or aryl groups at the ring boron position react exclusively
at the B(pin) moiety during Suzuki couplings with a diverse range
of aryl bromide coupling partners, but C6-B(pin) azaborines bear-
ing alkoxy groups or hydrogen at the ring boron position only tol-
erate a greatly restricted set of cross coupling conditions and cou-
pling partners.7 Conversely, azaborines bearing alkoxy groups, chlo-
ride, or hydrogen at boron readily react at boron via nucleophilic
addition/elimination,4,9,10 rhodium catalyzed arylation,11 or rhodi-
um catalyzed dehydrogenative borylation,12 whereas azaborines
bearing alkyl or aryl groups at boron do not undergo these reac-
tions.
A report from Jiao and coworkers describing the relatively mild
copper catalyzed oxidation of aryl ketones to aryl esters using mo-
lecular oxygen as the sole oxidant caught our attention as providing
a potentially viable alternative (Scheme 2, eq. 1).17 We postulated
that perceived similarities between the reactivity of the electrophilic
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carbonyl carbon involved in this transformation (Scheme 2, eq. 2) species (entry 5). Adding n-butanol to the reaction granted 2 in a
1
2
3
4
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6
7
8
and the known reactivity of the electrophilic boron atom of
azaborines (Scheme 2, eq. 3) may allow an analogous transfor-
mation to occur for azaborine substrates under similar conditions
using a copper (I) source and either molecular oxygen or a dial-
kylperoxide18 as the stoichiometric oxidant. Herein we describe the
successful application of a copper catalyzed protocol to carry out
the azaborine B-R to B-alkoxy transformation while leaving the
azaborine ring intact. We describe our initial investigations of the
mechanistic features of this transformation, how our experiments
reveal a mechanistic picture considerably different from what we
expected based on the work of Jiao, and the applications of this
method to access azaborines that require removal of a B-alkyl group
as a key synthetic step.
yield comparable to the total yield of B-OR material obtained from
the standard reaction conditions, demonstrating that an alcohol
additive is essential to achieve a relatively clean reaction (entry 6).
Removing the copper (entry 7) or everything besides 1, the sol-
vent, and oxygen (entry 8) resulted in high conversion of 1 but
poor yield of B-OR compounds 2 or 3, showing a largely unfavora-
ble direct reaction between molecular oxygen and the azaborine19
that was either suppressed or outpaced in the presence of the cop-
per and alcohol additives. The B-OR products demonstrated a high
degree of oxygen stability compared to that of B-alkyl 1, since the
yield of 2 and 3 remained high after extended reaction time (entry
9). Finally, adding BHT (butylated hydroxytoluene) to the reac-
tion strongly suppressed the conversion of 1 to any product or
byproduct, suggesting that radical pathways are essential to the
conversion of 1 in the presence of molecular oxygen (entry 10).
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Scheme 2. Mechanistic inspiration
n-BuOH (4.0 equiv)
CuBr (10 mol %)
O
O
pyridine (2.0 equiv)
Table 1. Reaction using molecular oxygen as oxidant
Me
(1)
(2)
O-n-Bu
R
R
PhCl, 130 °C, 24 h, air
n-dodecanol (1.4 equiv)
CuBr (10 mol %)
pyridine (2.0 equiv)
H
H
H
N
B
N
B
N
B
Mechanism proposed by Jiao
O2
CuII + Py
n-Bu
O-n-Bu
O-n-C12H25
CuII + Py
toluene, 130 °C, 20 min
O
HO O-R'
HO O-R'
HO O-R'
sealed, O2
1
2
3
R
C
R
C
R
C
R
C
Ph
Ph
Ph
Ph
Entry
Change from
Standard Conditions
H
H
H
H
H
O
O
H
O
Conversion of 1 Yield of 2 Yield of 3
(%)[a] (%)[a] (%)[a]
CuI + [PyH]+
CuI + [PyH]+
OH
R'-OH
O
1
2
3
4
5
6
7
8
none
94
2
15 64
0
4
5
25
73
5
Conceptual similarity of BN system
nitrogen atmosphere
air
air, reflux
n-dodecanol removed
n-butanol instead of n-dodecanol
CuBr removed
0
R
H
[Cu]
[Oxidant]
R1
R1
R1
44
53
77
89
79
32
42
0
0
39
0
N
B
N
B
N
B
H2O
O
C
(3)
R
O
R
R
O-R'
Ph
O-R'
O-R'
R'-OH
Py
H
[PyH]+
CuBr, alcohol, and pyridine removed 74
14
14
0
9
reaction run for two hours
BHT (2.0 equiv) added
100
64
4
2. RESULTS AND DISCUSSION
At the outset of this project, we tested the activity of the readily
10
5
[a] Conversion and yield obtained by GC using dodecane as a calibrated internal standard
available N-H, B-n-Bu azaborine 114 under conditions17 adapted
from Jiao and coworkers (Scheme 3). We were delighted to find
that a 11B NMR spectrum of the reaction revealed the complete
consumption of B-butyl azaborine 1 (11B shift ~ 35 ppm) and ap-
pearance of a peak corresponding with the desired B-butoxy mate-
rial 214 (11B shift ~ 30 ppm) and a minor peak assigned to one or
more B(OR)3 species produced as undesired side products (11B
shift ~ 20 ppm).
Although we demonstrated that the desired B-R to B-OR trans-
formation was possible under the aerobic conditions inspired by
Jiao and coworkers, the best yields were only modest due to com-
petitive decomposition of the azaborine material to B(OR)3 species
during the course of the reaction. Furthermore, we failed to detect
any aldehyde byproducts that would be expected if the mechanism
proposed by Jiao was operative in our case, and suspected the car-
bon leaving group on the azaborine may instead be expelled as a
radical during the progress of the reaction. The lessons we learned
from these aerobic reactions guided us to explore an alternate sys-
tem. First, we used di-tert-butylperoxide (DTBP)20 under a nitro-
gen atmosphere as the oxidant to potentially reduce the prevalence
of unwanted side reactions between the azaborine substrate and
molecular oxygen. Second, we examined the benzyl group as the
boron leaving group, since it should impart the same stability to-
wards cross coupling or other nucleophilic reaction conditions that
n-butyl would, and it would become a relatively stable radical spe-
cies in case this expulsion contributed to limiting the rate of the
overall reaction.
Scheme 3. Initial B-alkyl to B-alkoxy transformation
n-BuOH (4.0 equiv)
CuBr (10 mol %)
pyridine (2.0 equiv)
H
H
N
B
N
B
n-Bu
O-n-Bu
PhCl, 130 °C, 4 h, air
1
2
~90% by 11B NMR
25% Isolated Yield
Encouraged by this promising result, we explored the conse-
quences of modifying various reaction parameters. We replaced n-
butanol with n-dodecanol in the reaction for two reasons: the long-
er alkyl chain grants increased stability towards silica gel chroma-
tography to the B-alkoxide product 3, and we were able to distin-
guish products arising from incorporation of the alcohol versus
those arising from potential net oxygen insertion. After brief pre-
liminary reaction optimizations including a wide survey of alternate
metal salts in place of copper (I) bromide (Tables S1 and S2) re-
sulting in the standard conditions shown in Entry 1 of Table 1, we
confirmed that a supply of oxygen was necessary for reactivity (en-
tries 1-2) and that a sealed system with pure oxygen led to a cleaner
reaction than those run sealed with air or performed open to air at
reflux (entries 3-4). Removing the n-dodecanol additive from the
system led to an inefficient production of 2, indicating that a net
oxygen insertion is operative to some extent in production of this
Our synthesis of B-benzyl azaborines followed straightforward
protocols involving addition of a benzyl Grignard reagent to N-
TBS, B-Cl azaborine 44 to generate the N-TBS, B-benzyl azaborines
5 and 6 on gram scale in excellent yield. Both could undergo silyl
deprotection with TBAF in good yield on gram scale to yield N-H,
B-benzyl azaborines 7 and 8 (Scheme 4).
Scheme 4. Generation of B-benzyl azaborines
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second benzyl group to generate another equivalent of 9 and a
Cu(III) bisalkyl species22 that could produce bibenzyl by reductive
elimination and regeneration of a Cu(I) species.
1
2
3
4
5
6
7
8
Ph
DTBP
Ph
[Cu(I)]
10
Ph
[Cu(III)]
Ph
H
N
B
With N-H, B-benzyl substrate 7 in hand, we investigated the new
[Cu(II)] O-t-Bu
O
O-t-Bu
set of conditions as illustrated in Table 2. Switching oxidants and
substrates resulted in a cleaner transformation to the desired prod-
uct 3 with only a small amount of the B-O-t-Bu product 9 observed
and a nearly stoichiometric amount of bibenzyl 10 formed as a
byproduct (entry 1). In contrast to the reaction using molecular
oxygen, removal of the copper nearly completely suppressed the
conversion of 7 (entry 2) and some conversion was only seen when
heating the system to 130 °C (entry 3). The generation of bibenzyl
was also suppressed upon removal of CuBr. Removal of pyridine or
the substitution of pyridine with triethylamine or bipyridine result-
ed in similarly low conversions and yields for the reaction (entries
4-6). In the absence of n-dodecanol the B-O-tert-butyl product 9
was formed via incorporation of one half of DTBP into the
azaborine (entry 7). Without the oxidant present, the desired reac-
tion did not occur and only minimal conversion took place (entry
8). The reaction required elevated temperatures to occur (entry 9),
but could be run 40 °C lower than the reactions described in Table
1. When we replaced DTBP with tert-butyl hydrogen peroxide
(TBHP) we observed a less efficient reaction with a worse gap
between conversion and yield of 3 (entry 10). We ran a small num-
ber of experiments on B-benzyl substrate 7 with other copper
sources and with molecular O2 as oxidant, but observed less effi-
cient reactions in all cases (Table S3).
9
9
[Cu(I)]
+
•O-t-Bu
H
10
11
12
13
14
15
16
17
18
19
20
21
22
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N
B
Ph
O-t-Bu
Ph
H
11
N
B
[Cu(II)]
Ph
H
N
B
7
Ph
O-t-Bu
H
N
H
11
N
B
B
O-t-Bu
O-t-Bu
+ O-n-dodecyl
- H-O-t-Bu
H
9
N
B
O-n-dodecyl
3
Figure 2. Plausible mechanism for the B-R to B-OR transfor-
mation
With a set of optimized reaction conditions in hand we explored
the substrate scope with respect to the azaborine reagent in this
transformation (Table 3). Substrates with N-TBS groups gave
good isolated yields in comparison to those with N-H groups (en-
tries 1 vs 2) likely due to the greater tendency of N-H, B-OR
azaborines to bind to silica gel compared to the low silica gel affini-
ty of the silylated substrates. The only bibenzyl species observed
following the deprotection of 8 was the symmetrical product bear-
ing two OMe groups, demonstrating that there is no crossover
between the benzyl leaving group and the toluene solvent during
the course of this reaction (entry 3). Azaborines bearing alkyl and
aryl leaving groups also underwent the deprotection, albeit with
reduced yields compared to substrates bearing benzyl groups (en-
tries 4-10). The ability of the leaving group to stabilize a radical
seems to correlate with the degree of success of the reaction.
Azaborines bearing either a bromine or an n-propyl group at the
C3-position and a benzyl leaving group underwent the reaction in
modest yield (entries 11-12). Finally, an azaborine bearing a mesit-
yl group at boron failed to undergo the reaction, likely due to the
steric bulk of the mesityl group preventing nucleophilic attack at
boron.
Table 2. CuBr/DTBP-catalyzed boron deprotection of 7.
n-dodecanol (1.4 equiv)
CuBr (10 mol %)
pyridine (2.0 equiv)
DTBP (1.2 equiv)
H
H
H
0.5 equiv.
Ph
N
B
N
B
N
B
Bn
O-t-Bu
O-n-C12H25
Ph
toluene, 90 °C, 45 min
sealed, N2
7
9
3
10
Entry Change from Standard Conditions
Conversion of Yield of Yield of
7 (%)[a] 9 (%)[a] 3 (%)[a]
Yield of
10 (%)[a]
1
2
3
4
5
6
7
8
none
CuBr removed
100
1
1
0
75
0
81
1
CuBr removed, run at 130 °C
pyridine removed
NEt3 instead of pyridine
bipy (1.0 equiv), no pyridine
n-dodecanol removed
DTBP removed
14
24
16
72
81
2
0
0
0
1
59
0
5
15
9
48
0
0
7
23
16
60
59
2
9
reaction run for 2 hours at RT
TBHP instead of DTBP
0
76
0
0
0
42
0
37
10
[a] Conversion and yield obtained by GC using dodecane as a calibrated internal standard
Table 3: Scope of deprotection method
The experiments in Table 2 and Table S3 and the detailed
mechanistic studies performed by others18,20 prompt us to propose
a tentative mechanism for the B-R to B-OR transformation using
the system based on copper and DTBP (Figure 2). We propose an
initial generation of a Cu(II) alkoxide species from the reaction of a
Cu(I) species with the DTBP oxidant with concomitant formation
of a tert-butoxide radical.21 Next, the alkoxide radical attacks the
azaborine boron atom via a one-electron pathway to generate
azaborine radical 11. We believe that the Cu metal may serve as a
reservoir for the tert-butoxide radical. A Cu(I) species may then
mediate the removal of the boron benzyl group to generate the
azaborine product 9, which exchanges alkoxide groups with the n-
dodecanol in solution to generate the ultimate azaborine product 3.
The copper (II) benzyl species could finally mediate removal of a
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n-dodecanol (1.4 equiv)
CuBr (10 mol %)
pyridine (2.0 equiv)
DTBP (1.2 equiv)
Me
Known Compounds
R1
R1
1
2
3
N
B
N
H
H
N
B
Me
N
B
N
B
B
(1)
R2[a]
O-n-C12H25
Me
toluene, 90 °C, 45 min
sealed, N2
H
H
R3
R3
23
24
25
Entry Starting Material
Product
% Yield
4
5
6
7
8
9
Target
Isolated[b] (NMR)[c]
Me
TBS
N
TBS
N
B(pin)
[Pd]
H
H
H
1
90 (99)
B
Ph
Ph
B
N
B
N
B
N
B
(2)
Br
O-n-C12H25
Cross coupling
fails
5
12
R2
R2
H
for R2 = OR, H
H
H
25
N
B
N
2
3
66 (97)
61 (94)
B
Figure 3. BN-Ethylbenzene analogs.
Initial borylation of N-H, B-benzyl 7 under standard iridium cat-
O-n-C12H25
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
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43
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49
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52
53
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58
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60
7
3
H
OMe
N
B
alyzed borylation conditions23 granted C6-B(pin) azaborine 26 in
excellent yield, and this substrate underwent cross coupling with-
out difficulty to generate C6-vinyl azaborine 27 (Scheme 5). Com-
pound 27 was hydrogenated under mild conditions to produce C6-
ethyl azaborine 28, which cleanly underwent the boron deprotec-
tion protocol to grant access to B-OR azaborine 29. As the final
step in the synthesis, we reduced 29 to the target compound 25
using LiAlH4 followed by a mild acid, and isolated over 100 mg of
the volatile C6-ethyl, N-H, B-H azaborine.
3
8
TBS
N
B
4
5
6
12
3
69 (70)
59 (78)
54 (66)
49 (57)
35 (57)
37 (53)
n-Bu
13
H
N
B
n-Bu
1
TBS
N
B
Scheme 5. Synthesis of C6-Ethyl BN-Ethylbenzene
12
Me
14
B(pin)
H
H
Pd(dppf)Cl2 (2 mol %)
vinylbromide (4 equiv)
KOH (3 equiv)
H
[Ir(cod)(OMe)]2 (1.5 mol%)
dtbpy (3 mol%)
TBS
N
B
N
B
N
B
N
B
B2(pin)2 (1.6 equiv)
7
8
9
12
3
Bn
Bn
Bn
Ph
MTBE, RT, 2 h
Me
MTBE : H2O 2.4 : 1
7
26
88% Yield
27
84% Yield
15
80 °C, 2 h
H
N
B
Me
Me
n-dodecanol (1.4 equiv)
CuBr (10 mol %)
pyridine (2.0 equiv)
DTBP (1.2 equiv)
H
H
H
1) LiAlH4
2) H+
Ph
16
Pd/C (0.1 equiv)
H2 (1 atm)
N
B
N
B
N
B
C12H25
H
O
toluene, 90 °C, 45 min
sealed, N2
Bn
EtOAc, RT, 2 h
TBS
N
B
25
>100 mg
56% Yield
29
28
89% Yield
12
93% Yield by NMR
63% Isolated Yield
OMe
17
We next employed an intramolecular variant of this method to
generate BN-dihydrobenzofurans, which serve as BN/CC isosteres
of the dihydrobenzofuran moiety found in a variety of natural
products and drugs24 and as potential precursors to BN-
benzofurans. To the best of our knowledge there are no examples
of BN-isosteres of either class of compounds. The synthesis of BN-
dihydrobenzofurans involved a two-step process: a deprotona-
tion/epoxide ring opening sequence starting from azaborine 7
followed by the copper catalyzed boron oxidation reaction which
resulted in cyclization (Table 4). Six BN-dihydrobenzofuran
isosteres were produced in good yield over two steps with this
method including the parent compound 36, demonstrating the
potential for this method to be used to generate a library of BN-
dihydrobenzofurans by varying the substitution on the epoxide
reaction partner.
TBS
N
B
54 (59)
10
12
CF3
18
TBS
TBS
N
B
N
40 (57)
53 (65)
11
12
Ph
B
O-n-C12H25
19
TBS
20
Br
Br
TBS
N
B
N
B
Ph
O-n-C12H25
n-Pr
n-Pr
22
21
[a] Azaborines with R2=mesityl failed to undergo the reaction
[b] Isolated yields are an average of two runs. [c] NMR yields obtained
using 1,5-cyclooctadiene (cod) as a calibrated internal standard. All
NMR yields are an average of two runs.
With our new protocol in place for the boron deprotection of B-
benzyl azaborines, we used this strategy as a key step in the synthe-
sis of C6-ethyl BN-ethylbenzene 25 (Figure 3, eq. 1). Our group
has investigated the activity of BN-ethylbenzenes 23 and 24 to-
wards ethylbenzene dehydrogenase2b as well as ligands for engi-
neered T4 lysozymes,2a,2e and we desire access to more regioisomers
of BN-ethylbenzene to develop a systematic structure-activity rela-
tionship analysis of the effects of BN/CC isosterism in biological
settings. A straightforward strategy7 involving the cross coupling
between vinyl bromide and C6-borylated azaborines with labile
groups already installed at the boron atom failed due to the sensitiv-
ity of these azaborines towards the reaction conditions (Figure 3,
eq. 2).
Table 4. Synthesis of BN-dihydrobenzofurans
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R2
R1
1) n-BuLi (1.0 equiv)
THF, –78 °C, 30 min
lowing the transformation. Both reactions are assisted by the pres-
OH
CuBr (10 mol %)
pyridine (2.0 equiv)
DTBP (1.2 equiv)
1
2
3
4
5
6
7
8
R1
2)
ence of a copper salt as an additive, but both reactions still take
place without the copper, albeit with a significant loss of efficiency.
No metal or Lewis acid additive besides copper was able to effi-
ciently promote the reaction, and we determined that a key species
involved in the azaborine oxidation was most likely an alkoxy radi-
cal. We investigated the mechanistic features of the reactions by
designing straightforward experiments and discovering that biben-
zyl is formed as a stoichiometric byproduct during the deprotection
of B-benzyl substrates. The optimized deprotection protocol is
highly effective for the removal of benzyl groups from azaborines,
presumably because the benzyl radical that is expelled is relatively
stabilized compared to other alkyl or aryl radicals. We applied the
new method as the key step in the synthesis of C6-ethyl BN-
ethylbenzene, and in the synthesis of BN-dihydrobenzofurans and
BN-benzofurans which represent unexplored classes of heterocy-
cles. This method will be highly useful to chemists carrying out
multi-step transformations of azaborines in particular and perhaps
boron heteroarenes in general that require removal of carbon-based
boron protecting groups as part of the synthetic plans.
H
O
R1
R2
N
B
N
B
N
B
R2
O
toluene, 90 °C
Bn THF, RT, 12 h
Bn
7
30-35 30 min, sealed, N2
36-41
entry
epoxide
O
ring-opened product
(% Yield)[a]
BN-dihydrobenzofuran
(% Yield)[a]
OH
N
N
1
2
B
B
O
Bn
30
36
9
97% Yield
81% Yield
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
OH
N
O
N
B
B
O
Bn
31
37
71% Yield
77% Yield
Me
Me
OH
Me
Me
N
O
O
N
B
3
B
Me
O
Me
Bn
32
81% Yield
38
88% Yield
Ph
OH
Ph
N
N
B
ASSOCIATED CONTENT
Supporting Information.
Experimental procedures, spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Ph
4
5
B
O
Bn
33
80% Yield
OH
39
79% Yield
PhO
OPh
N
OPh
O
O
N
B
AUTHOR INFORMATION
B
O
Bn
34
40
Corresponding Author
* shihyuan.liu@bc.edu
95% Yield
84% Yield
HO
N
N
Present Addresses
† Department of Chemistry, Linfield College, McMinnville, Oregon
97128-8626, United States
6
B
B
O
Bn
35
41
40% Yield
26% Yield
[a] Yields shown are isolated yields and are the average of two runs.
Notes
Next, we explored the oxidation of several BN-
The authors declare no competing financial interest.
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
dihydrobenzofurans to the corresponding BN-benzofurans
(Scheme 6). Phenyl-substituted 39 was converted to the substitut-
ed BN-benzofuran 42 in good yield after refluxing in toluene in the
presence of Pd/C for 24 hours; however, only limited success was
observed when the same conditions were applied to the other sub-
strates. Vinyl-substituted 37 underwent isomerization rather than
oxidation, leading to the isolation of 43 in modest yield. Neither 36
nor 40 was converted to the corresponding BN-benzofurans under
these conditions, suggesting that the successful observed reactions
may be due to the driving force resulting from extension of π con-
jugation in 42 and 43.
ACKNOWLEDGMENT
This research was supported by the National Institutes of Health
NIGMS (R01-GM094541) and Boston College start-up funds. A. W.
B. thanks the LaMattina Family Graduate Fellowship in Chemical
Synthesis for support.
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H
H
R
H
N
B
N
B
N
B
•OR
OR
R
boron position
is protected
boron position
can be easily further
functionalized
10
11
12
13
14
15
16
17
18
19
20
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22
23
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