Synthesis of 2,1-Borazaroquinolines and 2,1-Borazaroisoquinolines from Vinylaminopyridines and Potassium Organotrifluoroborates by Microwave-Assisted Heating

Article abstract of DOI:10.1002/ejoc.201500622

Azaborines are an emerging class of compounds with applications in medicinal chemistry and materials science. The synthesis of a wide variety of borazaronaphthalenes has been reported in the last decade. However, access to other borazaro derivatives has been limited. A new approach to synthesize 2,1-borazaroquinolines and 2,1-borazaroisoquinolines from (vinylamino)pyridines and potassium organotrifluoroborates using microwave-assisted heating is reported. A substituted diverse set of new azaborines has been synthesized by this method, providing the first access to a family of 2,1-borazaroquinolines and 2,1-borazaroisoquinolines.

Full text of DOI:10.1002/ejoc.201500622

FULL PAPER
DOI: 10.1002/ejoc.201500622
Synthesis of 2,1-Borazaroquinolines and 2,1-Borazaroisoquinolines from
Vinylaminopyridines and Potassium Organotrifluoroborates by Microwave-
Assisted Heating
M. Rosa Sánchez Casado,*[a] Myriam Ciordia Jiménez,[a] Manuela Ariza Bueno,[b]
Morgane Barriol,[b] Joseph E. Leenaerts,[b] Chiara Pagliuca,[b]
Carolina Martínez Lamenca,[b] Ana Isabel De Lucas,[a] Aránzazu García,[a]
Andrés A. Trabanco,*[a] and Frederik J. R. Rombouts*[b]
Keywords: Nitrogen heterocycles / Boron heterocycles / Fused-ring systems / Bioisosteres / Aromaticity / Cyclization
Azaborines are an emerging class of compounds with appli-
cations in medicinal chemistry and materials science. The
synthesis of a wide variety of borazaronaphthalenes has been
reported in the last decade. However, access to other bor-
azaro derivatives has been limited. A new approach to syn-
thesize 2,1-borazaroquinolines and 2,1-borazaroisoquinol-
ines from (vinylamino)pyridines and potassium organotri-
fluoroborates using microwave-assisted heating is reported.
A substituted diverse set of new azaborines has been synthe-
sized by this method, providing the first access to a family of
2,1-borazaroquinolines and 2,1-borazaroisoquinolines.
Introduction
The design and synthesis of boron-containing com-
pounds has attracted much attention as a powerful way for
synthetic chemists to discover new compounds with appli-
cations in many diverse areas, including optoelectronic-ma-
terials science[1] and biomedical research.[2] Furthermore,
the inclusion of boron in biologically active molecules often
results in interesting new pharmacological properties, and
provides novelty in terms of intellectual property. In fact,
two boron-containing drugs have been approved by the US
food and drug administration (FDA): Bortezomib (1, Vel-
cadeTM), for the treatment of progressive multiple myeloma
in patients who have received at least one prior therapy,[3]
and Tavaborole (2, KerydinTM), a broad-spectrum antifun-
gal for the treatment of onychomycosis of the toenail due
to dermatophytes (Figure 1).[4]
Figure 1. Structures of VelcadeTM (1) and KerydinTM (2).
azaborinine derivatives 3–6 (Figure 2) as potential bioiso-
steric replacements for naphthalene rings, with improved
physicochemical and biological properties. In particular, the
high intrinsic lipophilicity of the naphthalene ring, which
has often limited its use in medicinal chemistry programs,
could be reduced by the introduction of the boron and
nitrogen atoms.[5] Although the aromaticity of the azabor-
Aromatic azaborines are an interesting class of boron de-
rivatives. In these compounds, two of the carbon atoms of
an aromatic system have been isoelectronically replaced by
boron and nitrogen. We have recently become interested in
[a] Janssen Research & Development, Neuroscience-Medicinal
Chemistry, Janssen-Cilag S. A.,
Jarama 75A, 45007 Toledo, Spain
E-mail: msanc117@its.jnj.com
atrabanc@its.jnj.com
http://www.janssen.es/
[b] Janssen Research & Development, Neuroscience-Medicinal
Chemistry, Janssen Pharmaceutica N. V.,
Turnhoutseweg 30, 2340 Beerse, Belgium
E-mail: frombout@its.jnj.com
http://www.janssenbelgium.be/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500622.
Figure 2. Naphthalene azaborinine analogues 3–6.
Eur. J. Org. Chem. 2015, 5221–5229
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M. R. Sánchez Casado, A. A. Trabanco, F. J. R. Rombouts et al.
FULL PAPER
Figure 3. Representative examples of (iso)quinoline-containing natural products (7 and 8) and drugs (9–15).
inine analogues is lower than that of naphthalene, their
Furthermore, Molander et al. have widely explored the
chemical stability is good, they can be handled without spe- reactivity of substituted borazaronaphthalenes in transi-
cial precautions, and they show a unique range of proper- tion-metal-catalysed cross-coupling reactions[8–10] and nu-
ties.[6]
cleophilic substitution reactions[11] to give a wide variety of
Bearing in mind these synthetic approaches to azabor-
Despite the fact that the first synthesis of substituted aza- diversely substituted borazaronaphthalenes.
borinine analogues of naphthalene from 2-aminostyrenes
was described by Dewar in the 1960s,[7a–7d] the field re- inine analogues of naphthalene, we were surprised to find
mained largely unexplored for decades, until Paetzold re- that the synthesis of quinoline and isoquinoline azaborinine
ported in 2004 a different strategy to build the borazaro- analogues has not yet been reported. Quinolines and iso-
naphthalene core starting from an aniline and phenylacet- quinolines are prominent motifs in pharmaceutical science,
ylene.[7e,7f] In 2013, Liu disclosed a method to post-func- and are found in a variety of natural products (Figure 3),
tionalize the aromatic boron chloride intermediate of De- such as quinine (7) and papaverine (8), and marketed drugs
war’s synthesis.[7g] Molander recently described a new and like tacrine (9), saquinavir (10), clioquinol (11), pitavastatin
general synthesis of borazaronaphthalenes from substituted (12), cabozantinib (13), bedaquiline (14), and fasudil
2-aminostyrenes, potassium organotrifluoroborates, and (15).[12]
SiCl4 using Et3N as a base and a 1:1 mixture of toluene/
In this paper, we report on the first synthesis of new 2,1-
cyclopentyl methyl ether (CPME) as the solvent. The pres- borazaroquinoline and 2,1-borazaroisoquinoline scaffolds
ence of SiCl4 as a fluorophile seemed to be crucial to gener- (Figure 4) using microwave-assisted heating.
ate the required organodihaloborane in situ. Molander’s
method represents a significant improvement over the
harsh reaction conditions developed by Dewar,[7a–7d] Paet-
zold,[7e,7f] and Liu.[7g] These latter methods also have the
disadvantage that the final compounds can be produced
with only a limited range of substituents on the boron and
nitrogen atoms (Scheme 1).
Figure 4. New 2,1-borazaroquinoline and 2,1-borazaroisoquinoline
scaffolds described in this work.
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2,1-Borazaroquinolines and 2,1-Borazaroisoquinolines
different temperatures (Table 1, entries 7–10), we found that
the desired borazaroquinoline (i.e., 17a) could be isolated
in 72% yield by heating the reaction mixture at 180 °C for
30 min under microwave irradiation. This initial result
prompted us to explore the scope of the reaction of ortho-
(vinylamino)pyridines 16 with different potassium organo-
trifluoroborates under the optimized reaction conditions
(Table 1, entry 9). The results obtained are shown in
Table 2.
Table 1. Reaction conditions tested for the synthesis of 17a.
Entry[a] Solvent
(concentration)
Base/equiv. T [°C]
t [min] 17a, yield
(%)
1
2
3
4
5
PhMe/CPME
(0.25 m)
PhMe/CPME
(0.25 m)
BTF/CPME
(0.5 m)
BTF (0.25 m)
Et3N/
0.75
Et3N/
1.5
Et3N/
0.75
Et3N/
1.5
60
80
80
80
80
1200
1440
1440
2880
2880
–
3[b]
–
5[b]
–
BTF (0.25 m)
DIPEA/
2.5
6
7
–
–
80
1440
5
–
–
PhMe/CPME
(0.5 m)
Et3N/
0.75
120 (MW)
Scheme 1. Previously described synthetic routes to borazaro-
8
PhMe/CPME
(0.5 m)
PhMe/CPME
(0.5 m)
PhMe/CPME
(0.5 m)
Et3N/
0.75
Et3N/
0.75
Et3N/
0.75
180 (MW) 15
180 (MW) 30
200 (MW) 20
11[b]
72[c]
26[c]
naphthalenes; BIPHEP
phenyl.
= 2,2Ј-bis(diphenylphosphino)-1,1Ј-bi-
9
10
Results and Discussion
[a] Reaction conditions: SiCl4 (1.0 equiv.), potassium methyltri-
fluoroborate (1.0 equiv.). [b] Yield of product determined by LCMS
UV analysis of the crude product mixture. [c] Isolated yield. BTF
= α,α,α-trifluorotoluene; DIPEA = diisopropylethylamine.
For the synthesis of borazaro(iso)quinolines, we consid-
ered the previously described synthetic routes to borazaro-
naphthalenes. Since Paetzold’s approach necessarily intro-
duces an aryl group at the 4-position of the bicycle, we fo-
Potassium alkyltrifluoroborates participated in the reac-
cussed our attention on the more general approaches by tion to give the corresponding alkyl borazaroquinolines
Dewar and Molander. Of these two, Molander’s protocol (i.e., 17a–17d) in moderate yields. Although isopropyl deriv-
seemed the more practical, and so it was chosen for the ative 17b was obtained in 63% yield (Table 2, entry 2),
initial attempts to synthesize substituted 2,1-borazaro- cyclopropyl derivative 17c (Table 2, entry 3) could only be
quinolines starting from 6-chloro-2-ethenylpyridin-3-amine isolated in 32% yield, with the main reaction product ob-
(16) as a model system. Unfortunately no reaction between served being B-OH derivative 18.[13] Benzylic derivative 17d
16 and potassium methyltrifluoroborate was observed in could also be prepared in moderate yield (Table 2, entry 4).
the presence of SiCl4 at 60 °C using traditional heating, The reaction of 16 with potassium alkenyltrifluoroborates,
most probably due to the decreased reactivity of the amine such as potassium vinyl- and [(E)-3-ethoxy-3-oxo-prop-1-
substituent on the electron-deficient pyridine ring. We var- enyl]trifluoroborates (Table 2, entries 5 and 6) was also suc-
ied the reaction conditions by using different solvents, cessful, and gave the corresponding desired products in
bases, and reaction times, but only traces of the expected 57% (17e) and 53% (17f) yields, together with variable
product (i.e., 17a) were observed in the crude product mix- amounts of 18.
ture (Table 1, entries 1–6). We hypothesized that this lack
Finally, B-aryl-substituted borazaroquinolines 17g–17k
of reactivity could be overcome by increasing the reaction could also be obtained by reaction with the corresponding
temperature, and we tested the procedure using controlled potassium aryltrifluoroborates, and thus the simple 1-
microwave heating. To our delight, after screening a set of phenyl-2,1-borazaroquinoline (17g) was isolated in 66%
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Table 2. Reaction of ortho-(vinylamino)pyridines 16 with different potassium organotrifluoroborates.
[a] Reaction conditions: 16 (1.0 equiv.), potassium organotrifluoroborate (1.0 equiv.), SiCl4 (1.0 equiv.), and Et3N (0.75 equiv.) in PhMe/
CPME (1:1; 0.50 m), 180 °C, 30 min, microwave irradiation. [b] Isolated yield. [c] LCMS UV trace vs. desired product in the crude product
mixture. [d] Compound 18 was not observed by LCMS UV analysis of the crude product mixture.
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2,1-Borazaroquinolines and 2,1-Borazaroisoquinolines
yield (Table 2, entry 7). Electron-rich and electron-poor 20b, and 20d, could be isolated in moderate yields (Table 3,
potassium aryltrifluoroborates yielded the corresponding entries 1, 2, and 4). Unfortunately, although derivative 20c
azaborine compounds in moderate yields. For instance, was observed in the crude product mixture by UV-LCMS
potassium 1,3-benzodioxol-5-yl-trifluoroborate led to the analysis (20%), it proved impossible to isolate this com-
expected derivative (i.e., 17h) in 34% yield (Table 2, en- pound due to its complete degradation into B-OH deriva-
try 8). Interestingly, potassium aryltrifluoroborates bearing tive 21c during purification (Table 3, entry 3). This instabil-
electron-withdrawing substituents were slightly better cou- ity could be due to the increased basicity of the pyridyl
pling partners, and 3-nitrophenyl (17i), 4-pyridyl (17j), and nitrogen in these scaffolds compared to 17g, 17m, and 17n.
6-fluoropyridin-3-yl (17k) boron-substituted azaborinines
could be synthesized in 44, 63, and 44% yields, respectively ther derivatization was also studied (Scheme 2). Suzuki–Mi-
(Table 2, entries 9–11). yaura (A) and Buchwald (B) couplings were successfully
Finally, the ability of these compounds to undergo fur-
We studied how well substituents on the nitrogen of the carried out on the chloro substituent of 17a, yielding 22
azaborinine were tolerated by synthesizing N-methyl-2- and 23 in good yields, and proving the synthetic potential
methyl-2,1-borazaroquinoline (17l; Table 2, entry 12), but of these new azaborinine derivatives.
this reaction proceeded in moderate yield (40%).
To further test the scope of the reaction, we next varied
the position of the halogen substituent in the starting anil-
ine (i.e., 16) to form haloazaborinines that could serve as
precursors for further chemical derivatization. Both 5- and
4-chloro-2-ethenylpyridin-3-amines reacted smoothly to
give the corresponding azaborinines (i.e., 17m and 17n) in
50 and 56% yields, respectively (Table 2, entries 13 and 14).
The pyridine-like nitrogen in 17m and 17n is significantly
more basic than that in 17a, but this does not apparently
preclude the reaction from proceeding.
In addition, the synthesis of the four possible borazaro-
(aza)quinoline cores 20a–20d was then studied by varying
the position of the pyridyl nitrogen in the corresponding
starting (vinylamino)pyridines. Potassium phenyltrifluoro-
borate was chosen as the boron source, and the reactions
were carried out under the optimized standard conditions
(Table 1, entry 9). As shown in Table 3, compounds 20a,
Table 3. Scope of the reaction with different aminopyridines 19a–
19d.
Scheme 2. Examples of derivatization of borazaroquinoline 17a; X-
Phos = 2-dicyclohexylphosphino-2Ј,4Ј,6Ј-triisopropylbiphenyl, dba
= dibenzylideneacetone.
Conclusions
We have described the first synthesis of 2,1-borazaro-
quinolines and 2,1-borazaroisoquinolines, new chemotypes
with potential applications in different scientific fields, in-
cluding medicinal chemistry.
An initial study of the reaction scope has revealed a wide
functional group tolerance for the boron substituent, and
thus alkyl-, alkenyl-, and aryl-boron-substituted borazaro-
quinolines have been prepared. In addition new bicyclic
azaborinines were prepared, where the position of the nitro-
gen in the fused pyridine ring was varied. We have also
demonstrated that these new ring systems can be further
derivatized using palladium-catalysed cross-coupling chem-
istry. The results of our further investigation of these com-
pounds will be reported in due course.
[a] Isolated yield. [b] LCMS UV trace vs. desired product in the
crude product mixture. [c] Compound 21d was not observed by
LCMS UV analysis of the crude product mixture.
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6-Chloro-2-isoproyl-1H-pyrido[2,3-e]azaborinine (17b): The crude
product was purified by column chromatography (silica; CH2Cl2 in
heptane, from 20:80 to 50:50) to give compound 17b (85 mg, 63%)
as a white solid, m.p. 121.31 °C. 1H NMR (400 MHz, CDCl3): δ =
Experimental Section
General Remarks: Toluene, CPME, and SiCl4 were purchased from
commercial sources and used as received. NMR spectra were re-
corded with a 500, 400, or 360 MHz spectrometer. 11B NMR spec-
tra were obtained using a spectrometer equipped with the appropri-
ate decoupling accessories. All 11B NMR chemical shifts were refer-
enced to external BF3·OEt2 (δ = 0.0 ppm), with a negative sign
indicating an upfield shift. Chemical shifts (δ) are given in parts
per million. Multiplicities are denoted as follows: s = singlet, d =
doublet, t = triplet, m = multiplet, br. = broad. Coupling constants
3
3
1.17 (d, JH,H = 7.48 Hz, 6 H), 1.44–1.64 (m, 1 H), 7.19 (dd, JH,H
3
= 11.9, 2.2 Hz, 1 H), 7.31 (d, JH,H = 8.6 Hz, 1 H), 7.53–7.57 (m,
3
1 H), 7.63 (br. s, 1 H), 8.10 (d, JH,H = 11.9 Hz, 1 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 19.49 (s, 2 C), 123.02 (s, 1 C), 128.27
(s, 1 C), 134.50 (s, 1 C), 142.59 (s, 1 C), 143.27 (s, 1 C), 144.86 (s,
1 C) ppm (C next to B were not detected). 11B NMR (128.5 MHz,
CDCl3): δ = 39.12 ppm. HRMS (CI): calcd. for C10H13BClN2 [M
+ H]+ 207.0860; found 207.0862.
1
(J) are given in Hertz. H NMR spectroscopic data are presented
as follows: chemical shift (multiplicity, coupling constant, integra-
tion). Analytical thin-layer chromatography (TLC) was carried out
on TLC silica gel plates (0.25 mm) precoated with a fluorescent
indicator. Standard flash chromatography procedures were fol-
lowed using 32–63 μm silica gel. Visualization was effected with
UV light. HRMS data were obtained by ESI using a TOF mass
spectrometer. All reactions were carried out under nitrogen.
6-Chloro-2-cycloproyl-1H-pyrido[2,3-e]azaborinine (17c): The crude
product was purified by column chromatography (silica; CH2Cl2 in
heptane, from 20:80 to 50:50) to give compound 17c (38 mg, 32%)
as a white solid, m.p. 154.27 °C. 1H NMR (400 MHz, CDCl3): δ =
3
0.25 (tt, JH,H = 9.7, 6.0 Hz, 1 H), 0.57–0.66 (m, 2 H), 0.87–0.94
3
(m, 2 H), 6.76 (dd, JH,H = 11.9, 2.2 Hz, 1 H), 7.25–7.32 (m, 1 H),
3
7.42–7.51 (m, 1 H), 7.51–7.63 (m, 1 H), 8.01 (d, JH,H = 12.1 Hz,
1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 6.40 (s, 2 C), 123.06
(s, 1 C), 127.75 (s, 1 C), 134.70 (s, 1 C), 142.51 (s, 1 C), 142.88 (s,
1 C), 144.84 (s, 1 C) ppm (C next to B were not detected). 11B
NMR (128.5 MHz, CDCl3): δ = 38.32 ppm. HRMS (CI): calcd. for
C10H11BClN2 [M + H]+ 205.0704; found 205.0706.
6-Chloro-2-vinyl-pyridin-3-amine (16): Tetrakis(triphenylphosphine)-
palladium(0) (0.75 g, 0.65 mmol) was added to a stirred suspension
of 6-chloro-2-iodo-pyridin-3-amine (3.3 g, 12.97 mmol) and pinac-
ol vinylboronate (2.31 mL, 13.62 mmol) in 1,4-dioxane (44 mL)
and saturated aq. Na2CO3 (4 mL). The mixture was stirred at 80 °C
for 18 h. Then, water was added, and the mixture was extracted
with EtOAc. The organic layer was separated, dried (Na2SO4), and
filtered, and the solvents were evaporated in vacuo. The crude
product was purified by flash column chromatography (silica;
CH2Cl2). The desired fractions were collected and evaporated in
vacuo to give compound 16 (1.0 g, 50%) as a yellow solid, m.p.
2-Benzyl-6-chloro-1H-pyrido[2,3-e]azaborinine (17d): The crude
product was purified by column chromatography (silica; EtOAc in
heptane, from 0:100 to 20:80) to give compound 17d (47 mg, 29%)
as a white solid, m.p. 121.85 °C. 1H NMR (400 MHz, CDCl3): δ =
3
2.88 (s, 2 H), 7.14 (dd, JH,H = 11.8, 2.1 Hz, 1 H), 7.16–7.23 (m, 3
3
H), 7.30–7.37 (m, 3 H), 7.37–7.42 (m, 1 H), 8.09 (d, JH,H
=
1
100.91 °C. H NMR (400 MHz, CDCl3): δ = 3.77 (br. s, 2 H), 5.54
11.9 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 123.08 (s, 1
C), 125.01 (s, 1 C), 128.33 (s, 1 C), 128.83 (s, 2 C), 128.88 (s, 2 C),
134.47 (s, 1 C), 140.78 (s, 1 C), 142.48 (s, 1 C), 143.52 (s, 1 C),
144.88 (s, 1 C) ppm (C next to B were not detected). 11B NMR
(128.5 MHz, CDCl3): δ = 37.86 ppm. HRMS (CI): calcd. for
C14H13BClN2 [M + H]+ 255.0860; found 255.0867.
3
3
(dd, JH,H = 11.00, 1.54 Hz, 1 H), 6.26 (dd, JH,H = 17.1, 1.65 Hz,
3
1 H), 6.74 (dd, JH,H = 17.1, 10.9 Hz, 1 H), 6.85–7.10 (m, 2 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 120.01 (s, 1 C), 123.38 (s,
1 C), 126.48 (s, 1 C), 130.07 (s, 1 C), 138.58 (s, 1 C), 140.26 (s, 1
C), 141.13 (s, 1 C) ppm. HRMS (CI): calcd. for C7H8ClN2 [M +
H]+ 155.0376; found 155.0374.
6-Chloro-2-vinyl-1H-pyrido[2,3-e]azaborinine (17e): The crude prod-
uct was purified by column chromatography (silica; CH2Cl2 in
heptane, from 20:80 to 50:50) to give compound 17e (70 mg, 57%)
as a white solid, m.p. 194.84 °C. 1H NMR (400 MHz, [D6]acetone):
General Procedure for the Synthesis of 2,1-Borazaroquinolines and
2,1-Borazaroisoquinolines: The potassium organotrifluoroborate
(1.0 equiv.) and 2-(vinylamino)pyridine (1.0 equiv.) were put into
an oven-dried Biotage microwave vial equipped with a stirrer bar.
The vial was sealed with a cap lined with a disposable Teflon
septum, evacuated under vacuum, and purged with nitrogen three
times. CPME (9 equiv.), toluene (10 equiv.), and SiCl4 (1.0 equiv.)
were added. The reaction mixture was stirred at room temperature
for 2 min, and then Et3N (0.75 equiv.) was added under nitrogen.
The resulting mixture was heated at 180 °C for 30 min under micro-
wave irradiation, and then it was cooled to room temperature. The
solvent was removed in vacuo, and the crude product was purified
by flash column chromatography. The reactions were carried out
using 100 mg of 2-(vinylamino)pyridine.
3
2
3
δ = 6.04 (dd, JH,H = 13.2, JH,H = 3.1 Hz, 1 H), 6.30 (dd, JH,H
19.8, JH,H = 3.7 Hz, 1 H), 6.53 (dd, JH,H = 19.7, 13.3 Hz, 1 H),
=
2
3
3
3
7.32–7.43 (m, 1 H), 7.45 (d, JH,H = 8.6 Hz, 1 H), 7.95 (d, JH,H
=
3
8.6 Hz, 1 H), 8.08 (d, JH,H = 11.7 Hz, 1 H), 9.75 (br. s, 1 H) ppm.
13C NMR (101 MHz, [D6]acetone): δ = 124.34 (s, 1 C), 130.28 (s,
1 C), 133.75 (s, 1 C), 136.57 (s, 1 C), 143.54 (s, 1 C), 143.81 (s, 1
C), 145.90 (s, 1 C) ppm (C next to B were not detected). 11B NMR
(128.5 MHz, [D6]acetone): δ = 32.61 ppm. HRMS (CI): calcd. for
C9H9BClN2 [M + H]+ 191.0547; found 191.0548.
Ethyl (E)-3-(6-Chloro-1H-pyrido[2,3-e]azaborinin-2-yl)prop-2-eno-
ate (17f): The crude product was purified by column chromatog-
6-Chloro-2-methyl-1H-pyrido[2,3-e]azaborinine (17a): The crude raphy (silica; EtOAc in heptane, from 0:100 to 20:80) to give com-
product was purified by column chromatography (silica; MeOH in
CH2Cl2, from 0:100 to 15:85) to give compound 17a (83 mg, 72%)
as a pale orange solid, m.p. 174.46 °C. 1H NMR (400 MHz,
pound 17f (90 mg, 53%) as a white solid, m.p. 197.67 °C. 1H NMR
3
(400 MHz, [D6]acetone): δ = 1.28 (t, JH,H = 7.15 Hz, 3 H), 4.21
3
3
(q, JH,H = 7.3 Hz, 2 H), 6.80 (d, JH,H = 18.1 Hz, 1 H), 7.37–7.59
(m, 3 H), 7.93–8.11 (m, 1 H), 8.18 (d, 3JH,H = 11.9 Hz, 1 H), 10.14
(br. s, 1 H) ppm. 13C NMR (101 MHz, [D6]acetone): δ = 13.67 (s,
1 C), 60.01 (s, 1 C), 123.77 (s, 1 C), 129.72 (s, 1 C), 135.17 (s, 1 C),
135.38 (s, 1 C), 142.67 (s, 1 C), 143.57 (s, 1 C), 145.75 (s, 1 C),
165.70 (s, 1 C) ppm (C next to B were not detected). 11B NMR
3
CDCl3): δ = 0.78 (s, 3 H), 7.11 (dd, JH,H = 11.9, 2.2 Hz, 1 H),
3
7.30 (d, JH,H = 8.6 Hz, 1 H), 7.44–7.54 (m, 1 H), 7.65 (br. s, 1 H),
8.04 (d, 3JH,H = 11.9 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 122.98 (s, 1 C), 127.97 (s, 1 C), 134.74 (s, 1 C), 142.40 (s, 1 C),
143.12 (s, 1 C), 144.24 (s, 1 C) ppm (C next to B were not detected).
11B NMR (128.5 MHz, CDCl3): δ = 38.32 ppm. HRMS (CI): calcd. (128.5 MHz, [D6]acetone): δ = 32.23 ppm. HRMS (CI): calcd. for
for C8H9BClN2 [M + H]+ 179.0547; found 179.0547.
C12H13BClN2O2 [M + H]+ 263.0759; found 263.0765.
5226
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5221–5229

2,1-Borazaroquinolines and 2,1-Borazaroisoquinolines
6-Chloro-2-phenyl-1H-pyrido[2,3-e]azaborinine (17g): The crude
product was purified by column chromatography (silica; EtOAc in
C), 123.94 (s, 1 C), 130.11 (s, 1 C), 132.88 (s, 1 C), 135.69 (s, 1 C),
3
141.81 (s, 1 C), 142.62 (s, 1 C), 145.33 (s, 1 C),146.92 (d, JC,F
=
=
2
1
heptane, from 0:100 to 20:80) to give compound 17g (102 mg, 66%) 8.07 Hz, 1 C), 152.92 (d, JC,F = 13.94 Hz, 1 C),165.56 (d, JC,F
as a white solid, m.p. 150.98 °C. 1H NMR (400 MHz, CDCl3): δ = 238.42 Hz, 1 C) ppm (C next to B were not detected). 11B NMR
3
7.38 (d, JH,H = 8.6 Hz, 1 H), 7.45–7.52 (m, 3 H), 7.57–7.68 (m, 2
(128.5 MHz, [D6]DMSO): δ = 33.94 ppm. HRMS (CI): calcd. for
3
H), 7.87–7.95 (m, 2 H), 8.08 (br. s, 1 H), 8.27 (d, JH,H = 11.9 Hz,
C12H9BFClN3 [M + H]+ 260.0562; found 260.0566.
1 H) ppm. 13C NMR (101.0 MHz, CDCl3): δ = 123.50 (s, 1 C),
128.41 (s, 2 C), 128.57 (s, 1 C), 130.28 (s, 1 C), 132.78 (s, 2 C),
134.77 (s, 1 C), 142.85 (s, 1 C), 143.73 (s, 1 C), 145.88 (s, 1 C) ppm
(C next to B were not detected). 11B NMR (128.5 MHz, CDCl3):
δ = 34.36 ppm. HRMS (CI): calcd. for C13H11BClN2 [M + H]+
241.0704; found 241.0709.
1,2-Dimethylpyrido[2,3-e]azaborinine (17l): The crude product was
purified by column chromatography (silica; CH2Cl2 in heptane,
from 20:80 to 100:0) to give compound 17l (48 mg, 40%) as an
1
orange oil. H NMR (400 MHz,CDCl3): δ = 0.90 (s, 3 H), 3.60 (s,
3 H), 7.06 (d, 3JH,H = 11.7 Hz, 1 H), 7.39 (dd, 3JH,H = 8.6, 4.40 Hz,
1 H), 7.82 (d, 3JH,H = 8.6 Hz, 1 H), 8.08 (d, 3JH,H = 11.7 Hz, 1 H),
3
8.53 (dd, JH,H = 4.4, 1.3 Hz, 1 H) ppm. 13C NMR (125.8 MHz,
2-(1,3-Benzodioxol-5-yl)-6-chloro-1H-pyrido[2,3-e]azaborinine
(17h): The crude product was purified by column chromatography
(silica; EtOAc in heptane, from 0:100 to 20:80) to give compound
17h (62 mg, 34 %) as a white solid, m.p. 195.93 °C. 1H NMR
CDCl3): δ = 34.48 (s, 1 C), 121.76 (s, 1 C), 122.33 (s, 1 C), 138.60
(s, 1 C), 142.42 (s, 1 C), 143.95 (s, 1 C), 144.82 (s, 1 C) ppm (C
next to B were not detected). 11B NMR (128.5 MHz, CDCl3): δ =
38.81 ppm. HRMS (CI): calcd. for C9H12BN2 [M + H]+ 159.1094;
found 159.1090.
3
(400 MHz, CDCl3): δ = 6.01 (s, 2 H), 6.95 (d, JH,H = 7.7 Hz, 1
3
3
H), 7.33 (d, JH,H = 1.1 Hz, 1 H), 7.36 (d, JH,H = 8.4 Hz, 1 H),
3
3
7.43 (dd, JH,H = 7.7, 1.1 Hz, 1 H), 7.51 (dd, JH,H = 11.9, 2.2 Hz,
1 H), 7.58–7.64 (m, 1 H), 7.93 (br. s, 1 H), 8.21 (d, 3JH,H = 11.9 Hz,
1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 100.95 (s, 1 C), 108.91
(s, 1 C), 111.96 (s, 1 C), 123.48 (s, 1 C), 127.54 (s, 1 C), 128.42 (s,
1 C), 134.82 (s, 1 C), 142.80 (s, 1 C), 143.59 (s, 1 C), 145.71 (s, 1
C), 148.05 (s, 1 C), 149.60 (s, 1 C) ppm (C next to B were not
detected). 11B NMR (128.5 MHz, CDCl3): δ = 34.13 ppm. HRMS
(CI): calcd. for C14H11BClN2O2 [M + H]+ 285.0602; found
285.0608.
7-Chloro-2-methyl-1H-pyrido[2,3-e]azaborinine (17m): The crude
product was purified by column chromatography (silica; MeOH in
CH2Cl2, from 0:100 to 5:95) to give compound 17m (58 mg, 50%)
as a white solid, m.p. 191.31 °C. 1H NMR (400 MHz, CDCl3): δ =
3
0.79 (s, 3 H), 7.07 (dd, JH,H = 11.7, 2.2 Hz, 1 H), 7.42–7.66 (m, 2
3
3
H), 8.09 (d, JH,H = 11.7 Hz, 1 H), 8.44 (d, JH,H = 2.2 Hz, 1 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 124.46 (s, 1 C), 130.42 (s,
1 C), 136.58 (s, 1 C), 141.56 (s, 1 C), 142.56 (s, 1 C), 145.23 (s, 1
C) ppm. 11B NMR (128.5 MHz, CDCl3): δ = 38.47 ppm. HRMS
(CI): calcd. for C8H9BClN2 [M + H]+ 179.0547; found 179.0547.
6-Chloro-2-(3-nitrophenyl)-1H-pyrido[2,3-e]azaborinine (17i): The
crude product was purified by column chromatography (silica;
CH2Cl2 in heptane, from 50:50 to 100:0) to give compound 17i
(81 mg, 44 %) as a pale yellow solid, m.p. 264.07 °C. 1H NMR
8-Chloro-2-methyl-1H-pyrido[2,3-e]azaborinine (17n): The crude
product was purified by flash column chromatography (silica;
CH2Cl2) to give compound 17n (66 mg, 57%) as a pale brown solid,
m.p. 100.52 °C. 1H NMR (400 MHz, CDCl3): δ = 0.85 (s, 3 H),
3
(400 MHz, [D6]DMSO): δ = 7.63 (d, JH,H = 8.4 Hz, 1 H), 7.66–
3
7.71 (m, 1 H), 7.80 (t, JH,H = 7.7 Hz, 1 H), 8.15–8.28 (m, 2 H),
3
7.15 (dd, 3JH,H = 11.7, 2.2 Hz, 1 H), 7.42 (d, JH,H = 5.1 Hz, 1 H),
3
3
8.33 (d, JH,H = 8.2 Hz, 1 H), 8.52 (d, JH,H = 7.3 Hz, 1 H), 8.90–
8.94 (m, 1 H), 11.11 (br. s, 1 H) ppm. 13C NMR (101 MHz, [D6]-
DMSO) δ = 122.52 (s, 1 C), 123.09 (s, 1 C), 125.84 (s, 1 C), 128.16
(s, 1 C), 128.77 (s, 1 C), 134.22 (s, 1 C), 138.83 (s, 1 C), 140.42 (s,
1 C), 141.30 (s, 1 C), 144.09 (s, 1 C), 146.44 (s, 1 C) ppm (C next
to B were not detected). 11B NMR (128.5 MHz, [D6]DMSO): δ
= 32.88 ppm. HRMS (CI): calcd. for C13H10BClN3O2 [M + H]+
286.0554; found 286.0558.
3
3
8.12 (d, JH,H = 12.1 Hz, 2 H), 8.40 (d, JH,H = 5.1 Hz, 1 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 122.60 (s, 1 C), 131.45 (s, 1 C),
133.30 (s, 1 C), 143.13 (s, 1 C), 144.09 (s, 1 C), 145.56 (s, 1 C) ppm
(C next to B were not detected). 11B NMR (128.5 MHz, CDCl3):
δ = 38.52 ppm. HRMS (CI): calcd. for C8H9BClN2 [M + H]+
179.0547; found 179.0547.
6-Chloro-2-hydroxy-1H-pyrido[2,3-e]azaborinine (18): The crude
product was purified by column chromatography (silica; MeOH in
CH2Cl2, from 0:100 to 7:93) to give compound 18 (42 mg, 36%) as
6-Chloro-2-(4-pyridyl)-1H-pyrido[2,3-e]azaborinine (17j): The crude
product was purified by prep. HPLC using as mobile phase 0.25%
NH4HCO3 solution in water and MeCN to give compound 17j
(99 mg, 63%) as a white solid, m.p. 225.05 °C. 1H NMR (400 MHz,
1
a yellow solid, m.p. 152.57 °C. H NMR (400 MHz, [D6]DMSO):
3
3
δ = 6.60 (dd, JH,H = 12.2, 2.3 Hz, 1 H), 7.35 (d, JH,H = 8.5 Hz,
1 H), 7.69 (d, 3JH,H = 8.6 Hz, 1 H), 7.78 (d, 3JH,H = 12.2 Hz, 1 H),
8.10 (s, 1 H), 9.01 (br. s, 1 H) ppm. 13C NMR (101.0 MHz, [D6]-
DMSO): δ = 123.40 (s, 1 C), 128.60 (s, 1 C), 137.55 (s, 1 C), 140.08
(s, 1 C), 140.58 (s, 1 C), 146.14 (s, 1 C) ppm (C next to B were
not detected). 11B NMR (128.5 MHz, [D6]DMSO): δ = 27.75 ppm.
HRMS (CI): calcd. for C7H5BClN2O [M – H]– 179.0184; found
179.0189.
3
3
[D6]acetone): δ = 7.55 (d, JH,H = 8.6 Hz, 1 H), 7.66 (dd, JH,H
=
11.9, 2.2 Hz, 1 H), 7.83–8.04 (m, 2 H), 8.08–8.20 (m, 1 H), 8.28 (d,
3JH,H = 11.9 Hz, 1 H), 8.58–8.72 (m, 2 H), 10.36 (br. s, 1 H) ppm.
13C NMR (101.0 MHz, [D6]acetone): δ = 123.89 (s, 1 C), 127.46 (s,
2 C), 129.96 (s, 1 C), 135.60 (s, 1 C), 142.63 (s, 1 C), 143.67 (s, 1
C), 146.34 (s, 1 C), 149.46 (s, 2 C) ppm (C next to B were not
detected). 11B NMR (128.5 MHz, [D6]acetone): δ = 33.56 ppm.
HRMS (CI): calcd. for C12H10BClN3 [M + H]+ 242.0656; found
242.0658.
2-Phenyl-1H-pyrido[2,3-e]azaborinine (20a): The crude product was
purified by flash column chromatography (silica; CH2Cl2 with 2%
6-Chloro-2-(2-fluoro-4-pyridyl)-1H-pyrido[2,3-e]azaborinine (17k): Et3N) to give compound 20a (66 mg, 37%) as a white solid, m.p.
The crude product was purified by column chromatography (silica;
180.54 °C. 1H NMR (400 MHz, CDCl3): δ = 7.40 (dd, 3JH,H = 8.1,
3
CH2Cl2 in heptane, from 60:40 to 100:0) to give compound 17k 4.4 Hz, 1 H), 7.46–7.54 (m, 3 H), 7.59 (dd, JH,H = 11.9, 2.2 Hz, 1
(74 mg, 44%) as a white solid, m.p. 273.67 °C. 1H NMR (400 MHz,
H), 7.71 (d, 3JH,H = 8.4 Hz, 1 H), 7.89–7.98 (m, 2 H), 8.39 (d, 3JH,H
[D6]DMSO): δ = 7.31 (d, 3JH,H = 7.0 Hz, 1 H), 7.50–7.73 (m, 2 H), = 11.9 Hz, 1 H), 8.58 (dd, 3JH,H = 4.4, 1.1 Hz, 1 H) ppm. 13C NMR
3
3
8.12 (d, JH,H = 8.6 Hz, 1 H), 8.19 (d, JH,H = 11.9 Hz, 1 H), 8.62
(125.8 MHz, CDCl3): δ = 120.92 (s, 1 C), 123.79 (s, 1 C), 126.38 (s,
2 C), 128.13 (s, 1 C), 130.88 (s, 2 C), 134.08 (s, 1 C), 141.20 (s, 1
C ) , 1 4 1 . 7 9 ( s, 1 C ) , 1 4 4 . 8 7 ( s, 1 C ) p p m . 1 1 B N M R
(t, JH,H = 7.81 Hz, 1 H), 8.90 (s, 1 H), 10.93 (br. s, 1 H) ppm. 13C
NMR (101 MHz, [D6]DMSO): δ = 109.31 (d, JC,C = 35.21 Hz, 1
3
3
Eur. J. Org. Chem. 2015, 5221–5229
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5227

M. R. Sánchez Casado, A. A. Trabanco, F. J. R. Rombouts et al.
FULL PAPER
(128.5 MHz,CDCl3): δ = 33.86 ppm. HRMS (CI): calcd. for
(br. s, 1 H) ppm. 13C NMR (125.8 MHz, [D6]DMSO): δ = 42.32
(s, 1 C), 44.47 (s, 2 C), 52.02 (s, 2 C), 112.78 (s, 1 C), 130.66 (s, 1
C), 131.87 (s, 1 C), 133.63 (s, 1 C), 137.42 (s, 1 C), 150.400 (s, 1 C)
ppm (C next to B were not detected). 11B NMR (128.5 MHz, [D6]-
DMSO): δ = 2.96 ppm. HRMS (CI): calcd. for C13H20BN4 [M +
H]+ 243.1781; found 243.1784.
C13H12BN2 [M + H]+ 207.1094; found 207.1097.
2-Phenyl-1H-pyrido[3,4-e]azaborinine (20b): The crude product was
purified by flash column chromatography [silica; NH3 (7 m in
MeOH) in CH2Cl2, from 0:100 to 10:90] to give compound 20b
(45 mg, 26 %) as a yellow solid, m.p. 175.23 °C. 1H NMR
(400 MHz, [D4]methanol): δ = 7.33 (d, 3JH,H = 11.4 Hz, 1 H), 7.41–
7.43 (m, 2 H), 7.46 (d, 3JH,H = 2.2 Hz, 1 H), 7.54 (d, 3JH,H = 5.9 Hz,
Starting Materials
General Procedure for Suzuki Coupling: Tetrakis(triphenylphos-
phine)palladium(0) (0.05 equiv.) was added to a stirred suspension
of halopyridine (1 equiv.) and vinylboronic acid pinacol ester
(1 equiv.) in 1,4-dioxane (4 mL/mmol) and saturated aq. Na2CO3
(1.4 mL/mmol). The mixture was heated under microwave irradia-
tion to 140 °C for 15 min. The reaction mixture was diluted with
EtOAc and water, and the two phases were separated. The aqueous
layer was extracted with EtOAc. The combined organic layers were
dried with MgSO4, and filtered, and the solvent was removed by
evaporation. The crude product was purified by column
chromatography.
3
1 H), 7.99–8.01 (m, 2 H), 8.13 (d, JH,H = 11.9 Hz, 1 H), 8.32 (d,
3JH,H = 5.5 Hz, 1 H), 8.74 (br. s, 1 H) ppm. 13C NMR (125.8 MHz,
[D4]methanol): δ = 112.88 (s, 1 C), 127.72 (s, 2 C), 129.45 (s, 2 C),
130.95 (s, 1 C), 132.99 (s, 2 C), 140.94 (s, 1 C), 144.08 (s, 1 C),
148.26 (s, 1 C) ppm. 11B NMR (128.5 MHz, [D4]methanol): δ =
32.28 ppm. HRMS (CI): calcd. for C13H12BN2 [M + H]+ 207.1094;
found 207.1096.
2-Phenyl-1H-pyrido[3,2-e]azaborinine (20d): The crude product was
purified by column chromatography (silica; EtOAc in heptane,
from 0:100 to 10:90) to give compound 20d (60 mg, 35%) as a white
1
solid, m.p. 103.97 °C. H NMR (500 MHz, CDCl3): δ = 7.17 (dd,
4-Chloro-2-vinyl-pyridin-3-amine: The crude product was purified
by column chromatography (silica; MeOH in CH2Cl2, from 0:100
to 30:70) to give 4-chloro-2-vinyl-pyridin-3-amine (272 mg, 48%)
3
3JH,H = 4.6, 7.8 Hz, 1 H), 7.34 (dd, JH,H = 2.0, 11.6 Hz, 1 H),
3
7.45–7.51 (m, 3 H), 7.94–7.96 (m, 3 H), 8.07 (d, JH,H = 11.6 Hz,
3
1
1 H), 8.51 (dd, JH,H = 1.7, 4.6 Hz, 1 H), 8.79 (br. s, 1 H) ppm.
as a colourless oil. H NMR (360 MHz, CDCl3): δ = 4.19 (br. s, 2
13C NMR (125.8 MHz, CDCl3): δ = 117.55 (s, 1 C), 120.12 (s, 1
C), 128.35 (s, 2 C), 130.21 (s, 2 C), 133.02 (s, 1 C), 137.37 (s, 1 C),
144.68 (s, 1 C), 148.72 (s, 1 C), 151.05 (s, 1 C) ppm (C next to B
were not detected). 11B NMR (128.5 MHz, CDCl3): δ = 35.48 ppm.
HRMS (CI): calcd. for C13H12BN2 [M + H]+ 207.1094; found
207.1095.
3
3
H), 5.58 (dd, JH,H = 10.79, 1.65 Hz, 1 H), 6.25 (dd, JH,H = 17.0,
3
3
1.7 Hz, 1 H), 6.85 (dd, JH,H = 17.2, 11.0 Hz, 1 H), 7.12 (d, JH,H
= 5.1 Hz, 1 H), 7.94 (d, JH,H = 5.1 Hz, 1 H) ppm.
3
4-Vinylpyridin-3-amine: The crude product was purified by column
chromatography (silica; MeOH in CH2Cl2, from 0:100 to 6:94) to
give 4-vinylpyridin-3-amine (900 mg, 96%) as a yellow oil. 1H
3
N,N-Dimethyl-4-(2-methyl-1H-pyrido[2,3-e]azaborinin-6-yl)aniline
(22): A mixture of 17a (1 equiv.), [4-(dimehtylamino)phenyl]-
boronic acid (1.2 equiv.), and potassium carbonate (2 equiv.) in 1,4-
dioxane (25.5 equiv.) and distilled water (120 equiv.) was degassed
under N2 flow for 5 min. Then, tetrakis(triphenylphosphine)palla-
dium (0.05 equiv.) was added, and the mixture was heated at 120 °C
for 15 min under microwave irradiation. Then, water was added,
and the mixture was extracted with EtOAc. The organic layer was
separated, dried (MgSO4), and filtered, and the solvents were evap-
orated in vacuo. The crude product was purified by column
chromatography (silica; EtOAc in heptane, from 0:100 to 20:80) to
give compound 22 (82 mg, 81%) as a yellow solid, m.p. 196.52 °C.
1H NMR (360 MHz, [D6]DMSO): δ = 0.73 (s, 3 H), 2.97 (s, 6 H),
NMR (400 MHz, [D6]DMSO): δ = 5.42 (dd, JH,H = 1.2, 11.1 Hz,
1 H), 5.44 (br. s, 2 H), 5.89 (d, 3JH,H = 1.2, 17.3 Hz, 1 H), 6.94 (dd,
3JH,H = 11.1 and 17.6 Hz, 1 H), 7.26 (d, 3JH,H = 5.1 Hz, 1 H), 7.77
3
(d, JH,H = 4.9 Hz, 1 H), 8.04 (br. s, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 117.51 (s, 1 C), 119.82 (s, 1 C), 127.43
(s, 1 C), 131.67 (s, 1 C), 138.10 (s, 1 C), 139.33 (s, 1 C), 142.54 (s,
1 C) ppm.
3-Vinylpyridin-2-amine: The crude product was purified by column
chromatography (silica; MeOH in CH2Cl2, from 0:100 to 6:94) to
1
give 3-vinylpyridin-2-amine (124 mg, 18%) as a colourless oil. H
3
NMR (400 MHz, CDCl3): δ = 4.60 (br. s, 2 H), 5.38 (d, JH,H
=
=
3
3
11.1 Hz, 1 H), 5.65 (d, JH,H = 17.3 Hz, 1 H), 6.64 (dd, JH,H
3
11.1, 17.3 Hz, 1 H), 6.69 (d, JH,H = 5.1, 7.6 Hz, 1 H), 7.49–7.51
3
6.81 (d, JH,H = 9.1 Hz, 2 H), 6.97 (dd, 3JH,H = 11.7, 1.8 Hz, 1 H),
(m, 1 H), 8.00 (d, JH,H = 1.4, 4.9 Hz, 1 H) ppm. 13C NMR
3
7.79–7.93 (m, 2 H), 7.93–8.10 (m, 3 H), 10.11 (s, 1 H) ppm. 13C
NMR (125.8 MHz, [D6]DMSO): δ = 112.56 (s, 2 C), 119.14 (s, 2
C), 126.76 (s, 1 C), 127.05 (s, 1 C), 127.22 (s, 1 C), 127.54 (s, 2 C),
135.34 (s, 1 C), 141.60 (s, 1 C), 145.52 (s, 1 C), 150.16 (s, 1 C),
150.97 (s, 1 C), ppm (C next to B were not detected). 11B NMR
(128.5 MHz, [D6]DMSO): δ = 2.75 ppm. HRMS (CI): calcd. for
C16H18BN3 [M + H]+ 264.1672; found 264.1674.
(101 MHz, CDCl3): δ = 115.13 (s, 1 C), 117.65 (s, 1 C), 118.97 (s,
1 C), 132.14 (s, 1 C), 135.48 (s, 1 C), 147.72 (s, 1 C), 156.06 (s, 1
C) ppm.
Acknowledgments
The analytical department of Janssen (Toledo and Beerse) is ac-
knowledged for analysing the NMR spectra and HRMS.
2-Methyl-6-(4-methylpiperazin-1-yl)-1H-pyrido[2,3-e]azaborinine
(23): A solution of 1-methylpiperazine (1 equiv.), 17a (1 equiv.), so-
dium tert-butoxide (4 equiv.), bis(dibenzylideneacetone)palla-
dium(0) (0.06 equiv.), and X-Phos (0.12 equiv.) in toluene
(51.6 equiv.) was stirred at 120 °C for 20 min under microwave irra-
diation under N2. The solvent was evaporated in vacuo, and the
product was purified by column chromatography (silica; MeOH in
CH2Cl2, from 0:100 to 10:90) to give compound 23 (70 mg, 40%)
as an orange solid, m.p. 133.25 °C. 1H NMR (360 MHz, [D6]-
DMSO): δ = 0.70 (s, 3 H), 2.79 (d, 3JH,H = 3.9 Hz, 3 H), 3.09–3.29
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3
(m, 2 H), 3.37–3.64 (m, 4 H), 4.55 (d, JH,H = 13.9 Hz, 2 H), 7.05
3
3
(dd, JH,H = 11.7, 1.32 Hz, 1 H), 7.42 (br. d, JH,H = 9.5 Hz, 1 H),
8.07 (d, 3JH,H = 9.3 Hz, 1 H), 8.34 (d, 3JH,H = 10.3 Hz, 1 H), 10.43
5228
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5221–5229

2,1-Borazaroquinolines and 2,1-Borazaroisoquinolines
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[13] We carried out a set of NMR experiments that suggest an oxi-
dative degradation process. Details are provided in the Sup-
porting Information.
Received: May 13, 2015
Published Online: July 8, 2015
Eur. J. Org. Chem. 2015, 5221–5229
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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