Synthesis of Functionalized 1,3,2-Benzodiazaborole Cores Using Bench-Stable Components

Article abstract of DOI:10.1021/acs.joc.6b00435

The azaborine motif provides a unique opportunity to develop core isosteres by inserting B-N units in place of C-C bonds within aromatic scaffolds, creating new pseudoaromatic building blocks that retain comparable structural features. Previous synthetic routes to the 1,3,2-benzodiazaborole core have used organoboron dichlorides and boronic acids as the boron precursors. The transformation developed herein utilizes entirely bench stable starting materials, including organotrifluoroborates, enabling a wider array of substrate analogues under facile reaction conditions. Furthermore, physical, structural, and electronic properties of these compounds were explored computationally to understand the influence of the B-N replacement on the structure, aromaticity, and isosteric viability of these analogues.

Full text of DOI:10.1021/acs.joc.6b00435

Article
pubs.acs.org/joc
Synthesis of Functionalized 1,3,2-Benzodiazaborole Cores Using
Bench-Stable Components
Geraint H. M. Davies and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: The azaborine motif provides a unique opportunity to develop core isosteres by inserting B−N units in place of
CC bonds within aromatic scaffolds, creating new pseudoaromatic building blocks that retain comparable structural features.
Previous synthetic routes to the 1,3,2-benzodiazaborole core have used organoboron dichlorides and boronic acids as the boron
precursors. The transformation developed herein utilizes entirely bench stable starting materials, including organo-
trifluoroborates, enabling a wider array of substrate analogues under facile reaction conditions. Furthermore, physical, structural,
and electronic properties of these compounds were explored computationally to understand the influence of the B−N
replacement on the structure, aromaticity, and isosteric viability of these analogues.
INTRODUCTION
■
The ability to create isosteric compounds that alter both the
bioavailability and reactivity of molecules without significantly
modifying the geometrical shape (isostructural) or the
electronic distribution (isoelectronic) of that within the parent
Figure 2. Indole isosteres.
structure molecule provides a great advantage for drug
development1 and other chemistry-oriented applications.2 To
species between the amino groups of o-phenylenediamine.8
that end, B−N isosterism for a carbon−carbon double bond
(Figure 1) affords an opportunity to create new core isosteric
Literature reports have revealed the incorporation of different
substituents on boron through the use of alkyl-,8a trialkyl-,8b
and dichloroboranes9a and, in later contributions, condensation
reactions with boronic acids9b−e or electron-deficient boronate
esters.9f The major limitation of the currently available methods
is the required use of air- and/or moisture-sensitive boron
precursors that limit the diversity within these indole isosteres.
Recently, our group reported the ability to employ bench-
stable organotrifluoroborates10 as precursors for the synthesis
of closely related 2,1-borazaronaphthalene cores.11 This
straightforward method enabled access to a library of molecules
through activation of the organotrifluoroborate precursors
using a fluorophile (e.g., chlorosilane reagents)12 and
subsequent reaction with o-aminostyrene derivatives. Applica-
tion of this strategy to the indole azaborines was envisioned to
provide an easily accessible, robust route toward the 1,3,2-
benzodiazaborole core in a similar fashion.
Figure 1. B−N isosterism for CC bonds.
building blocks for aromatic systems (azaborines). Since the
initial synthesis of borazine, a completely inorganic isostere of
benzene and the first member of the azaborine class,3 a whole
range of azaborines have been prepared.4a,b Further analysis of
these cores revealed their unique spectroscopic4c and medicinal
properties.4d−f
The indole structural motif has a demonstrated prominence
in biological targets,5 and therefore accessing isosteric species
would be of value for both academic and pharmaceutical
applications. Currently, there are two known azaborine
isosteres of indole: (i) the 1,3,2-benzodiazaborole (1), where
the 2−3 carbon−carbon double bond is replaced by a B−N
bond,6 and (ii) the “fused” B−N indole7 (2), in which the
adjacent bond in the bicycle is exchanged (Figure 2). The
indole-azaborine 1 is particularly valuable because it provides
access to an indole isostere in one step via chelation of a boron
RESULTS AND DISCUSSION
Synthetic Method. Initial reaction condition screening,
using o-phenylenediamine 3a and phenyltrifluoroborate 4a,
■
Received: February 27, 2016
© XXXX American Chemical Society
A
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indicated that the system established for the 2,1-borazaronaph-
thalenes11 could be applied almost directly to the synthesis of
1,3,2-benzodiazaboroles (Table 1). As previously observed,
silicon tetrachloride could be used to activate a potassium
organotrifluoroborate, generating a highly reactive dichlorobor-
ane species,12 providing good conversion to 5a (Table 1, entry
1). In exploring more user-friendly fluorophiles, which have
recently been shown to activate organotrifluoroborates,13 we
noticed that trivalent, electron-poor boron species could also
promote the reaction (Table 1, entries 3−11) but had better
effectiveness when used in excess. With boron fluorophiles,
initial organotrifluoroborate deprotection generates a difluor-
oborane species that has significantly poorer reactivity in
comparison to the dichloroborane intermediates,14 thereby
requiring excess boron reagent to abstract both of the
remaining fluorides. The best results were obtained when
using 3 equiv of boron trifluoride ethylamine complex as the
fluorophile (Table 1, entry 9), a particularly appealing reagent
because it was the sole reagent tested that was a bench-stable
solid.
These modified reaction conditions were then applied to
prepare 1,3,2-benzodiazaborole analogues using various potas-
sium aryltrifluoroborates (Table 2). In addition to alkyl groups
(5b−d) and halogens (5e−g), the relatively mild reaction
conditions enabled vinyl (5h), ether (5i−l,n) and ester (5m)
functional groups to be tolerated. Whereas steric hindrance at
either the ortho position of the aryltrifluoroborate (5b,c,e,i,l) or
Table 1. Optimization of Fluorophile for Reaction
Conditions
a
entry
fluorophile
amt, equiv
P:IS
1
SiCl4
1
1
3
3
3
3
3
3
3
2
1
4.60
2.49
4.21
1.21
1.85
1.60
0.42
0.43
6.85
5.55
3.80
2
TMSCl
3
BCl3 (1.5 M in hexane)
BH3·SMe2
BF3·CH3CN
BF3·SMe2
BF3·THF
BF3·OEt2
BF3·NH2Et
BF3·NH2Et
BF3·NH2Et
4
5
6
7
8
9
10
11
a
Product (P) to internal standard (IS) ratios determined by GCMS
using 4,4′-di-tert-butylbiphenyl as internal standard.
c
Table 2. Scope of Reaction with (Hetero)aryltrifluoroborates
a
b
c
Reaction run under ambient atmosphere. Reaction run on 30 mmol scale. Reaction conditions: 1.0 equiv of diamine, 1.0 equiv of potassium
organotrifluoroborates, 3.0 equiv of BF3·NH2Et, 1/1 toluene/CPME (0.5 M), 80 °C, 18 h.
B
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a
Table 3. Scope of Reaction with Substituted o-Phenylenediamines
a
Reaction conditions: 1.0 equiv of diamine, 1.0 equiv of trifluoroborates, 3.0 equiv of BF3·NH2Et, 1/1 toluene/CPME (0.5 M), 80 °C, 18 h.
a
Table 4. Scope of Reactions of Alkyl- and Alkenyltrifluoroborates
a
Reaction conditions: 1.0 equiv of diamine, 1.0 equiv of organotrifluoroborates, 3.0 equiv of BF3·NH2Et, 1/1 toluene/CPME (0.5 M), 80 °C, 18 h.
on one of the diamine nitrogen atoms (5d,g,s) did not deeply
affect the reaction, the presence of some electron-withdrawing
substituents such as nitro (5o) or cyano (5p) groups resulted in
lower yields. Heteroaryltrifluoroborates containing sulfur (5q)
or oxygen (5r,s) atoms were well tolerated. Unfortunately, the
method could not be extended to nitrogen-containing
heteroaryls such as pyridyl subunits (5t).
The utility of this protocol, using all air-stable starting
materials, consequently allowed the reaction to proceed even in
the absence of an argon purge of the reaction vessel or solvents
(88% under air versus 90% under argon for 5a). It is of note
that, for several of the reactions, the only purification required
was a basic aqueous (saturated NaHCO3) workup followed by
extraction with ethyl acetate, highlighting the ease of access
toward these cores. In most remaining cases, the only additional
purification required was passage through a flash plug of silica
gel.
Desymmetrization of the starting phenylenediamine enabled
the synthesis of unsymmetrical azaborine cores (Table 3). Use
of functionalized phenylenediamines allowed the facile
introduction of versatile synthetic handles such as bromo
(5w), carbonyl (5x), and nitro (5y) groups. Some difficulty was
encountered when using 2,3-naphthalenediamine (5z), pre-
sumably because of the heterogeneity of the reaction mixture
under these reaction conditions.
C
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2
The scope of the method was further advanced to other Csp -
3
hybridized as well as Csp -hybridized groups on the boron atom
(Table 4). Alkenyltrifluoroborates were well tolerated under
these conditions (Table 4, left), affording the corresponding
azaborines in good yields (6a−c). An alkynyltrifluoroborate was
also utilized to exhibit that the procedure could be extended to
sp-hybridized centers (6d). N-Methylation of the diamine did
not affect the reaction (6e,f), and the presence of a bulky N-
phenyl group was tolerated when using sterically small
organotrifluoroborates (6g,h). However, only starting diamine
was observed when attempting to cyclize such substrates with
larger aliphatic or aryl substituents on the organoboron
precursors.
Figure 3. NICS values calculated.
explored by Liu7 to similar 6−5 aromatic ring systems indicated
that they most closely resemble the indole framework. It is thus
visually apparent that both azaborines present a greater likeness
to indole [compare 2-methylindole (8a) and 2-methylbenzi-
midazole (9) to their azaborine analogues 7a and 2a],
supporting the notion that the B−N bond displays some of
the electronic properties of a CC bond. An even stronger
likeness can be seen on comparison of N-alkylated azaborines
8b,c to 7f and 2b, respectively. The strong similarity between
the electrostatic potential maps in these isosteric systems
presumably results from enhanced electron availability from the
methylated nitrogen within the five-membered ring. In the case
of 7f, although this would enhance electron density, it would
also reduce competitive conjugation of the lone pairs of the
now desymmetrized nitrogen atoms. Quantitatively, this is
observed by a slight lengthening of the MeN−B bond (1.439
Å) in comparison to the HN−B bond (1.435 Å). This factor is
also noticed in the indole and “fused” B−N indole, though to
lesser extents (see the Supporting Information for a full bond
length table). When taken together, these factors lead to an
electronic hybrid between 8c and 8b where the dimethylated
1,3,2-benzodiazaborole core closely resembles the A ring of 8b
while having a B ring more similar to that of 8c.
3
Substituted azaborine compounds with Csp -hybridized units
on the boron (Table 4, right) were found to be less stable than
2
their Csp -hybridized counterparts. The B-alkyl compounds,
when subjected to the standard workup, readily decomposed in
the presence of water. This problem was overcome by
foregoing the aqueous workup and directly subjecting the
reaction mixture to a flash plug of silica, allowing access to pure
material in moderate (7c) to good yields (7g). Once isolated
and stored as solids on the benchtop, no degradation of the
products were observed. Using this modified workup
procedure, primary (7a,e−h), secondary (7b,c), and tertiary
(7d) alkyl substituted azaborines were isolated. N-Alkylated
diamines could be used as reaction partners, affording the
corresponding azaborines, often in very good yields (7f−h).
Physical Properties and Computationally Derived
Results. With the primary objective of the project achieved
(development of a straightforward method of synthesis of the
1,3,2-benzodiazaborole core involving only bench-stable
partners), attention was next focused on understanding the
potential value and versatility of these indole isosteres. Initially,
the pKa value of the azaborine N−H was determined via
bracketing experiments (see the Supporting Information), and
a pKa of roughly 18.2 (in DMSO) was found for the
monoalkylated derivative 5d. This value falls slightly lower
than the pKa for indole (20.9)15 and significantly below that of
the “fused” B−N indole (around 30).7 Considering the pKa for
aniline (30.6) or phenylacetamide (21.5), the lower pKa
suggests that the 1,3,2-benzodiazaborole anion is better at
inductively stabilizing the negative charge generated on
deprotonation.
Computational models were further studied as a means of
assessing the structural and electronic correlation between
azaborine cores and indole. Liu,16 and more recently North-
rop,9e previously looked at various computational methods for
analyzing the core of the indole-azaborine systems, but we were
primarily interested in the effect caused by substitution around
the core. All calculations were carried out using Gaussian 09,17
and the structures were visualized via WebMO.18 Geometry
optimizations were performed in the gas phase at the B3LYP/6-
311+G(2d,p) level of theory.19 Stationary points were
characterized by frequency analysis at 298 K. To probe the
ring current in these systems, NICS values were determined at
the GIAO-B3LYP/6-311+G(2d,p) level of theory at distances
of 0.0 Å [A(0) and B(0)] and 1 Å [A(1) and B(1)] from each
ring system as well from the center of the bicyclic systems
[Center(1)] in the perpendicular direction (Figure 3).
Nuclear independent chemical shift (NICS) calculations20
were performed to assess the relative aromatic character of each
ring (Table 5). NICS calculations provide quantitative
correlations for aromaticity using “theoretical nuclei” at the
center of a ring system to probe electron shielding.20 A more
negative NICS value indicates greater electron shielding via a
stronger ring current and thus more π-electron delocalization.
Enhanced delocalization is indicative of greater aromatic
character. Because of ring current effects, only rings of similar
size can be compared.21 Across a selection of several molecules
(Table 5), a few preliminary trends for the indole-azaborines
can be ascertained. Initially, an increase in aromaticity in the A
ring from o-phenylenediamine 3 to the cyclized azaborine
products was observed, presumably caused by the nitrogen lone
pairs becoming locked in plane with the rest of the π cloud
upon annulation. Furthermore, the A rings of the 1,3,2-
benzodiazaborole 7a share values similar to those for the
corresponding indole 8a and benzimidazole 9. However, on
examination of the B ring, there is a lower electron shielding
effect for the azaborine, presumably caused by incomplete π
delocalization with the B−N bond. This is confirmed by the
NICS calculation for “fused” B−N indole 2a, where lower
electron shielding occurs in both rings caused by the conjoined
B−N bond. Similar values for related compounds have been
observed by Liu.16 Furthermore, B-ring deshielding is perturbed
by the hybridization of groups bound to boron (5a−7a, 6d),
presumably caused by orbital overlap or the electron-donating
character of these functional groups. This hybridization effect
has been previously observed within the benzene-azaborine
We first evaluated the electrostatic potentials of indole
azaborines and their carbon analogues (Figure 4). A pictorial
comparison of the electrostatic potential maps for both the
1,3,2-benzodiazaborole core and the “fused” B−N indole core
D
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Figure 4. Electrostatic potentials (from +31.38 to −31.38 kcal/mol) of the 1,3,2-benzodiazaborole in comparison to indole.
a
Table 5. NICS Comparisons (ppm) of 1,3,2-Benzodiazaborole and Its Relative Carbon Isosteres
a
All structures are fully optimized to local minima (B3LYP/6-311+G(2d,p)).
CH2Cl2 or MeCN as the solvent. NMR spectra (1H, 13C, 11B, 19F)
scaffold,22 where sp-hybridized groups generally induce
shielding relative to its phenyl counterpart.
1
were performed at 298 K. H (500.4 MHz) and 13C (125.8 MHz)
NMR chemical shifts are reported relative to internal TMS (δ 0.00
ppm) or to residual protiated solvent. 11B (128.4 MHz) and 19F NMR
(282.4 MHz) chemical shifts were referenced to external BF3·Et2O
(0.0 ppm) and CFCl3 (0.0 ppm), respectively. Data are presented as
follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, sept = septet, m = multiplet), coupling constant J
(Hz), and integration.
CONCLUSIONS
■
The synthetic approach to the 1,3,2-benzodiazaboroles
described highlights the ability to synthesize these azaborine
cores via bench-stable reagents in a facile procedure, tolerant to
atmospheric conditions. Furthermore, the simple workup and
purification conditions employed enable rapid access to
molecules with valuable isosteric potential. The physical and
computational data suggest that this class of azaborine
compounds demonstrates some aromatic tendencies, which
could be leveraged for potential application of this core isostere
of indole.
General Procedure for Synthesis of Aryl 1,3,2-Benzodiaza-
boroles 5a−z. Diamine (1 equiv, 1 mmol), organotrifluoroborate (1
equiv, 1 mmol), and BF3·NH2Et (3 equiv, 3 mmol) were added to an
oven-dried Biotage microwave vial with a stir bar. The vial was sealed
with a cap, which was lined with a disposable Teflon septum, and the
reaction vessel was subsequently evacuated and purged three times
with argon. A 1/1 mixture of CPME (1 mL) and toluene (1 mL) was
added, and the reaction mixture was heated to 80 °C. After it was
stirred overnight, the reaction mixture was diluted with 5 mL of
saturated NaHCO3 and extracted with EtOAc (2 × 5 mL). The
organic phase was washed with brine and dried (MgSO4), before being
condensed under vacuum to afford the azaborine.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were carried out under an
inert atmosphere of argon in oven-dried glassware, unless otherwise
noted. Toluene and cyclopentyl methyl ether (CPME) were dried
using a J. C. Meyer solvent system. o-Phenylenediamine (99%) was
recrystallized from toluene. Standard flash chromatography procedures
were followed using 32−63 μm silica gel. Column chromatography
was performed by Combiflash using RediSep Rf Gold Normal-Phase
Silica columns. Melting points (°C) are uncorrected. HRMS data were
obtained by either ESI or CI using a TOF mass spectrometer in
2-Phenyl-2,3-dihydro-1H-1,3,2-benzodiazaborole9d (5a). Thirty
millimole scale reaction in a 200 mL round-bottom flask. Obtained as a
1
tan solid (4.949 g, 85%). Mp: 198−200 °C. H NMR (500.4 MHz,
CDCl3): δ 7.76−7.74 (m, 2H), 7.49−7.41 (m, 3H), 7.14 (dd, J = 5.3,
3.4 Hz, 2H), 6.99 (ddd J = 5.6, 3.3 Hz, 0.9 Hz, 2H), 6.79 (s, 2H). 13C
NMR (125.8 MHz, CDCl3): δ 136.4, 133.2, 129.9, 128.3, 119.5, 111.3.
E
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11B NMR (128.4 MHz, MeCN): δ 28.5. IR (neat): 3441, 3418, 1421,
746, 699, 597 cm−1. HRMS (ESI) m/z: calcd for C12H12BN2 [M + H]+
195.1094, found 195.1100.
2-(2-Methoxyphenyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole24
1
(5i). Obtained as a tan solid (175 mg, 78%). Mp: 123−124 °C. H
NMR (500.4 MHz, DMSO-d6): δ 8.77 (s, 2H), 7.86 (d, J = 7.2 Hz,
1H), 7.39 (t, J = 7.7 Hz, 1H), 7.11 (dd, J = 5.7, 3.3 Hz, 2H), 7.05−6.95
(m, 2H), 6.81 (dd, J = 5.8, 3.2 Hz, 2H), 3.89 (s, 3H). 13C NMR (125.8
MHz, DMSO-d6): δ 163.2, 136.9, 135.3, 131.0, 120.1, 118.0, 110.7,
110.4, 55.0. 11B NMR (128.4 MHz, MeCN): δ 27.4. IR (neat): 3460,
3423, 1598, 1418, 1243, 743, 619 cm−1. HMRS (CI) m/z: calcd for
C13H14BN2O [M + H]+ 225.1199, found 225.1201.
2-(o-Tolyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole23 (5b). Ob-
1
tained as a tan solid (173 mg, 83%). Mp: 107−110 °C. H NMR
(500.4 MHz, CDCl3): δ 7.65 (d, J = 7.3 Hz, 1H), 7.36 (t, J = 7.3 Hz,
1H), 7.28 (d, J = 7.3 Hz, 2H), 716 (dd, J = 5.6, 3.4 Hz, 2H), 7.02 (dd,
J = 5.6, 3.4 Hz, 2H), 6.73 (s, 2H), 2.59 (s, 3H). 13C NMR (125.8
MHz, CDCl3): δ 142.0, 136.2, 134.4, 130.0, 129.6, 125.4, 119.5, 111.2,
23.1. 11B NMR (128.4 MHz, MeCN): δ 28.6. IR (neat): 3457, 3423,
1605, 1416, 1351, 740, 612 cm−1. HRMS (CI) m/z: calcd for
C13H14BN2 [M + H]+ 209.1250, found 209.1242.
2-(3-Methoxyphenyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole24
(5j). Product further purified via recrystallization from boiling toluene.
1
Obtained as a brown solid (139 mg, 62%). Mp: 150−152 °C. H
NMR (500.4 MHz, DMSO-d6): 9.11 (s, 2H), 7.51 (s, 1H), 7.47 (d, J =
7.1 Hz, 1H), 7.33 (td, J = 7.7, 2.1 Hz, 1H), 7.06 (dt, J = 5.6, 2.6 Hz,
2H), 6.96 (d, J = 8.1 Hz, 1H), 6.82 (dt, J = 5.6, 2.7 Hz, 2H), 3.81 (s,
3H). 13C NMR (125.8 MHz, DMSO-d6): δ 156.9, 137.1, 129.0, 125.6,
118.5, 118.3, 115.0, 110.7, 54.9. 11B NMR (128.4 MHz, MeCN): δ
28.4. IR (neat): 3414, 1425, 750, 698, 634 cm−1. HMRS (CI) m/z:
calcd for C13H14BN2O [M + H]+ 225.1199, found 225.1201.
2-(3-Methoxyphenyl)-1-methyl-2,3-dihydro-1H-1,3,2-benzodia-
zaborole (5k). Obtained as a dark brown solid (191 mg, 80%). Mp:
86−88 °C. 1H NMR (500.4 MHz, CDCl3): δ 7.40 (t, J = 7.4 Hz, 1H),
7.30 (d, J = 7.4 Hz, 1H), 7.25 (s, 1H), 7.14−7.04 (m, 3H), 7.03−6.97
(m, 2H), 6.66 (s, 1H), 3.87 (s, 3H), 3.51 (s, 3H). 13C NMR (125.8
MHz, CDCl3): δ 159.4, 139.0, 135.8, 129.5, 126.1, 119.32, 199.31,
119.2, 114.5, 110.9, 108.9, 55.3, 30.0. 11B NMR (128.4 MHz, MeCN):
δ 28.4. IR (neat): 3427, 1575, 1402, 1254, 749, 702, 608 cm−1. HMRS
(CI) m/z: calcd for C14H16BN2O [M + H]+ 239.1356, found
239.1359.
2-(2,6-Dimethylphenyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole
1
(5c). Obtained as a tan solid (186 mg, 84%). Mp: 124−126 °C. H
NMR (500.4 MHz, CDCl3): δ 7.24 (t, J = 7.7 Hz, 1H), 7.15 (dd, 5.4,
3.6 Hz, 2H), 7. 08 (d, J = 7.7 Hz, 2H), 7.01 (dd, J = 5.4, 3.4 Hz, 2H),
6.54 (s, 2H), 2.33 (s, 6H). 13C NMR (125.8 MHz, CDCl3): δ 141.8,
136.2, 128.9, 126.4, 119.3, 111.2, 23,2. 11B NMR (128.4 MHz,
MeCN): δ 29.5. IR (neat): 3421, 3054, 2925, 1440, 1352, 739, 617
cm−1. HRMS (CI) m/z: calcd for C14H14BN2 [M − H]− 221.1250,
found 221.1257.
1-Methyl-2-phenyl-2,3-dihydro-1H-1,3,2-benzodiazaborole9c
(5d). Three mmol scale reaction in a 20 mL microwave vial. Obtained
1
as a dark red solid (171 mg, 82%). Mp: 84−88 °C. H NMR (500.4
MHz, CDCl3): δ 7.74−7.70 (m, 2H), 7.47−7.44 (m, 3H), 7.18−7.07
(m, 3H), 7.03 (td, J = 7.6, 1.3 Hz, 1H), 6.66 (s, 1H), 3.52 (s, 3H). 13C
NMR (125.8 MHz, CDCl3): δ 139.1, 135.9, 133.8, 129.2, 128.2, 119.3,
119.3, 110.1, 106.8, 30.0. 11B NMR (128.4 MHz, MeCN): δ 28.8. IR
(neat): 3431, 3054, 3045, 1409, 736, 703, 587 cm−1. HRMS (CI) m/z:
calcd for C13H13BN2 [M]+ 208.1172, found 208.1172.
2-(2-Phenoxyphenyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole
(5l). Product further purified via a plug of silica with hexane/EtOAc
(4/1) as eluent. Obtained as a brown solid (178 mg, 62%). Mp: 81−
2-(2,6-Difluorophenyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole
(5e). Product further purified via a plug of silica with hexane/EtOAc
(4:1) as eluent. Obtained as a tan solid (154 mg, 67%). Mp: 148−151
1
83 °C. H NMR (500.4 MHz, CDCl3): δ 7.79−7.75 (m, 1H), 7.41−
1
°C. H NMR (500.4 MHz, DMSO-d6): δ 9.01 (s, 2H), 7.54 (tt, J =
7.32 (m, 3H), 7.17 (dt, J = 11.4, 7.3 Hz, 2H), 7.12−7.07 (m, 4H), 7.03
(s, 2H), 6.96 (d, J = 3.2 Hz, 1H), 6.95 (d, J = 3.3 Hz, 1H), 6.89−6.86
(m, 1H). 13C NMR (125.8 MHz, CDCl3): δ 161.8, 157.2, 136.3, 135.1,
131.4, 130.1, 123.8, 123.3, 119.6, 119.4, 118.1, 111.2. 11B NMR (128.4
MHz, CDCl3): δ 27.1. IR (neat): 3431, 3186, 2946, 2865, 1458, 1274,
738, 575 cm−1. HMRS (CI) m/z: calcd for C18H15BN2ONa [M +
Na]+ 309.1175, found 309.1181.
8.2, 6.9 Hz, 1H), 7.18 (dd, J = 5.7, 3.3 Hz, 2H), 7.16−7.12 (m, 2H),
6.96−6.74 (m, 2H). 13C NMR (125.8 MHz, CDCl3): δ 167.0 (dd, J =
247.5, 13.4 Hz), 135.7, 132.2 (t, J = 11.3 Hz), 119.7, 111.5, 111.4 (dd,
J = 23.1, 5.6 Hz). 11B NMR (128.4 MHz, MeCN): δ 24.6. 19F NMR
(282.4 MHz, CDCl3): δ −103.0. IR (neat): 3450, 3054, 1624, 1453,
979, 779, 735, 590 cm−1. HRMS (CI) m/z: calcd for C12H9BN2F2
[M]+ 230.0827, found 230.0827.
2-(4-(Methoxycarbonyl)phenyl)-2,3-dihydro-1H-1,3,2-benzodia-
2-(4-Bromophenyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole9c
zaborole (5m). Obtained as a tan solid (130 mg, 51%). Mp: 171−172
1
1
(5f). Obtained as a tan solid (184 mg, 68%), Mp: 216−218 °C. H
°C. H NMR (500.4 MHz, DMSO-d6): δ 9.33 (s, 2H), 8.54 (s, 1H),
NMR (500.4 MHz, CDCl3): δ 7.61−7.54 (m, 4H), 7.12 (dd, J = 5.4,
3.3 Hz, 2H), 6.99 (dd, J = 5.3, 4.4 Hz, 2H), 6.76 (s, 2H). 13C NMR
(125.8 MHz, CDCl3): δ 136.3, 134.8, 131.5, 124.5, 119.7, 111.4. 11B
NMR (128.4 MHz, MeCN): δ 28.2. IR (neat): 3418, 1584, 1427,
1275, 751, 599 cm−1. HRMS (CI) m/z: calcd for C12H10BN2Br [M]+
272.0120, found 272.0133.
8.16 (d, J = 7.9 Hz, 1H), 7.99 (dt, J = 8.1, 1.7 Hz, 1H), 7.58 (td, J =
7.6, 1.7 Hz, 1H), 7.16−7.02 (m, 2H), 6.83 (dt, J = 5.6, 2.5 Hz, 2H),
3.90 (s, 3H). 13C NMR (125.8 MHz, DMSO-d6): δ 166.6, 138.1,
137.1, 134.0, 130.0, 129.3, 128.3, 118.4, 111.0, 52.1. 11B NMR (128.4
MHz, MeCN): δ 28.0. IR (neat): 3424, 3404, 2950, 1701, 1431, 1282,
1263, 741, 690 cm−1. HMRS (CI) m/z: calcd for C14H14BN2O2 [M +
H]+ 253.1148, found 253.1137.
2-(4-Fluorophenyl)-1-methyl-2,3-dihydro-1H-1,3,2-benzodiaza-
borole (5g). Obtained as a brown solid (185 mg, 82%). Mp: 114−115
2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-dihydro-1H-1,3,2-
1
°C. H NMR (500.4 MHz, CDCl3): δ 7.68 (dd, J = 8.8, 5.7 Hz, 2H),
benzodiazaborole (5n). Obtained as a tan solid (191 mg, 76%). Mp:
1
7.19−7.12 (m, 2H), 7.12−7.03 (m, 3H), 7.00 (t, J = 6.8 Hz, 1H), 6.61
(s, 1H), 3.48 (s, 3H). 13C NMR (125.8 MHz, CDCl3): δ 163.8 (d, J =
248.4 Hz), 139.0, 135.8, 135.6 (d, J = 7.9 Hz), 119.4, 119.4, 115.4 (d, J
= 19.9 Hz), 110.9, 108.9, 30.0. 11B NMR (128.4 MHz, MeCN): δ 28.0.
19F NMR (282.4 MHz, CDCl3): δ −112.5. IR (neat): 3437, 3054,
2910, 1596, 1397, 1217, 830, 738, 576 cm−1. HMRS (CI) m/z: calcd
for C13H12BN2F [M]+ 226.1078, found 226.1080.
199−201 °C. H NMR (500.4 MHz, CDCl3): δ 7.24−7.20 (m, 2H),
7.10 (dd, J = 5.3, 3.4 Hz, 2H), 6.98−6.93 (m, 3H), 6.68 (s, 2H), 4.30
(s, 4H). 13C NMR (125.8 MHz, CDCl3): δ 145.3, 143.6, 136.5, 126.5,
121.9, 119.4, 117.4, 111.1, 64.7, 64.5. 11B NMR (128.4 MHz, MeCN):
δ 28.5. IR (neat): 3446, 3416, 2995, 2940, 2875, 1575, 1245, 1126,
745, 547 cm−1. HMRS (CI) m/z: calcd for C14H14BN2O2 [M + H]+
253.1148, found 253.1157.
2-(3-Nitrophenyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole9c (5o).
Product further purified via a plug of silica with hexane/EtOAc (4/1)
as eluent. Obtained as a tan solid (62 mg, 26%). Mp: 210−211 °C. 1H
NMR (500.4 MHz, DMSO-d6): δ 9.46 (s, 2H), 8.79 (s, 1H), 8.32 (d, J
= 7.1 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.09
(dd, J = 5.8, 3.1 Hz, 2H), 6.86 (dt, J = 5.7, 3.1 Hz, 2H). 13C NMR
(125.8 MHz, DMSO-d6): δ 147.6, 139.7, 136.9, 129.5, 127.5, 123.9,
118.7, 111.1. 11B NMR (128.4 MHz, MeCN): δ 27.7. IR (neat): 3397,
1620, 1429, 1346, 1270, 737, 687 cm−1. HMRS (CI) m/z: calcd for
C12H11BN3O2 [M + H]+ 240.0944, found 240.0937.
2-(3-Vinylphenyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole (5h).
Obtained as a light brown solid (162 mg, 73%). Mp: 119−121 °C.
1H NMR (500.4 MHz, DMSO-d6): δ 9.16 (s, 2H), 8.05 (s, 1H), 7.80
(d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H),
7.09−7.02 (m, 2H), 6.84−6.81 (m, 2H), 6.77 (dd, J = 17.5, 10.8 Hz,
1H), 5.92 (d, J = 17.6 Hz, 1H), 5.31 (d, J = 10.9 Hz, 1H). 13C NMR
(125.8 MHz, DMSO-d6): δ 137.1, 136.9, 136.5, 133.0, 131.1, 128.2,
127.3, 118.3, 114.1, 110.8. 11B NMR (128.4 MHz, MeCN): δ 28.5. IR
(neat): 3445, 3425, 3054, 1353, 904, 746, 688, 564 cm−1. HMRS (CI)
m/z: calcd for C14H14BN2 [M + H]+ 221.1250, found 221.1244.
F
DOI: 10.1021/acs.joc.6b00435
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The Journal of Organic Chemistry
Article
2-(3-Cyanophenyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole (5p).
Obtained as a tan solid (53 mg, 24%). Mp: 195−196 °C. H NMR
NMR (500.4 MHz, DMSO-d6): δ 9.68 (s, 1H), 9.44 (s, 1H), 7.96−
7.85 (m, 2H), 7.74−7.66 (m, 2H), 7.66−7.59 (m, 1H), 7.58−7.51 (m,
3H), 7.45 (t, J = 4.6 Hz, 3H), 7.39 (dd, J = 8.1, 2.5 Hz, 1H), 7.19 (dd,
J = 8.4, 2.8 Hz, 1H). 13C NMR (125.8 MHz, DMSO-d6): δ 195.4,
142.0, 139.0, 137.0, 133.5, 131.3, 129.8, 128.2, 128.0, 127.5, 122.7,
112.6, 110.3. 11B NMR (128.4 MHz, MeCN): δ 30.2. IR (neat): 3460,
3372, 1603, 1428, 1287, 707, 630 cm−1. HMRS (CI) m/z: calcd for
C19H16BN2O [M + H]+ 299.1356, found 299.1348.
1
(500.4 MHz, CDCl3): δ 8.01 (s, 1H), 7.94 (dt, J = 7.5, 1.3 Hz, 1H),
7.71 (dt, J = 7.8, 1.5 Hz, 1H), 7.54 (td, J = 7.6, 0.7 Hz, 1H), 7.19−7.13
(m, 2H), 7.01 (dd, J = 5.7, 3.1 Hz, 2H), 6.86 (s, 2H). 13C NMR (125.8
MHz, CDCl3): δ 137.2, 136.7, 136.1, 133.0, 129.0, 120.1, 119.1, 112.7,
111.7. 11B NMR (128.4 MHz, CDCl3): δ 27.6. IR (neat): 3415, 3378,
3065, 2232, 1434, 1273, 745, 693, 561 cm−1. HMRS (CI) m/z: calcd
for C13H11BN3 [M + H]+ 220.1046, found 220.1048.
5-Nitro-2-phenyl-2,3-dihydro-1H-1,3,2-benzodiazaborole9c (5y).
Product further purified via recrystallization from boiling toluene.
2-(Thiophen-3-yl)-2,3-dihydro-1H-1,3,2-benzodiazaborole (5q).
1
1
Obtained as a tan solid (128 mg, 64%). Mp: 221−222 °C. H NMR
Obtained as an orange solid (148 mg, 62%). Mp: 195−196 °C. H
(500.4 MHz, CDCl3): δ 7.75−7.73 (m, 1H), 7.45 (dd, J = 4.7, 2.6 Hz,
1H), 7.42 (d, J = 4.6 Hz, 1H), 7.11 (dd, J = 7.5, 3.8 Hz, 2H), 6.97 (dd,
J = 5.7, 3.3 Hz, 2H), 6.70 (s, 2H). 13C NMR (125.8 MHz, CDCl3): δ
136.3, 131.9, 131.2, 126.1, 119.5, 111.2. 11B NMR (128.4 MHz,
MeCN): δ 26.4. IR (neat): 3427, 1431, 740, 662, 600 cm−1. HMRS
(CI) m/z: calcd for C10H9BN2S [M]+ 200.0580, found 200.0601.
2-(2-Benzofuranyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole (5r).
NMR (500.4 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.70 (s, 1H), 7.94−
7.86 (m, 4H), 7.50−7.45 (m, 3H), 7.20 (d, J = 8.5 Hz, 1H). 13C NMR
(125.8 MHz, DMSO-d6): δ 143.7, 139.8, 137.1, 133.6, 130.2, 128.1,
116.0, 110.1, 105.9. 11B NMR (128.4 MHz, MeCN): δ 31.0. IR (neat):
3435, 3415, 3380, 1610, 1435, 1303, 695, 631 cm−1. HMRS (ESI-) m/
z: calcd for C12H9BN3O2 [M − H]− 238.0788, found 238.0788.
2-Phenyl-2,3-dihydro-1H-1,3,2-naphthodiazaborole9c (5z). Prod-
uct further purified via recrystallization from boiling toluene. Obtained
1
Obtained as a tan solid (132 mg, 57%). Mp: 220−222 °C. H NMR
1
(500.4 MHz, CDCl3): δ 7.66 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.2 Hz,
1H), 7.39−7.32 (m, 1H), 7.29−7.23 (m, 2H), 7.16 (dd, J = 7.4, 3.7
Hz, 2H), 7.01 (dd, J = 5.8, 3.2 Hz, 2H), 6.96 (s, 2H). 13C NMR (125.8
MHz, DMSO-d6): δ 156.5, 136.7, 128.0, 125.0, 122.7, 121.5, 118.7,
115.5, 111.2, 111.1. 11B NMR (128.4 MHz, MeCN): δ 24.8. IR (neat):
3436, 1569, 1411, 1337, 735, 602 cm−1. HMRS (CI) m/z: calcd for
C14H12BN2O [M + H]+ 235.1043, found 235.1053.
as a tan solid (33.5 mg, 14%). Mp: > 250 °C. H NMR (500.4 MHz,
DMSO-d6): δ 9.30 (s, 2H), 8.00−7.95 (m, 2H), 7.77 (dd, J = 6.6, 3.3
Hz, 2H), 7.48−7.44 (m, 3H), 7.42 (s, 2H), 7.22 (dd, J = 6.9, 3.1 Hz,
2H). 13C NMR (125.8 MHz, DMSO-d6): δ 139.0, 133.7, 129.9, 128.6,
128.0, 126.4, 122.0, 105.4. 11B NMR (128.4 MHz, MeCN): δ 30.8. IR
(neat): 3429, 1435, 862, 695, 588 cm−1. HMRS (CI) m/z: calcd for
C16H14BN2 [M + H]+ 245.1250, found 245.1252.
2-(Furan-2-yl)-1-methyl-2,3-dihydro-1H-1,3,2-benzodiazaborole
(5s). Product further purified via a plug of silica with hexane/EtOAc
(4/1) as eluent. Obtained as a brown solid (144 mg, 73%). Mp: 73−
75 °C. 1H NMR (500.4 MHz, CDCl3): δ 7.75 (s, 1H), 7.60 (d, J = 1.4
Hz, 1H), 7.06−7.03 (m, 3H) 6.99 (dt, J = 7.4, 1.4 Hz, 1H), 6.66 (s,
1H), 6.57 (s, 1H) 3.49 (s, 3H). 13C NMR (125.8 MHz, CDCl3): δ
147.4, 143.2, 138.9, 119.2, 119.1, 113.2, 110.8, 108.6, 30.0. 11B NMR
(128.4 MHz, MeCN): δ 26.4. IR (neat): 3431, 3054, 2947, 1478,
1345, 733, 541 cm−1. HMRS (CI) m/z: calcd for C11H11BN2O [M]+
198.0964, found 198.0965.
General Procedure for Synthesis of Alkyl and Alkenyl 1,3,2-
Benzodiazaboroles 6a−h and 7a−h. Diamine (1 equiv, 1 mmol),
organotrifluoroborate (1 equiv, 1 mmol), and BF3·NH2Et (3 equiv, 3
mmol) were placed in an oven-dried Biotage microwave vial with a stir
bar. The vial was sealed with a cap, which was lined with a disposable
Teflon septum. The reaction vessel was subsequently evacuated and
purged three times with argon. A 1/1 mixture of CPME (1 mL) and
toluene (1 mL) was added, and the reaction mixture was heated to 80
°C. After it was stirred overnight, the reaction mixture was diluted with
2 mL of hexane and run though a 2 in. silica plug, with 10% EtOAc in
hexane as eluent. The reaction mixture was then condensed under
vacuum to afford the azaborine compound.
5-Methyl-2-phenyl-2,3-dihydro-1H-1,3,2-benzodiazaborole9c
1
(5u). Obtained as a tan solid (164 mg, 79%). Mp: 212−214 °C. H
NMR (500.4 MHz, CDCl3 with 1% TMS): δ 7.74−7.71 (m, 2H),
7.44−7.41 (m, 3H), 7.00 (dd, J = 7.9, 3.4 Hz, 1H), 6.94 (s, 1H), 6.79
(d, J = 7.9 Hz, 1H), 6.69 (s, 2H), 2.40 (d, J = 3.4 Hz, 3H). 13C NMR
(125.8 MHz, CDCl3 with 1% TMS): δ 136.6, 134.2, 133.1, 129.8,
129.0, 128.3, 120.1, 112.0, 110.8, 21.5. 11B NMR (128.4 MHz,
MeCN): δ 28.6. IR (neat): 3440, 3054, 2915, 1603, 1419, 805, 695,
569 cm−1. HMRS (CI) m/z: calcd for C13H14BN2 [M + H]+ 209.1250,
found 209.1247.
(E)-2-(Prop-1-en-1-yl)-2,3-dihydro-1H-1,3,2-benzodiazaborole
1
(6a). Obtained as a brown solid (110 mg, 70%). Mp: 72−74 °C. H
NMR (500.4 MHz, CDCl3): δ 7.05 (dd, J = 5.7, 3.3 Hz, 2H), 6.94 (dd,
J = 5.8, 3.2 Hz, 2H), 6.60−6.33 (m, 3H), 5.90 (d, J = 17.7 Hz, 1H),
1.95 (d, J = 6.4 Hz, 3H). 13C NMR (125.8 MHz, CDCl3): δ 143.8,
136.3, 119.1, 110.9, 22.1. 11B NMR (128.4 MHz, CDCl3): δ 27.0. IR
(neat): 3385, 3185, 1500, 1272, 743 cm−1. HMRS (CI) m/z: calcd for
C9H12BN2 [M + H]+ 159.1094, found 159.1100.
5-Fluoro-2-phenyl-2,3-dihydro-1H-1,3,2-benzodiazaborole (5v).
1
2-(Cyclohex-1-en-1-yl)-2,3-dihydro-1H-1,3,2-benzodiazaborole
(6b). Obtained as a brown solid (156 mg, 79%). Mp: 123−125 °C. 1H
NMR (500.4 MHz, CDCl3): δ 7.03 (dd, J = 5.6, 3.2 Hz, 2H), 6.92 (dd,
J = 5.6, 3.2 Hz, 2H), 6.41 (s, 3H), 2.29−2.25 (m, 2H), 2.21−2.16 (m,
2H), 1.74−1.67 (m, 4H). 13C NMR (125.8 MHz, CDCl3): δ 138.0,
136.3, 119.0, 110.8, 27.3, 26.7, 22.8, 22.4. 11B NMR (128.4 MHz,
CDCl3): δ 27.9. IR (neat): 3430, 2923, 2852, 1627, 1431, 738, 594
cm−1. HMRS (CI) m/z: calcd for C12H16BN2 [M + H]+ 199.1407,
found 199.1411.
Obtained as a brown solid (160 mg, 76%). Mp: 186−188 °C. H
NMR (500.4 MHz, CDCl3): δ 7.73−7.70 (m, 2H), 7.47−7.41 (m,
3H), 6.98 (dd, J = 8.4, 4.9 Hz, 1H), 6.85 (dd, J = 9.3, 2.5 Hz, 1H), 6.78
(s, 1H), 6.71−6.66 (m, 2H). 13C NMR (125.8 MHz, CDCl3): δ 157.9
(d, J = 233.9 Hz), 136.9 (d, J = 11.9 Hz), 133.1, 132.6, 130.0, 128.4,
110.7 (d, J = 9.9 Hz), 105.8 (d, J = 24.1 Hz), 99.0 (d, J = 26.8 Hz). 11B
NMR (128.4 MHz, MeCN): δ 29.2. 19F NMR (282.4 MHz, CDCl3): δ
−124.9. IR (neat): 3441, 1424, 1365, 1255, 1139, 700, 587 cm−1.
HMRS (CI) m/z: calcd for C12H11BN2F [M + H]+ 213.0999, found
213.1000.
2-Vinyl-2,3-dihydro-1H-1,3,2-benzodiazaborole (6c). Product fur-
ther purified via a plug of silica with hexane/EtOAc (4/1) as eluent.
5-Bromo-2-phenyl-2,3-dihydro-1H-1,3,2-benzodiazaborole (5w).
Eight millimole scale reaction in a 20 mL microwave vial. Obtained as
a brown solid (1.64 g, 76%). Mp: 157−159 °C. 1H NMR (500.4 MHz,
CDCl3): δ 7.77−7.63 (m, 2H), 7.45 (d, J = 6.0 Hz, 3H), 7.24 (s, 1H),
7.12−7.05 (m, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.77 (s, 2H). 13C NMR
(125.8 MHz, CDCl3): δ 137.8, 135.5, 133.2, 130.2, 128.4, 122.2, 114.3,
112.2, 112.0. 11B NMR (128.4 MHz, MeCN): δ 28.8. IR (neat): 3435,
1599, 1420, 803, 697, 566 cm−1. HMRS (CI) m/z: calcd for
C12H10BBrN2 [M]+ 272.0120, found 272.0127.
5-Phenylcarbonyl-2-phenyl-2,3-dihydro-1H-1,3,2-benzodiaza-
borole (5x). Eight millimole scale reaction in a 20 mL microwave vial.
Product further purified via recrystallization from boiling toluene.
Obtained as a burnt orange solid (1.31 g, 55%). Mp: 186−187 °C. 1H
1
Obtained as a tan solid (97 mg, 68%). Mp: 106−108 °C. H NMR
(500.4 MHz, CDCl3): δ 7.05 (dt, J = 7.3, 3.6 Hz, 2H), 6.94 (dd, J =
5.7, 3.2 Hz, 2H), 6.52 (s, 2H), 6.31 (dd, Jtrans = 20.0, Jcis = 13.7 Hz,
1H), 6.08−5.85 (m, 2H). 13C NMR (125.8 MHz, CDCl3): δ 136.1,
131.8, 119.4, 111.1. 11B NMR (128.4 MHz, MeCN): δ 27.5. IR (neat):
3415, 3054, 1615, 1407, 1270, 954, 750, 631 cm−1. HMRS (CI) m/z:
calcd for C8H9BN2 [M]+ 144.0859, found 144.0849.
2-(1-Propynyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole (6d). Ob-
1
tained as a white solid (122 mg, 78%). Mp: 130−131 °C. H NMR
(500.4 MHz, CDCl3): δ 7.06−7.03 (m, 2H), 6.96 (dd, J = 5.7, 3.2 Hz,
2H), 6.59 (s, 2H), 2.02 (s, 3H). 13C NMR (125.8 MHz, CDCl3): δ
135.5, 119.7, 111.2, 5.0. 11B NMR (128.4 MHz, MeCN): δ 20.2. IR
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DOI: 10.1021/acs.joc.6b00435
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The Journal of Organic Chemistry
Article
(neat): 3422, 3057, 2204, 1418, 1352, 1266, 729, 624 cm−1. HMRS
(CI) m/z: calcd for C9H9BN2 [M]+ 156.0859, found 156.0844.
1-Methyl-2-vinyl-2,3-dihydro-1H-1,3,2-benzodiazaborole (6e).
2-(tert-Butyl)-2,3-dihydro-1H-1,3,2-benzodiazaborole8a (7d). Half
millimole scale reaction. Product further purified via a plug of silica
with hexane/EtOAc (4/1) as eluent. Obtained as a tan solid (63 mg,
1
1
72%). Mp: 90−91 °C. H NMR (500.4 MHz, CDCl3): δ 7.05−6.99
Obtained as a dark red oil (136 mg, 86%). H NMR (500.4 MHz,
(m, 2H), 6.95−6.88 (m, 2H), 6.26 (s, 2H), 1.13 (s, 9H). 13C NMR
(125.8 MHz, CDCl3): δ 136.2, 119.1, 110.8, 100.1, 29.1. 11B NMR
(128.4 MHz, CDCl3): δ 33.08. IR (neat): 3438, 3390, 3345, 3194,
2939, 1477, 1435, 585, 568 cm−1. HMRS (CI) m/z: calcd for
C10H15BN2 [M]+ 174.1328, found 174.1328.
CDCl3): δ 7.05 (d, J = 7.4 Hz, 1H), 7.02−6.99 (m, 2H), 6.96 (dt, J =
7.1, 2.7 Hz, 1H), 6.50 (s, 1H), 6.41 (dd, J = 18.6, 15.5 Hz, 1H), 5.98
(d, J = 18.6 Hz, 2H), 3.40, (s, 3H). 13C NMR (125.8 MHz, CDCl3): δ
135.8, 131.8, 119.2, 119.1, 110.7, 108.5, 29.5. 11B NMR (128.4 MHz,
MeCN): δ 26.71. IR (neat): 3428, 3054, 2930, 1614, 1443, 1399,
1010, 733 cm−1. HMRS (CI) m/z: calcd for C9H12BN2 [M + H]+
159.1094, found 159.1090.
2-Phenethyl-2,3-dihydro-1H-1,3,2-benzodiazaborole25 (7e). Ob-
1
tained as a brown solid (198 mg, 89%). Mp: 112−114 °C. H NMR
(500.4 MHz, CDCl3): δ 7.31 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 1.4 Hz,
2H), 7.21 (t, J = 7.2 Hz, 1H), 7.00 (dd, J = 5.7, 3.2 Hz, 2H), 6.91 (dd,
J = 5.7, 3.2 Hz, 2H), 6.29 (s, 2H), 2.90 (t, J = 8.1 Hz, 2H), 1.59 (t, J =
8.1 Hz, 2H). 13C NMR (125.8 MHz, CDCl3): δ 144.4, 136.2, 128.6,
128.1, 125.9, 119.0, 110.7, 32.0. 11B NMR (128.4 MHz, MeCN): δ
31.0. IR (neat): 3433, 2925, 1434, 1267, 732, 593 cm−1. HMRS (CI)
m/z: calcd for C14H15BN2 [M]+ 222.1328, found 222.1328.
(E)-1-Methyl-2-(prop-1-en-1-yl)-2,3-dihydro-1H-1,3,2-benzodia-
zaborole (6f). Obtained as a dark brown solid (153 mg, 89%). Mp:
81−85 °C. 1H NMR (500.4 MHz, CDCl3): δ 7.02 (d, J = 7.5 Hz, 1H),
6.99 (d, J = 3.4 Hz, 2H), 6.94 (dd, J = 7.0, 4.3 Hz, 1H), 6.49−6.42 (dd,
J = 18.0, 6.0 Hz, 1H), 6.40 (s, 1H), 5.98 (dd, J = 18.0, 1.8 Hz, 1H),
3.37 (s, 3H), 1.96 (dd, J = 6.0, 1.8 Hz, 3H). 13C NMR (125.8 MHz,
CDCl3): δ 143.7, 138.9, 136.0, 118.9, 118.8, 110.4, 108.2, 29.4, 22.3.
11B NMR (128.4 MHz, MeCN): δ 27.0. IR (neat): 3424, 2905, 1645,
1,2-Dimethyl-2,3-dihydro-1H-1,3,2-benzodiazaborole (7f). Five
1412, 1240, 984, 733 cm−1. HMRS (CI) m/z: calcd for C10H14BN2 [M
millimole scale reaction in a 20 mL microwave vial. Obtained as a
1
+ H]+ 173.1250, found 173.1254.
dark brown solid (0.66 g, 90%). Mp: 80−82 °C. H NMR (500.4
MHz, CDCl3): δ 7.04−6.96 (m, 3H), 6.96−6.90 (m, 1H), 6.29 (s,
1H), 3.31 (s, 3H), 0.65 (s, 3H). 13C NMR (125.8 MHz, CDCl3): δ
138.8, 136.1, 118.7, 118.5, 110.1, 107.9, 29.2. 11B NMR (128.4 MHz,
MeCN): δ 30.3. IR (neat): 3425, 3054, 2910, 1615, 1413, 1368, 1356,
732, 586 cm−1. HMRS (CI) m/z: calcd for C8H11BN2 [M]+ 146.1051,
found 146.1021.
2-(3-Chloropropyl)-1-methyl-2,3-dihydro-1H-1,3,2-benzodiaza-
borole (7g). Obtained as a brown oil (194 mg, 94%). 1H NMR (500.4
MHz, CDCl3): δ 7.03−6.87 (m, 3H), 6.93 (dt, J = 6.93, 2.5 Hz, 1H),
6.26 (s, 1H), 3.60 (t, J = 6.7 Hz, 2H), 3.31 (s, 3H), 2.08−1.98 (m,
2H), 1.36 (t, J = 8.0 Hz, 2H). 13C NMR (125.8 MHz, CDCl3): δ
138.7, 135.9, 119.0, 118.8, 110.4, 108.2, 47.4, 29.3, 29.3. 11B NMR
(128.4 MHz, CDCl3): δ 30.6. IR (neat): 3327, 2928, 1617, 1307, 1052,
910, 731 cm−1. HMRS (CI) m/z: calcd for C10H14BN2Cl [M]+
208.0939, found 208.0939.
1-Phenyl-2-vinyl-2,3-dihydro-1H-1,3,2-benzodiazaborole (6g).
Ten millimole scale reaction in a 50 mL round-bottom flask. Product
was further purified via combiflash with hexane/EtOAc as solvents.
1
Obtained as a deep red oil (0.93 g, 42%). H NMR (500.4 MHz,
CDCl3): δ 7.47 (t, J = 7.1 Hz, 2H), 7.40−7.29 (m, 3H), 7.13 (d, J =
7.7 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 6.94 (t,
J = 7.6 Hz, 1H), 6.70 (s, 1H), 6.25 (dd, Jtrans = 20.1, Jcis = 13.9 Hz, 1H),
5.99−5.84 (m, 2H). 13C NMR (125.8 MHz, CDCl3): δ 140.6, 137.8,
135.7, 132.4, 129.4, 126.9, 120.1, 119.3, 111.3, 110.1. 11B NMR (128.4
MHz, MeCN): δ 26.7. IR (neat): 3430, 3054, 1596, 1396, 1269, 736,
696 cm−1. HMRS (CI) m/z: calcd for C14H14BN2 [M + H]+ 221.1250,
found 221.1254.
(E)-1-Phenyl-2-(1-propenyl)-2,3-dihydro-1H-1,3,2-benzodiaza-
borole (6h). Product further purified via a plug of silica with hexane/
EtOAc (4/1) as eluent. Obtained as a red solid (178 mg, 76%). Mp:
1
2-Methyl-1-phenyl-2,3-dihydro-1H-1,3,2-benzodiazaborole (7h).
Ten millimole scale reaction in a 50 mL round-bottom flask. Product
was further purified via Combiflash with hexane/EtOAc as solvents.
61−63 °C. H NMR (500.4 MHz, CDCl3): δ 7.53−7.43 (m, 2H),
7.40−7.29 (m, 3H), 7.13−7.08 (m, 1H), 7.08−7.03 (m, 1H), 7.03−
6.97 (m, 1H), 6.96−6.90 (m, 1H), 6.59 (s, 1H), 6.49−6.34 (m, 1H),
5.84 (d, J = 18.9 Hz, 1H), 1.91−1.84 (m, 3H). 13C NMR (125.8 MHz,
CDCl3): δ 144.5, 140.8, 138.0, 136.0, 129.3, 127.0, 125.9, 119.9, 119.1,
111.0, 109.8, 22.2. 11B NMR (128.4 MHz, CDCl3): δ 26.8. IR (neat):
3387, 1597, 1495, 1315, 746, 691 cm−1. HMRS (CI) m/z: calcd for
C14H13BN2 [(M + H) − CH3]+ 220.1172, found 220.1172.
1
Obtained as a deep red oil (0.93 g, 32%). H NMR (500.4 MHz,
CDCl3): δ 7.46 (t, J = 7.9 Hz, 2H), 7.37−7.28 (m, 3H), 7.06 (dt, J =
10.9, 7.9 Hz, 2H), 6.97 (t, J = 7.7 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H),
6.48 (s, 1H), 0.64 (s, 3H). 13C NMR (125.8 MHz, CDCl3): δ 141.0,
137.7, 136.0, 129.3, 126.6, 125.7, 119.6, 118.9, 110.7, 109.6. 11B NMR
(128.4 MHz, MeCN): δ 30.6. IR (neat): 3433, 1597, 1409, 1356,
1271, 734, 697 cm−1. HMRS (CI) m/z: calcd for C13H14BN2 [M +
H]+ 209.1250, found 209.1250.
2-Methyl-2,3-dihydro-1H-1,3,2-benzodiazaborole8b (7a). Product
further purified via a plug of silica with hexane/EtOAc (4/1) as eluent.
1
Obtained as a tan solid (94 mg, 71%). Mp: 67−68 °C. H NMR
(500.4 MHz, CDCl3): δ 7.00 (dd, J = 5.7, 3.2 Hz, 2H), 6.91 (dd, J =
5.7, 3.2 Hz, 2H), 6.30, (s, 2H), 0.63 (s, 3H). 13C NMR (125.8 MHz,
CDCl3): δ 136.4, 118.9, 110.5. 11B NMR (128.4 MHz, CDCl3): δ 30.3.
IR (neat): 3421, 3385, 3054, 2905, 1612, 1263, 739, 600 cm−1. HMRS
(CI) m/z: calcd for C7H8BN2 [M − H]− 131.0781, found 131.0783.
2-Isopropyl-2,3-dihydro-1H-1,3,2-benzodiazaborole8a (7b). Prod-
uct further purified via a plug of silica with hexane/EtOAc (4:1) as
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00435.
■
S
pKa study of 1-methyl-2-phenyl-2,3-dihydro-1H-1,3,2-
benzodiazaborole (5d), calculated bond lengths, geom-
etry optimized Cartesian coordinates for computed
1
eluent. Obtained as a tan solid (107 mg, 67%). Mp: 78−79 °C. H
NMR (500.4 MHz, CDCl3): δ 7.07−6.97 (m, 2H), 6.94−6.86 (m,
2H), 6.31 (s, 2H), 1.52 (sept, J = 7.4 Hz, 1H), 1.15 (d, J = 6.7 Hz,
6H). 13C NMR (125.8 MHz, CDCl3): δ 136.2, 119.0, 110.8, 20.1. 11B
NMR (128.4 MHz, CDCl3): δ 32.4. IR (neat): 3432, 3385, 3186,
2945, 1458, 1431, 1274, 738, 576 cm−1. HMRS (CI) m/z: calcd for
C9H13BN2 [M]+ 160.1172 found 160.1177.
1
molecules, and H, 13C, 11B, and 19F NMR spectra for
all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
Notes
■
2-Cyclopropyl-2,3-dihydro-1H-1,3,2-benzodiazaborole (7c).
Product further purified via a plug of silica with hexane/EtOAc (4/
1) as eluent. Obtained as a dark brown solid (90 mg, 57%). Mp: 64−
1
66 °C. H NMR (500.4 MHz, CDCl3): δ 7.01−6.94 (m, 2H), 6.92−
The authors declare no competing financial interest.
6.86 (m, 2H), 6.15 (s, 2H), 0.82 (dt, J = 9.4, 3.8 Hz, 2H), 0.50 (dd, J =
6.6, 3.8 Hz, 2H), 0.21 (tt, J = 9.4, 6.3 Hz, 1H). 13C NMR (125.8 MHz,
CDCl3): δ 136.3, 118.9, 110.5, 5.6. 11B NMR (128.4 MHz, MeCN): δ
31.2. IR (neat): 3414, 2998, 2925, 1440, 900, 733, 588 cm−1. HMRS
(CI) m/z: calcd for C9H11BN2 [M]+ 158.1015, found 158.1008.
ACKNOWLEDGMENTS
This research was supported by the NIH/NIGMS (R01 GM-
111465) and Eli Lilly. Frontier Scientific is acknowledged for
■
H
DOI: 10.1021/acs.joc.6b00435
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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their generous donation of potassium organotrifluoroborates.
Evan L. T. Davies (Georgia Tech) is acknowledged for
computational help with the NICS calculations. Matthieu
Jouffroy and Christopher B. Kelly (University of Pennsylvania)
are acknowledged for their thoughtful discussions and guidance.
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DOI: 10.1021/acs.joc.6b00435
J. Org. Chem. XXXX, XXX, XXX−XXX