Synthesis and stability study of isocyano aryl boronate esters and their synthetic applications

Article abstract of DOI:10.1039/C5RA27624A

A facile synthesis of isocyano arylboronate esters is reported. Although tri-coordinate boron functional groups are commonly recognized as vulnerable to nucleophilic attack, the newly reported tri-coordinate isocyano arylboronate esters were found to be stable, albeit owing to the presence of an isocyano group. Theoretical calculations, using the DFT/B3LYP/6-31G(d,p) method, revealed that the electron delocalization between the aryl group and the boron atom might contribute to this stability. UV-vis spectroscopic investigations on 2-(4-isocyanophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2a) were in agreement with the theoretical studies, showing a red-shifted absorption compared with that of phenylisonitrile. The reported strategy allows boronate ester substrates to survive throughout two-step operations. Two of the compounds synthesized were successfully exploited in Ugi and Passerini multicomponent reactions to afford corresponding products. In addition, two boron-containing tetrazoles were also prepared under environmentally benign conditions. These results demonstrated that functionalized isocyanides are stable and can be used as strategically as synthetic building blocks.

Full text of DOI:10.1039/C5RA27624A

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PAPER
Synthesis and Stability Study of Isocyano Aryl Boronate Esters
and their Synthetic Applications
Received 00th January 20xx,
Accepted 00th January 20xx
HaoꢀPing Fang, ChiaꢀChieh Fu, ChinꢀKuen Tai, KenꢀHao Chang, RuꢀHan Yang, MengꢀJu Wu,
HsienꢀChi Chen, ChiaꢀJung Li, ShiꢀQing Huang, WanꢀHsiang Lien, ChihꢀHsin Chen, ChungꢀHung
Hsieh, BoꢀCheng Wang, SiuꢀFung Cheung, PoꢀShen Pan*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A facile synthesis of isocyano arylboronate esters is reported. Although triꢀcoordinate boron functional groups are
commonly recognized as vulnerable to nucleophilic attack, the newly reported triꢀcoordinate isocyano arylboronate esters
were found to be stable albeit owing to the presence of an isocyano group. Theoretical calculations, using the
DFT/B3LYP/6ꢀ31G(d,p) method, revealed that the electron delocalization between the aryl group and the boron atom might
contribute to this stability. UVꢀvis spectroscopic investigations on 2ꢀ(4ꢀisocyanophenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀ
dioxaborolane (2a) were in agreement with the theoretical studies, showing a redꢀshifted absorbtion compared with that of
phenylisonitrile. The reported strategy allows boronate ester substrates to survive throughout twoꢀstep operations. Two of
the compounds synthesized were successfully exploited in Ugi and Passerini multicomponent reactions to afford
corresponding products. In addition, two boronꢀcontaining tetrazoles were also prepared under environmentally benign
conditions. These results demonstrated that functionalized isocyanides are stable and can be used as strategically as
synthetic building blocks.
they were able to isolate and characterize the product, they
found it hard to handle, requiring storage under nitrogen at –30
°C to avoid rapid decomposition. The observed instability of
Introduction
Isocyanides are exceptional moieties that exhibit unique
bifunctional reactivity, in which the divalent isocyano carbon
can act as a nucleophile or electrophile. Owing to this
distinctive feature, isocyanides are frequently used in
heterocycle synthesis1 and multicomponent reactions.2 From a
synthetic standpoint, the value of isocyanide dramatically
increases when an additional functional group is added, because
the resulting “functionalized” isocyanide can serve as a multiꢀ
purpose synthetic building block, providing opportunities to
prepare previously inaccessible targets.3
the boronꢀsubstituted methyl isocyanide originated from
intermolecular complexation between the electrophilic boron
and the nucleophilic isocyano group.12 Previously, our
laboratory has successfully employed isocyanideꢀbased
Ugi/Passerini multicomponent reactions to construct a series of
boronꢀcontaining compounds.13 In contrast to van Leusen’s
approach, we noticed that boronꢀcontaining building blocks
could be used along with the isocyanide building blocks
without jeopardizing the overall reaction outcomes (Scheme
1bꢀd). These results led us to speculate that the aryl group of
the boronic acid substrate could help to reduce the boron’s
electrophilicity, thus making it less susceptible to complexation
with isocyanide. This assumption has prompted us to explore
the possibility of synthesizing triꢀcoordinated boronꢀsubstituted
phenyl/benzyl isocyanides. Since there are few reports
Boronic acidꢀcontaining molecules are used in a wide range of
organic reactions, including SuzukiꢀMiyaura coupling,4 Chanꢀ
Lam coupling,5 LiebeskindꢀSrogl coupling,6 conjugate
addition,7 homologation,8 electrophilic allyl shifts,9 and CꢀH
coupling reactions.10 Thus, forging boryl and isocyano groups
into one molecule could create a highly valuable synthetic
material (Fig. 1).
regarding
the
preparation
of
these
functionalized
isocyanides,11,14,15 this proposed approach could serve as a
valuable complementary method towards currently limited
synthetic strategies.
In 1995, van Leusen and coꢀworkers reported the first example
of this compound class by converting chloromethylboronates
into the corresponding isocyanide (Scheme 1a).11 Although
CꢀC Bond Formation
Multicomponent Reactions
Y2B
NC
Medicinal Applications
Heterocycle Synthesis
Figure 1 Potential applications of isocyano boronic acids.
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O
1) NaN(CHO)2, MeCN, 80 oC, 2h
2) MeOH, rt., 1h
O
CCl4, PPh3, Et3
CH2Cl2, 40 o
N
O
O
B
O
NC
Table 1 NꢀFormylation of boronꢀsubstituted phenyl amine.
B
O
Cl
B
O
N
H
(a)
H
C
75%
B(OH)2
O
H
NC
NH2
O
O
(b)
microwave, 45 o
MeOH, 0.5h
C
H
N
OH
+
+
+
N
B(OH)2
O
81%
O
H
NH2
NC
O
Time Yield
[min] [%]
microwave, 50 o
MeOH, 0.5h
C
O
(c)
H
+
+
+
N
Entry Formylating agent
Solvent Temp
OH
O
N
O
B
O
B
O
O
F
F
74%
1
Formic acid
EtOAc
r.t.
r.t.
20
< 1
O
H
O
O
H
O
NC
O
H
N
microwave, 45 o
H2O, 2.5h
C
(d)
+
+
O
O
O
B
B
O
88%
2
HCOONa/formic acid Free
270 21
Scheme
1
(a) Synthesis of boronꢀsubstituted methyl
isocyanides via van Leuson’s strategy; (b) synthesis of boronꢀ
containing Ugiꢀ4CR compounds from 3ꢀformylphenyl boronic
acids; (c) synthesis of boronꢀcontaining Ugiꢀ4CR compounds
from (4ꢀ(aminomethyl)ꢀ2ꢀfluoro)phenyl boronic acid pinacol
ester; (d) synthesis of boronꢀcontaining Passeriniꢀ3CR
compounds from 4ꢀcarboxyphenyl boronic acid pinacol ester.
3
Ethyl formate
Free
THF
THF
THF
Et2O
60 °C 360 55
4
N
N
N
N
N
N
N
N
N
N
ꢀFormylsaccharin
ꢀFormylsaccharin
ꢀFormylsaccharin
ꢀFormylsaccharin
ꢀFormylsaccharin
ꢀFormylsaccharin
ꢀFormylsaccharin
ꢀFormylsaccharin
ꢀFormylsaccharin
ꢀFormylsaccharin
r.t.
r.t.
r.t.
r.t.
15
60
90
90
90
60
30
90
30
10
55
73
95
31
93
95
80
90
99
98
5
Results and Discussion
Due to their excellent performance in formylating aniline,16
formic acid (table 1, entry 1) and sodium ethyl formate/formic
acid (table 1, entry 2) were tested in the formylation of 4ꢀ
aminophenylboronic acid pinacol ester. Unexpectedly, the
results of these reactions were far from ideal, perhaps caused by
the pinacolꢀprotected boronic acid of 1a reverting back to the
unprotected form under acidic conditions, making it vulnerable
to attack from the nucleophilic amino group of the starting
material. When ethyl formate was used to formylate 1a under
neutral conditions, the yield increased dramatically to 55%
6
7
8
Acetone r.t.
Acetone r.t.
Acetone r.t.
CH2Cl2 r.t.
CH2Cl2 r.t.
CH2Cl2 r.t.
9
(table 1, entry 3).17 Developed by Cossy and coꢀworkers, 18
Nꢀ
formylsaccharin is a novel formylating reagent capable of
formylating amines at ambient temperature under neutral
conditions. The most significant feature of Nꢀformylsaccharin is
10
11
12
that it chemoselectively formylates amines in the presence of
hydroxyl groups. To our delight, we found this reagent suitable
for delivering the desired product in moderate yield in just 15
min (table 1, entry 4, 55%). Increasing the reaction period from
to 90 min greatly improved the yield to 95% (table 1, entries 4–
6). Interestingly, changing the solvent from THF to ethyl ether
dramatically reduced the yield to 31% (table 1, entry 7). This
observation indicated that the reaction was highly sensitive to
solvent polarity. Similarly to THF, acetone afforded an
excellent yield after 90 min (table 1, entry 8, 93%). The yield
was not significantly affected when the reaction time was
reduced to 60 min (table 1, entry 9, 96%); however, when the
reaction time was further decreased to 30 min, a notable
decrease in yield was observed (table 1, entry 10, 80%). We
were pleased to find that, in dichloromethane, the reaction
period could be dramatically reduced from 90 to 10 min while
maintaining an excellent yield (table 1, entries 11–13, 98%).
13
a
1a was previously synthesized via a different synthetic strategy.19
With the optimized
entry 13), seven additional
benzyl amines were synthesized (1b
N
ꢀformylation conditions in hand (table 1,
ꢀformylated boronꢀsubstituted
), with the results are
N
ꢀ
h
summarized in table 2. The yields ranged from 45–79%.
.
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Table 2 Synthesis of
1b
ha
N
ꢀformylated boronꢀsubstituted amines speculate that formation of the desired product was highly
ꢀ
.
dependent on reaction temperature. It is well documented that
the dehydration of Nꢀformamide using POCl3 takes place at low
temperatures, thus representing a promising option for the
synthesis of the desired isocyanides. Indeed, we were able to
obtain desired product 2a in excellent yield (98%, table 3, entry
3).
H
N-formylsaccharin
10 mins, r.t. CH2Cl2
N
H
NH2
R
R
O
1b-h
Entry
1
R
Product
Yield [%]
74
Table 3 Synthesis of isocyano phenyl boronate ester 2a
.
H
N
H
NC
condition
1b
O
pinB
pinB
2a
2
3
4
5
6
7
78
57
67
45
43
54
1c
1d
1e
1f
Dehyd.
Temp. Conc. Time Yield
Entry
Base Solvent
agent
[°C]
[M] [mins] [%]
1
2
3

T3P TEA CH2Cl2
80
50
0
0.5
0.5
0.5
300
3
18
66
98
TCT TEA CH2Cl2
POCl3 TEA CH2Cl2
60
1g
1h
The structure of 2a was determined unambiguously by Xꢀray
crystallography (Fig. 2). To the best of our knowledge, this is
the first report of the crystal structure of a boronꢀsubstituted
phenyl isocyanide.
a
All reactions were carried out using boronꢀsubstituted aryl
amine (1.0 equiv.), ꢀformylsaccharin (1.1 equiv.) in
dichloromethane (0.2 M).
N
CN
O
B
Three representative dehydration protocols15,20 were evaluated;
the results are summarized in table 3. Compared with other
traditional dehydrating reagents, propylphosphonic anhydride
O
(

T3P) has several significant advantages, including low
toxicity and generally delivering high product yields.
Furthermore, products generated by T3P can be purified via
simple extraction due to the T3P byproduct being water
Figure 2 Xꢀray crystal structures of 2a, thermal ellipsoids drawn at
the 50% probability level.

By utilizing the optimized conditions (table 3, entry 3), seven
additional boronꢀsubstituted isocyanides were synthesized
accordingly (2bꢀh). Results are shown in table 4.

soluble.21 Thus, it was chosen an ideal dehydrating agent to
convey the boronꢀsubstituted isocyanides. Unfortunately, the
use of
T3P resulted in low yields of the desired products
Table 4 Synthesis of isocyano benzyl boronate esters under
optimized conditions.
(table 3, entry 1, 18%). Porcheddu et al. reported a facile
microwaveꢀassisted synthesis using cyanuric chloride as the
dehydrating agent,22 which went to completion in under 10 min
at 50 °C. Under these conditions, we were able to obtain the
desired product in much higher yield (table 3, entry 2, 66%).
This improved yield at a lower temperature caused us to
H
POCl3, TEA
N
H
NC
R
R
CH2Cl2, 0oC
O
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1
2
3
90.00°
Entry
1
R
Product
Yield [%]
80
2b
15.95°
2.74°
2
3
4
5
6
7
2c
2d
2e
2f
88
58
65
52
75
71
Projected density of state (pDOS) analysis of the HOMO and
LUMO states of 2a was also retrieved using the DFT/B3LYP/6ꢀ
31G(d,p) method; the results are shown in table 6. It was found that
when the dihedral angle between the phenyl group and the boron
functional group was 90.00°, and the relative charge density of
boron was 1.3 in the LUMO state (table 6, entry 1), while at 15.95o,
the value increased noticeably to 6.7 (table 6, entry 2). This indicated
that an electron delocalization event would occur when pꢀorbitals of
the aryl group and boron atom aligned properly. Similar results were
also obtained with the optimal dihedral angle, where the value was
6.8 (table 6, entry 3).
2g
2h
Unlike highly unstable boronꢀsubstituted methyl isocyanides,
the boronꢀsubstituted phenyl and benzyl isocyanides produced
in this study (table 4) could be stored at ambient temperature
without a N2 atmosphere for one week (for a month if stored at
0 °C). In order to investigate how phenyl groups contributed to
this improved stability, a series of theoretical calculations were
Table 6. Calculated projected density of state values (pDOS, %) for
the HOMO/LUMO orbital of 2a
.
Dihedral
Entry
HOMO
LUMO
performed using
a
DFT/B3LYP/6ꢀ31G(d,p) method by
Angle
controlling the dihedral angle between the phenyl group and
boron functional group. It was found that when the dihedral
angle between the phenyl and boron functional groups in 2a
was 90.00°, the electron density of the phenyl group did not
delocalize to the boron functional group (table 5, entry 1,
LUMO state). However, when the dihedral angle changed to
15.95° (based on Xꢀray crystallography of 2a), delocalization of
the electron density from the phenyl group to the boron
functional group was observed (table 5, entry 2, LUMO state).
This result was also observed when 2a was at the optimized
dihedral angle of 2.74° (table 5, entry 3).
OO
B
ph
NC
OO
B
ph
NC
1
2
3
90.00°
15.95°
2.74°
4.2 0.8 76.7 18.3 5.5 1.3 72.9 20.2
8.4 0.3 73.8 17.5 8.1 6.7 69.2 16.0
8.8 0.3 73.5 17.4 7.9 6.8 69.4 15.9
The UVꢀvis spectroscopic study was employed to validate the
abovementioned theoretical prediction (Fig. 3). The maximum
absorption of phenylisonitrile at 228 nm was assigned to the
HOMOꢀLUMO transition based on theoretical predictions. It was
found that after attaching a boron functional group at the para-
position (2a), this absorption band redꢀshifted to 237 nm. Such a
phenomenon could be recognized as evidence of the establishment
of a conjugation system in 2a. This observation was also in
agreement with theoretical calculations.
Table 5. Electron density diagram of HOMO/LUMO states in
2a.
Entry
Dihedral
Angle
HOMO
LUMO
.
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OH
OH
O
H
NC
B
B
N
N
N
B(OH)2
O
O
N
H
F
O
O
(a) Bortezomib (VelcadeTM
)
(b) AN2690 (KerydinTM
)
(c) AN2728 (phase III)
Anticancer
Onychomycosis
Psoriasis
O
N
B(OH)2
N
B(OH)2
N
O
N
H
N
O
H
O
NH
O
O
NH2
B(OH)2
HN
MeO
(d) TRC150c (phase III)
(e) PT100 (Phase III)
(f) PHX1149 (phase III)
Anticoagulant
Anticancer
Type II Diabetes
Figure 4 Boronꢀcontaining pharmaceuticals.
Figure 3. UVꢀvis spectrum of phenylisonitrile and 2a
.
Br
Therefore, the improved stability of isocyano arylboronate
esters could be attributed to the delocalization of electrons from
the phenyl group to the electrophilic boron atom. Hence, this
extended conjugation system made the triꢀcoordinate boron
functional group more resistant to nucleophilic attack from the
isocyano group. This conjugation effect was also observed by
Mayr and coꢀworkers, who found that electrophilic aldehydes
attached to conjugated systems were less prone to nucleophilic
attack compared with those without conjugated systems.23
Due to the successes of Bortezomib (Fig. 4a)24 and Kerydin
O
Acid, Amine, Aldehyde
O
B
O
H
MeOH (0.5 M), 60 oC, 2.5 hr
N
N
Microwave (150 W)
O
3 (56%)
Br
O
H
N
O
Acid, Aldehyde
O
CN
B
O
B
O
H2O (1.0 M), 45 oC, 2.5 hr
Microwave (150 W)
O
O
4 (46%)
(Fig.
4b),25
the
development
of
boronꢀcontaining
O
B
O
pharmaceutical agents has progressed significantly. (Fig. 4cꢀ
f).26 The current strategies for making these agents mainly
depend on linear27 or convergent approaches.28 Despite their
different synthetic tactics, they all have a limitation in common,
where the position of the boron group must be preꢀdetermined.
Any attempt to reꢀposition the boron group was synthetically
demanding. Given that the biological activities of these
compounds was highly dependent on the location of the boron
group, for applications in drug discovery programs, it would be
ideal to find a way of generating analogues that have a common
core structure, but with the boron group revolving around it.
Previously, our laboratory had reported the use of isocyanideꢀ
based multicomponent reactions to accomplish this objective.13
By simply exchanging the boronꢀsubstituted building blocks,
we were able to relocate the boron group within the molecular
framework without revamping the synthetic strategy. This
strategy; however, was not fully realized due to the exclusion of
isocyano arylboronate esters. By introducing previously
inaccessible boronꢀsubstituted isocyanides, this strategy was
now validated. The results are shown in scheme 2aꢀb.
N
N
N
N
Cl
TMS-N3
5 (14%)
TFE (0.4 M), 60 oC, 2.5 hr
cat. HCl, Microwave (150 W)
O
O
N
N
B
N
N
6 (32%)
Scheme 2 Applications of isocyano aryl boronate esters.
The reported isocyanides could not only be utilized in
multicomponent reactions, but also in heterocycle synthesis.
Among heterocycles, tetrazole is of particular interest.29
Compared with peptides substrates, tetrazoles tend to have an
improved absorption profile with greater metabolic stability. In
this report, we have developed microwaveꢀassisted conditions
that allowed the preparation of two boronꢀcontaining tetrazoles
5
and
obtained in crystalline form in CH2Cl2/nꢀhexane solution. The
structures of and
30 were later confirmed by single crystal Xꢀ
ray diffraction (Fig. 5 and 6).
6 (scheme 2c). These tetrazoles were stable and easily
5
6
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H
N
N
N
H
N
N
O
Bpin
O
B
N
-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl)formamide (1a)19
O
Cl
Figure 5. Xꢀray crystal structure of 5, thermal ellipsoids drawn
at the 50% probability level.
A 100 mL round bottom flask containing 4ꢀ(4,4,5,5ꢀtetramethylꢀ
1,3,2ꢀdioxaborolanꢀ2ꢀyl) aniline (219.00 mg, 1.0 mmol, 1.0 equiv),
Nꢀformylsaccharin (232.30 mg, 1.1 mmol, 1.1 equiv), and
dichloromethane (10 mL) was stirred at ambient temperature for 10
min. After the reaction was complete, NaHCO3(aq) (20 mL) was
added to the reaction mixture and stirred for additional 5 min. The
resulting organic solution was collected using a separatory funnel,
dried with MgSO4, and filtered. The filtrate was then concentrated in
vacuo and the crude material purified by short flash column
chromatography using a ethyl acetate/nꢀhexane (2:8) eluent, to
afford the desired product as a brown solid in 98% yield (242.00 mg);
mp 111 °C; 1HꢀNMR (600 MHz, CDCl3) δ 8.78 (d, J = 11.4 Hz,
0.5H), 8.45–8.40 (br, 1H), 8.37 (s, 0.5H), 7.77 (t, 2H), 7.54 (d, J =
8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 1.39 (s, 12H); 13CꢀNMR (150
MHz, CDCl3) δ 162.2, 158.9, 139.4, 139.3, 136.4, 135.8, 118.7,
117.1, 83.9, 83.7, 24.82; 11BꢀNMR (192.5 MHz, CDCl3) δ 30.81.
HRMS (ESI): m/z calcd for C13H19O3NB: 248.1453 [M+H]+; found:
248.1449.
N
N
N
N
O
B
O
Figure 6. Xꢀray crystal structure of 6, thermal ellipsoids drawn at
the 50% probability level.
Experimental Section
O
General methods and materials
N
H
H
All starting materials were obtained from commercial suppliers
and used without further purification unless otherwise noted.
Reactions were performed in a CEM Discover BenchmateTM
microwave reactor with sealed vessels. Temperatures of the
microwaveꢀassisted reactions were monitored using an external
Bpin
N
-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)benzyl)formamide (1b)
1
IR sensor. Unless otherwise specified H and 13C NMR spectra
were recorded on a Bruker ACꢀ300 FTꢀNMR spectrometer at
300 and 75.5 MHz, respectively. 19F NMR spectra were
recorded on a Bruker AVIII 400 FTꢀNMR spectrometer at
376.5 MHz. 11B NMR spectra were recorded on a Bruker
Avance 600 FTꢀNMR spectrometer at 192.5 MHz. All 11B
chemical shifts were referenced to external BF3•OEt2 (0.0 ppm).
Data are represented as follows: chemical shifts (ppm),
multiplicity (s: singlet, d: doublet, t: triplet, m: multiplet, br:
Following the general procedure for preparation of boronꢀsubstituted
formamides,
(4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)phenyl)methanamine (267.00 mg, 1.2 mmol, 1.0 equiv), Nꢀ
formylsaccharin (278.77 mg, 1.32 mmol, 1.1 equiv), and
dichloromethane (6.0 mL) afforded compound 1b as a brown oil in
74% yield (221.30 mg); 1HꢀNMR (300 MHz, CDCl3) δ 8.26 (s, 1H),
7.77 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 4.48 (d, J = 5.9 Hz,
2H), 1.39 (s, 12H); 13CꢀNMR (150 MHz, CDCl3) δ 161.0, 140.5,
135.3, 135.2, 127.0, 126.0, 126.1, 83.8, 42.1, 24.8; 11BꢀNMR (192.5
MHz, CDCl3) δ 30.88. HRMS (ESI): m/z calcd for C14H21O3NB:
262.1614 [M+H]+; found: 262.1606.
broad), coupling constant
J (Hz). Melting points were
determined using a Fargo MPꢀ2D melting point apparatus and
are uncorrected. Highꢀresolution ESI mass spectra were
obtained using
a Finnigan MAT 95S instrument. Xꢀray
O
crystallography data was obtained using a Bruker APEX II Xꢀ
ray Single Crystal Diffractometer. UVꢀvis spectroscopy data
was collected using a Thermo Scientific Evolution 60S UVꢀ
Visible Spectrophotometer.
N
H
H
Bpin
N
-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
General procedure for the preparation of boron-substituted
formamides
yl)benzyl)formamide (1c)
Following the general procedure for preparation of boronꢀsubstituted
formamides,
(3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
.
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yl)phenyl)methanamine (280.00 mg, 1.2 mmol, 1.0 equiv), Nꢀ N-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
formylsaccharin (278.77 mg, 1.32 mmol, 1.1 equiv), and yl)benzyl)formamide (1f)
dichloromethane (6.0 mL) afforded compound 1c as a brown oil in
78% yield (247.70 mg); 1HꢀNMR (600 MHz, CDCl3) δ 8.10 (s, 1H),
Following the general procedure for preparation of boronꢀsubstituted
formamides, (3ꢀfluoroꢀ4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)phenyl)methanamine (467.40 mg, 1.9 mmol, 1.0 equiv), Nꢀ
formylsaccharin (441.38 mg, 2.09 mmol, 1.1 equiv), and
dichloromethane (7.0 mL) afforded compound 1f as a brown oil in
45% yield (257.20 mg); 1HꢀNMR (600 MHz, CDCl3) δ 8.21 (s, 1H),
7.64 (t, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 10.2 Hz, 1H),
6.51–6.42 (br, 1H), 4.42 (d, J = 6.0 Hz, 2H), 1.32 (s, 12H); 13Cꢀ
NMR (150 MHz, CDCl3) δ 168.08, 166.41, 164.74, 161.20, 143.73,
137.17, 122.63, 114.23, 114.06, 83.90, 41.37, 24.71; 19F NMR
(376.5 MHz, CDCl3) δ ꢀ102.1; 11BꢀNMR (183 MHz, CDCl3) δ 30.16.
HRMS (ESI): m/z calcd for C14H20O3NBF: 280.1520 [M+H]+; found:
280.1514.
7.65 (s, 2H), 7.27–7.24 (m, 2H), 6.62–6.50 (br, 1H), 4.37 (s, 2H),
1.28 (s, 12H); 13CꢀNMR (150 MHz, CDCl3) δ 161.1, 136.9, 136.7,
136.6, 130.6, 128.1, 127.9, 83.8, 41.8, 24.6; 11BꢀNMR (192.5 MHz,
CDCl3) δ 30.92. HRMS (ESI): m/z calcd for C14H21O3NB: 262.1614
[M+H]+; found: 262.1608.
N-(2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzyl)formamide (1d)
Following the general procedure for preparation of boronꢀsubstituted
formamides, (2ꢀfluoroꢀ5ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)phenyl)methanamine (340.00 mg, 1.4 mmol, 1.0 equiv), Nꢀ
formylsaccharin (325.23 mg, 1.54 mmol, 1.1 equiv), and
dichloromethane (9.0 mL) afforded compound 1d as a brown oil in
57% yield (215.40 mg); 1HꢀNMR (300 MHz, CDCl3) δ 8.18 (s, 1H),
7.74–7.66 (m, 2H), 7.00 (t, 1H), 6.34–6.25 (br, 1H), 4.49 (d, J = 6
Hz, 2H), 1.31 (s, 12H); 13CꢀNMR (150 MHz, CDCl3) δ 164.5, 164.0,
162.4, 160.8, 136.8, 136.5, 136.4, 123.8, 84.1, 36.0, 24.8; 19F NMR
(376.5 MHz, CDCl3) δ ꢀ114.2; 11BꢀNMR (192.5 MHz, CDCl3) δ
30.50. HRMS (ESI): m/z calcd for C14H20O3NBF: 280.1520 [M+H]+;
found: 280.1513.
N-(4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzyl)formamide (1g)
Following the general procedure for preparation of boronꢀsubstituted
formamides, (4ꢀchloroꢀ3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)phenyl)methanamine (700.00 mg, 2.6 mmol, 1.0 equiv), Nꢀ
formylsaccharin (604.00 mg, 2.86 mmol, 1.1 equiv), and
dichloromethane (13.0 mL) afforded compound 1g as a brown oil in
53% yield (410.60 mg); 1HꢀNMR (300 MHz, CDCl3) δ 8.17 (s, 1H),
7.78 (s, 1H), 7.29–7.20 (m, 2H), 6.26–6.24 (br, 1H), 4.39 (d, J = 5.8
Hz, 2H), 1.34 (s, 12H); 13CꢀNMR (150 MHz, CDCl3) δ 163.4, 163.4,
138.5, 135.4, 135.4, 135.2, 131.1, 129.5, 84.2, 41.1, 24.6; 11BꢀNMR
(192.5 MHz, CDCl3) δ 30.53.
N-(4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzyl)formamide (1e)
Following the general procedure for preparation of boronꢀsubstituted
formamides, (4ꢀfluoroꢀ3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)phenyl)methanamine (444.00 mg, 1.8 mmol, 1.0 equiv), Nꢀ
formylsaccharin (418.15 mg, 1.98 mmol, 1.1 equiv), and
dichloromethane (7.0 mL) afforded compound 1e as a brown oil in
67% yield (330.60 mg); 1HꢀNMR (300 MHz, CDCl3) δ 8.24 (s, 1H),
7.68–7.55 (m, 1H), 7.44–7.36 (m, 1H), 6.99 (t, 1H), 5.98–5.90 (br,
1H), 4.44 (d, J = 5.9 Hz, 2H), 1.34 (s, 12H); 13CꢀNMR (150 MHz,
CDCl3) δ 167.4, 165.7, 164.5, 160.9, 136.0, 136.0, 132.9, 129.5,
115.7, 84.1, 41.4, 24.7; 19F NMR (376.5 MHz, CDCl3) δ ꢀ104.2; 11Bꢀ
NMR (192.5 MHz, CDCl3) δ 30.25. HRMS (ESI): m/z calcd for
C14H20O3NBF: 280.1520 [M+H]+; found: 280.1512.
N-(2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzyl)formamide (1h)
Following the general procedure for preparation of boronꢀsubstituted
formamides, (2ꢀmethylꢀ5ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)phenyl)methanamine (777.00 mg, 3.2 mmol, 1.0 equiv), Nꢀ
formylsaccharin (743.38 mg, 3.52 mmol, 1.1 equiv), and
dichloromethane (16.0 mL) giving compound 1h as a brown oil in
54% yield (467.40 mg); 1HꢀNMR (300 MHz, CDCl3) δ 8.17 (s, 1H),
7.76 (s, 2H), 7.17 (d, J = 9.3 Hz, 1H), 5.92–5.88 (br, 1H), 4.46 (d, J
= 5.4 Hz, 2H), 2.36 (s, 3H), 1.34 (s, 12H); 13CꢀNMR (150 MHz,
CDCl3) δ 160.7, 140.0, 134.8, 134.4, 134.3, 134.3, 130.1, 83.8, 40.1,
24.1, 19.2; 11BꢀNMR (192.5 MHz, CDCl3) δ 30.83. HRMS (ESI):
m/z calcd for C15H23O3NB: 276.1771 [M+H]+; found: 276.1765.
General procedure for the preparation of boron-substituted
isocyanides
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yl)benzyl)formamide (1c) (278.00 mg, 1.1 mmol, 1.0 equiv),
triethylamine (0.7 mL, 7.4 mmol, 6.5 equiv), phosphoryl chloride
(0.1 mL, 1.2 mmol, 1.1 equiv), and dichloromethane (2.0 mL)
afforded compound 2c as a brown oil in 88% yield (229.00 mg); IR
(KBr) 2156.98 cm–1; 1HꢀNMR (600 MHz, CDCl3) δ 7.79 (d, J = 7.2
Hz, 2H), 7.46 (d, J = 7.8 Hz, 1H), 7.41 (t, 1H), 4.62 (s, 2H), 1.33 (s,
12H); 13CꢀNMR (150 MHz, CDCl3) δ 157.6, 134.6, 132.8, 131.6,
129.3, 128.3, 83.9, 45.3, 24.7; 11BꢀNMR (192.5 MHz, CDCl3) δ
30.54; HRMS (ESI): m/z calcd for C14H18O2NBNa: 266.1322
[M+Na]+; found: 266.1322.
2-(4-Isocyanophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(2a)
A 100 mL round bottom flask containing Nꢀ(4ꢀ(4,4,5,5ꢀtetramethylꢀ
1,3,2ꢀdioxaborolanꢀ2ꢀyl)phenyl) formamide (1a) (484.00 mg, 2.0
mmol, 1.0 equiv), and dichloromethane (3.0 mL) was stirred at 0 °C
for 5 min. Triethylamine (1.3 mL, 9.0 mmol, 4.5 equiv) was then
added dropwise slowly to the mixture, followed by dropꢀwise
addition of dichloromethane (1.0 mL) containing phosphoryl
chloride (0.2 mL, 2.2 mmol, 1.1 equiv). The reaction mixture was
then stirred for 1 h at 0 °C. After the reaction was complete,
NaHCO3(aq) (20 mL) was added to the reaction mixture and stirred
for an additional 20 min. The resulting organic solution was
collected using a separatory funnel, dried with MgSO4, and filtered.
The filtrate was then concentrated in vacuo to afford the desired
product as an orange solid in 98% yield (449.00 mg); mp 75 °C; IR
(KBr) 2126.45, cm–1; 1HꢀNMR (600 MHz, CDCl3) δ 7.81 (d, J = 7.2
Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 1.33 (s, 12H); 13CꢀNMR (150
MHz, CDCl3) δ 164.9, 135.7, 128.5, 125.4, 84.2, 24.8; 11BꢀNMR
2-(4-Fluoro-3-(isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2d)
Following the general procedure for preparation of boronꢀsubstituted
isocyanides, Nꢀ(2ꢀfluoroꢀ5ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ
2ꢀyl)benzyl)formamide (1d) (508.00 mg, 1.80 mmol, 1.0 equiv),
triethylamine (1.1 mL, 8.2 mmol, 4.5 equiv), phosphoryl chloride
(0.18 mL, 1.98 mmol, 1.1 equiv) and dichloromethane (2.0 mL)
afforded compound 2d as a brown oil in 58% yield (277.00 mg); IR
(KBr) 2978.70, 2937.06, 2154.34, 1613.10, 1590.89, 1368.84 cm–1;
1HꢀNMR (600 MHz, CDCl3) δ 7.89 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H),
7.08 (t, 1H), 4.66 (s, 2H), 1.34 (s,12H); 13CꢀNMR (150 MHz, CDCl3)
δ 162.9, 161.2, 158.1, 137.4, 137.4, 135.7, 119.3, 119.2, 115.1, 84.1,
39.6, 24.8; 19F NMR (376.5 MHz, CDCl3) δ ꢀ114.1; 11BꢀNMR (192.5
MHz, CDCl3) δ 30.37; HRMS (ESI): m/z calcd for C14H20O3NBF:
280.1520 [M+H3O]+; found: 280.1513.
(192.5 MHz, CDCl3)
δ 30.40; HRMS (ESI): m/z calcd for
C13H17BNO2: 230.1347 [M+H]+; found: 230.1347.
2-(4-(Isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2b)
Following the general procedure for preparation of boronꢀsubstituted
isocyanides,
Nꢀ(4ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)benzyl)formamide (1b) (166.00 mg, 0.6 mmol, 1.0 equiv),
triethylamine (0.4 mL, 2.9 mmol, 5.0 equiv), phosphoryl chloride
(0.07 mL, 0.7 mmol, 1.1 equiv), and dichloromethane (1.3 mL)
afforded compound 2b as a brown oil in 80% yield (153.85 mg); IR
2-(2-Fluoro-5-(isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2e)
1
(KBr) 2153.78, 1613.93 cm–1; HꢀNMR (600 MHz, CDCl3) δ 7.83
Following the general procedure for preparation of boronꢀsubstituted
isocyanides, Nꢀ(4ꢀfluoroꢀ3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ
2ꢀyl)benzyl)formamide (1e) (232.00 mg, 0.8 mmol, 1.0 equiv),
triethylamine (0.5 mL, 3.7 mmol, 4.6 equiv), phosphoryl chloride
(0.09 ml, 0.9 mmol, 1.1 equiv), and dichloromethane (2.0 mL)
afforded compound 2e as a brown oil in 65% yield (142.00 mg); IR
(KBr) 2978.61, 2934.20, 2370.77, 2343.02, 2151.51, 1621.38 cm–1;
1HꢀNMR (600 MHz, CDCl3) δ 7.67 (s, 1H), 7.43 (s, 1H), 7.06 (t,
1H), 4.59 (s, 2H), 1.35 (s, 12H); 13CꢀNMR (150 MHz, CDCl3) δ
(d, J = 7.2 Hz, 2H), 7.34 (d, J = 7.2 Hz, 2H), 4.66 (s, 2H), 1.31 (s,
12H); 13CꢀNMR (150 MHz, CDCl3) δ 156.3, 135.3, 135.1, 125.7,
125.6, 83.9, 45.5, 24.8; 11BꢀNMR(192.5 MHz, CDCl3) δ 30.88;
HRMS (ESI): m/z calcd for C14H18O2NBNa: 266.1322 [M+Na]+;
found: 266.1325.
167.7, 166.1, 157.7, 135.3, 131.7, 127.7, 155.9, 84.1, 44.8, 24.7; 19
F
NMR (376.5 MHz, CDCl3) δ ꢀ103.0; 11BꢀNMR (192.5 MHz, CDCl3)
δ 30.05; HRMS (ESI): m/z calcd for C13H17O2NBF: 235.306 [Mꢀ
NC]+; found: 235.1299.
2-(3-(Isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2c)
Following the general procedure for preparation of boronꢀsubstituted
isocyanides,
Nꢀ(3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
.
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2-(2-Fluoro-4-(isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2f)
Following the general procedure for preparation of boronꢀsubstituted
isocyanides, Nꢀ(3ꢀfluoroꢀ3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ
2ꢀyl)benzyl)formamide (1f) (232.80 mg, 0.8 mmol, 1.0 equiv),
triethylamine (0.5 mL, 3.7 mmol, 4.6 equiv), phosphoryl chloride
(0.09 mL, 0.9 mmol, 1.1 equiv), and dichloromethane (1.7 mL)
afforded compound 2f as a brown oil in 52% yield (113.60 mg). IR
1
(KBr) 2978.70, 2928.74, 2870.45, 2154.34, 1685.26 cm–1; HꢀNMR
N-(1-(4-Bromophenyl)-2-oxo-2-((4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzyl)amino)ethyl)-N-phenylisobutyramide
(3)
(600 MHz, CDCl3) δ 7.75 (t, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.03 (d, J
= 7.8 Hz, 1H), 4.65 (s, 2H), 1.34 (s, 12H); 13CꢀNMR (150 MHz,
CDCl3) δ 168.16, 166.48, 158.71, 137.77, 137.59, 121.52, 113.53,
113.36, 83.91, 44.99, 24.75; 19F NMR (376.5 MHz, CDCl3) δ ꢀ102.2;
11BꢀNMR (183 MHz, CDCl3) δ 30.07; HRMS (ESI): m/z calcd for
C14H17BFNO2Na: 284.1228 [M+Na]+; found: 284.1229.
A 10 mL glass tube containing aniline (0.082 mL, 0.9 mmol, 1.0
equiv), 4ꢀbromobenzaldehyde (166.70 mg, 0.9 mmol, 1.0 equiv), and
methanol (1.8 mL) was microwaved for 60 min (60 °C, 150 W).
Then, isobutyric acid (0.081 mL, 0.9 mmol, 1.0 equiv) and 2ꢀ(4ꢀ
(isocyanomethyl)phenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane
(206.50 mg, 0.9 mmol, 1.0 equiv) were added to the reaction mixture.
Microwave irradiation was applied for 120 min (60 °C, 150 W) with
mediumꢀspeed magnetic stirring. After the reaction was complete,
the crude material was concentrated and reꢀdissolved in
dichloromethane. The resulting organic solution was washed with 1
N HCl(aq) followed by saturated NaHCO3(aq) combined with brine.
The resulting organic layer was collected, dried with MgSO4, and
concentrated in vacuo. The resulting crude material was purified by
short flash column chromatography using ethyl acetate/nꢀhexane
(3:7) eluent to afford the desired product as a colorless oil in 56%
yield (301.00 mg); 1HꢀNMR (Bruker ACꢀ600 FTꢀNMR spectrometer
at 600 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.8 Hz,
2H), 7.31–7.20 (d, 8H), 6.99 (d, J = 8.4 Hz, 2H), 6.49 (br, NH), 6.01
(s, 1H), 4.49 (s, 2H), 2.38 (m, 1H), 1.33 (s, 12H), 1.01 (q, J = 6.6,
6H); 13CꢀNMR (Bruker ACꢀ600 FTꢀNMR spectrometer at 150.9
MHz, CDCl3) δ 178.1, 169.3, 141.1, 139.7, 135.2, 135.0, 134.4,
133.4, 131.9, 130.2, 130.1, 129.0, 128.3, 128.2, 127.0, 126.7, 122.6,
83.7, 64.2, 43.6, 31.8, 31.8, 24.8, 19.6; 11BꢀNMR (CDCl3) δ 30.79;
HRMS (ESI): m/z calcd for C31H37BBrN2O4: 591.2024 [M+H]+;
found: 591.2024.
2-(2-Chloro-5-(isocyanomethyl)phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (2g)
Following the general procedure for preparation of boronꢀsubstituted
isocyanides, Nꢀ(4ꢀchloroꢀ3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ
2ꢀyl)benzyl)formamide (1g) (456.00 mg, 1.6 mmol, 1.0 equiv),
triethylamine (1.0 mL, 7.4 mmol, 4.6 equiv), phosphoryl chloride
(0.17 mL, 1.8 mmol, 1.1 equiv), and dichloromethane (2.0 mL)
afforded compound 2g as a brown oil in 75% yield (216.00 mg); IR
(KBr) 2151.43 cm–1; 1HꢀNMR (600 MHz, CDCl3) δ 7.61 (s, 1H),
7.45–7.28 (m, 2H), 4.48 (s, 2H), 1.30 (s, 12H);13CꢀNMR (150 MHz,
CDCl3) δ 158.0, 139.7, 134.6, 133.9, 130.3, 130.0, 129.7, 84.2, 44.8,
24.7; 11BꢀNMR (192.5 MHz, CDCl3) δ 30.65; HRMS (ESI): m/z
calcd for C13H17BClO2: 251.101 [MꢀNC]+; found: 251.100.
General procedure for the preparation of Passerini-3CR
analogues
2-(3-(Isocyanomethyl)-4-methylphenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (2h)
Following the general procedure for preparation of boronꢀsubstituted
isocyanides, Nꢀ(2ꢀmethylꢀ5ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ
2ꢀyl)benzyl)formamide (1h) (700.00 mg, 2.6 mmol, 1.0 equiv),
triethylamine (0.6 mL, 4.6 mmol, 1.7 equiv), phosphoryl chloride
(0.26 mL, 2.86 mmol, 1.1 equiv), and dichloromethane (2.0 mL)
afforded compound 2h as a brown oil in 71% yield (302.00 mg); IR
(KBr) 2984.25, 2146.02 cm–1; 1HꢀNMR (600 MHz, CDCl3) δ 7.76 (s,
1H), 7.71 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 4.56 (s, 2H),
2.38 (s, 3H), 1.37 (s, 12H); 13CꢀNMR (150 MHz, CDCl3) δ 157.3,
139.2, 135.3, 134.4, 134.4, 130.1, 130.1, 83.8, 43.9, 24.8, 19.0; 11Bꢀ
NMR (192.5 MHz, CDCl3) δ 30.71; HRMS (ESI): m/z calcd for
C15H21O2NB: 258.1659 [M+H]+; found: 258.1662.
1-(4-Bromophenyl)-2-((2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzyl)amino)-2-oxoethyl benzoate (4).
A 10 mL glass tube containing benzoic acid (47.26 mg, 0.4 mmol,
1.3 equiv), 4ꢀbromobenzaldehyde (59.73 mg, 0.3 mmol, 1.0 equiv),
and deionized H2O (1.0 mL) was microwave irradiated for 6 min (45
°C, 150 W) with medium speed magnetic stirring. Then, 2ꢀ(3ꢀ
(Isocyanomethyl)ꢀ4ꢀmethylphenyl)ꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀ
dioxaborolane (100.00 mg, 0.4 mmol, 1.3 equiv) was added to the
reaction mixture, and microwave irradiation was applied for a further
General procedure for the preparation of Ugi-4CR analogues
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150 min (45 °C, 150 W) with medium speed magnetic stirring. After 12H). 13CꢀNMR (Bruker ACꢀ600 FTꢀNMR spectrometer at 150.9
MHz, CDCl3) δ 140.31, 136.64, 135.76, 120.04, 84.42, 24.87. 11Bꢀ
being diluted in dichloromethane, the resulting reaction mixture was
washed twice with saturated NaHCO3(aq) and then brine. The
resulting organic layer was collected, dried over MgSO4, and
concentrated in vacuo. The resulting crude material was purified by
short flash column chromatography with ethyl acetate/nꢀhexane (3:7)
to afford the desired product as a yellow colored solid in 46% yield
(84.40 mg), mp: 162 °C; 1HꢀNMR (Bruker ACꢀ600 FTꢀNMR
spectrometer at 600 MHz, CDCl3) δ 8.04 (d, J = 7.8 Hz, 2H), 7.65–
7.42 (m, 9H), 7.19 (d, J = 7.2 Hz, 1H), 6.29 (s, 1H), 6.27 (br, NH),
4.58–4.44 (dd, J = 5.4, 46.8 Hz, 2H), 2.25 (s, 3H), 1.33 (s, 12H);
13CꢀNMR (Bruker ACꢀ600 FTꢀNMR spectrometer at 150.9 MHz,
CD3OD) δ 167.4, 164.8, 140.2, 135.0, 134.6, 134.4, 133.7, 131.9,
130.2, 129.8, 128.9, 128.6, 123.1, 83.8, 75.2, 41.8, 24.8, 19.1; 11Bꢀ
NMR (CDCl3) δ 30.87. HRMS (ESI): m/z calcd for C29H32BBrNO5:
564.1551 [M+H]+; found: 564.1552.
NMR (CDCl3) δ 30.56. HRMS (ESI): m/z calcd for C13H18BN4O2:
273.1523 [M+H]+; found: 273.1516.
Conclusions
In conclusion, we successfully developed a synthetic strategy
for the preparation of boronꢀsubstituted phenyl/benzyl
isocyanides. A combination of Xꢀray crystallography data,
theoretical calculations, and UVꢀspectroscopic studies provided
direct evidence of electron delocalization in these compounds.
Delocalization sufficiently reduced the electrophilicity of
boron, making them stable enough for storage at ambient
temperature for one week. The application of the reported
products to isocyanideꢀbased Ugiꢀ4CR/Passeriniꢀ3CR, as well
as tetrazole formation, was also described. These results
demonstrate the stability of the reported boronꢀsubstituted
phenyl/benzyl isocyanides, and their applications in various
types of synthetic reaction.
General procedure for the preparation of boron-containing
tetrazoles
Acknowledgements
This research was supported by the Ministry of Science and
Technology in Taiwan (MOSTꢀ103ꢀ2113ꢀMꢀ032ꢀ010, MOSTꢀ
104ꢀ2113ꢀMꢀ032ꢀ001). We thank Professor HsiuꢀFu Hsu from
Department of Chemistry of Tamkang University for insightful
discussions, the Department of Chemistry of Tamkang
University for equipment and financial support, TingꢀShen Kuo
from the Department of Chemistry of National Taiwan Normal
University for conducting Xꢀray experiments, Professor
ChiungꢀCheng Huang from Department of Chemical
Engineering of Tatung University and Dr. YiꢀJhen Feng from
the Department of Chemistry of National Taiwan University for
conducting 19F NMR experiments, and ShenꢀShen Chen from
the Department of Chemistry of Tamkang University for
conducting 11BꢀNMR experiments.
1-(4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzyl)-1H-tetrazole (5)
A 10 mL glass tube containing 2g (175.5 mg, 0.666 mmol, 1.0
equiv), TMSꢀN3 (0.131 mL, 1.000 mmol, 1.5 equiv), and TFE (1.660
mL) was stirred at ambient temperature for 150 min. Then, 1 N HCl
(1.33 mL) was added to the glass tube, followed by microwave
irradiation for 150 minutes (60 °C, 150 W) with medium speed
magnetic stirring. After the reaction was complete, the crude
material was washed twice with saturated NaHCO3(aq) and
dichloromethane. The resulting organic layer was collected, dried
over MgSO4, and concentrated in vacuo to afford the desired product
1
in 14% yield (28.9 mg). mp 123 °C. HꢀNMR (Bruker ACꢀ600 FTꢀ
NMR spectrometer at 600 MHz, CDCl3) δ 8.49 (s, 1H), 7.65 (s, 1H),
7.40–7.38 (d, 1H), 7.26 (d, 1H), 5.54 (s, 2H), 1.36 (s, 12H). 13Cꢀ
NMR (Bruker ACꢀ600 FTꢀNMR spectrometer at 150.9 MHz, CDCl3)
δ 142.22, 141.08, 136.38, 131.64, 130.59, 130.40, 84.58, 51.45,
24.80. 11BꢀNMR (CDCl3) δ 30.36. HRMS (ESI): m/z calcd for
C14H19BClN4O2: 321.1290 [M+H]+; found: 321.1282.
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