A Practical Preparation of Imatinib Base

Article abstract of DOI:10.1055/s-0035-1562498

A practical preparation of imatinib base was reported in this article. Compared with reported works, the features of this work were the concise procedures, the industrially available starting materials, the avoidance of expensive or highly toxic transition-metal catalysts or reagents, and the genotoxic impurities 6-methyl-N ¹-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine and 4-(chloromethyl)-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide. The method was scalable to at least 100 mmol, and the products were separated by simple recrystallizations.

Full text of DOI:10.1055/s-0035-1562498

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
X. Zhang et al.
Letter
Synlett
A Practical Preparation of Imatinib Base
Br
Xu Zhang
N
Me
N
O
N
Jingjing Sun
Tian Chen
Me
NH
N
Br
HN
N
N
1) K2CO3, DCE
0 °C to rt, 1 h
Chenggen Yang
Lei Yu*
HN
Me
NH2
O
DMEDA, CuI, K2CO3
2) 1-methylpiperazine
reflux, 3 h
NH2
+
1,4-dioxane, 100 °C
N2, 24 h, 62–73%
N
Jiangsu Co-innovation Center for Prevention and Control of
Important Animal Infectious Diseases and Zoonoses,
School of Chemistry and Chemical Engineering, Yangzhou
University, Yangzhou, 225002, P. R. of China
yulei@yzu.edu.cn
Cl
Cl
N
N
O
Me
N
Me
Imatinib base
Received: 28.03.2016
Accepted after revision: 21.05.2016
Published online: 23.06.2016
Generally, there are several typical references on the
synthesis of imatinib. The first work was reported by Zim-
mermann in 1993 (Scheme 1).2 In their work, 2-methyl-5-
nitroaniline (2) was chosen as the starting material. Heat-
ing 2 with cyanamide in ethanol in the presence of HNO3
afforded the 1-(2-methyl-5-nitrophenyl) guanidine salt 3,
which led to the intermediate 5 through the reaction with
(E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one
(4). After reduction, 5 was easily transformed to 6, which
afforded the final product 1 through the reaction with 7
(Scheme 1). There are many disadvantages for Zimmer-
mann’s synthetic routes and the major defect should be its
isolation procedure. Since the processes generated many
impurities, flash chromatography was required to isolate
the final product from byproducts, limiting the application
of this synthetic methodology in large-scale preparation.
DOI: 10.1055/s-0035-1562498; Art ID: st-2016-w0218-l
Abstract A practical preparation of imatinib base was reported in this
article. Compared with reported works, the features of this work were
the concise procedures, the industrially available starting materials, the
avoidance of expensive or highly toxic transition-metal catalysts or re-
agents, and the genotoxic impurities 6-methyl-N1-[4-(pyridin-3-yl)py-
rimidin-2-yl]benzene-1,3-diamine and 4-(chloromethyl)-N-(4-methyl-
3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide. The meth-
od was scalable to at least 100 mmol, and the products were separated
by simple recrystallizations.
Key words practical method, total synthesis, medicinal chemistry,
imatinib, copper
Imatinib mesylate (Gleevec, {4-(4-methylpiperazin-1-
ylmethyl)-N-4-[methyl-3-(4-pyridin-3-yl)pyrimidin-2-yl-
amino]phenyl}benzamide methane sulfonate, Figure 1) is
an inhibitor of tyrosine kinases that has been approved by
the FDA since 7th November, 2001. It is indicated for the
treatment of chronic myeloid leukemia (CML) and gastroin-
testinal stromal tumors (GIST) and attracted much atten-
tion in particular due to its positive effects on those pa-
tients with CML in recent years.1
Me
Me
NH
H
N
NH2
HNO3, EtOH, cyanamide
reflux, 21 h
. HNO3
NH2
NO2
NO2
3
2
Me
O
Me
H
N
H
N
N
N
NMe2
Pd/C, EtOAc
r.t., 7 h
N
N
4
N
Me
H
NH2
NO2
i-PrOH, NaOH
N
N
reflux, 12 h
N
N
N
N
5
N
6
HN
N
Me
N
. 2 HCl
NMe
O
7
ClOC
1
imatinib base 1
pyridine, rt, 24 h
Figure 1 Chemical structure of imatinib base 1
Scheme 1 Zimmermann’s routes for the synthesis of imatinib base 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
X. Zhang et al.
Letter
Synlett
Latter, Loiseleur et al. described the second synthetic
route for imatinib base 1 by the palladium-catalyzed cross-
coupling of 4-(pyridin-3-yl)pyrimidin-2-amine (12) with
N-(3-bromo-4-methylphenyl)-4-[(4-methylpiperazin-1-yl)
methyl]benzamide (11, Scheme 2).3 The shortcomings of
this synthetic methodology were the special sonication
equipment, as well as tedious purification of the product by
flash chromatography and separating the desired from the
undesired isomers using reverse-phase preparative chro-
matography. Besides using noble-metal platinum and palla-
dium as catalysts not only enhanced the production cost
but also led to the highly toxic metal residual in final prod-
uct, which should be strictly controlled in the medicine
synthesis. Amala et al.,4 Szakács et al.,5 Szczepek et al.,6 and
Kompella et al.7 then improved the above synthetic routes,
but there are still shortcomings such as the use of excess
moles of tin(II) chloride/Raney nickel and hydrazine hy-
drate reagents for the reduction of the nitropyrimidine in-
termediate to prepare the corresponding amino compound
6. In 2012, Lee et al. tried to improve the last step of
Loiseleur’s routes using polystyrene-supported CuO as cata-
lyst, but resulted in very low yield of the product imatinib
base (15%).8
practical in large-scale preparation, but the inevitable re-
sidual of genotoxic impurities such as the 6-methyl-N1-[4-
(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (6) and
4-(chloromethyl)-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimi-
din-2-yl]amino}phenyl)benzamide (15) is the major short-
coming of this method.
Me
N2H4.H2O/FeCl3
Br
12
6
5
MeOH, reflux, 6–8 h
84%
DMEDA, CuI, K2CO3
dioxane, 100 °C, 20 h
82%
NO2
13
Me
H
COCl
N
N
1-methylpiperazine
reflux, 3 h
Cl
14
N
N
1
Cl
91 %
THF, Et3N
0 °C, 3 h
93%
HN
O
15
Scheme 3 Wang’s routes for the synthesis of imatinib base 1
Our group aimed to develop the practical synthetic
methodologies with great application potential.10–11 During
our continuous cooperative projects with industrial cir-
cles,11 we recently paid attention to the synthesis of imati-
nib base because of its huge market prospect in China. Re-
cently, we developed a novel synthetic route for the prepa-
ration of imatinib base. Herein, we wish to report our
findings.
1-methylpiperazine
MeOH
MeOOC
O
H
N
MeOOC
Pt/C, 5 bar H2
80 °C, 20 h
70%
N
9
Me
8
Me
The major synthetic routes were illustrated in Scheme
4.12–16 We chose 3-bromo-4-methylaniline (10) as the start-
ing material because it was an industrially available chemi-
cal with very low price (ca. $16/kg in China). Treating 10
with the cheap reagent 4-(chloromethyl)benzoyl chloride
(14, ca. $3/kg in China) afforded the intermediate 16 in ex-
cellent yield.13 Compound 16 could be smoothly trans-
formed to the intermediate 11 by refluxing in 1-methylpip-
erazine.14 The copper-catalyzed coupling of 11 with 12 led
to the final product imatinib base 1 in moderate yield.15
Compared with Wang’s work, this method avoided the gen-
eration of the genotoxic intermediates 6 and 15 by adjust-
ing the introduction order of the functional groups. Its last
step was very similar to that of Loiseleur’s routes (Scheme
2), but considering the fact that copper is less toxic and ex-
pensive than palladium,16 we preferred to choose the cop-
per-catalyzed coupling, although it suffered from the lower
product yield. It should be notable that in all of the above
procedures, the products could be isolated by recrystalliza-
tion, which was a very convenient procedure from the point
of industrial view. Finally, magnified reactions of 11 with
12 in 100 mmol and 1 mol led to the imatinib base 1 in 73%
and 71% yield, respectively, further confirming the practica-
bility of the method.
H2N
Me
Br
Br
10
N
Et3N, toluene, Ar
40 °C, 30 min
75%
HN
O
N
Me
11
N
N
N
NH2
12
imatinib base 1
Pd2(dba)3/CHCl3, rac-BINAP, t-BuONa
Ar, xylene, reflux, 5 h
72%
Scheme 2 Loiseleur’s routes for the synthesis of imatinib base 1
In 2008, Wang et al. reported a new synthetic route to
prepare imatinib 1.9 As shown in Scheme 3, the method
started from 2-bromo-1-methyl-4-nitrobenzene (13), an
industrially available material. Latter, Lee et al. tried to im-
prove this method using the recyclable polystyrene-sup-
ported CuO as catalyst in the coupling of 12 with 13
(Scheme 3).8 But since copper is not an expensive metal, the
easily available inorganic copper salt might be the prefera-
ble catalyst from the point of industrial view. The avoidanc-
es of noble-metal catalysts made this methodology more
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
X. Zhang et al.
Letter
Synlett
metal catalyst, Wang’s work should be the most practical
routes, but unfortunately, it suffers from both of the geno-
toxic intermediates 6 and 15. Avoiding noble-metal catalyst
and the genotoxic intermediates 6 and 15, our routes
should be more practical and safe.
Me
Br
Me
Br
K2CO3
Cl
DCE
Cl
+
Cl
0 °C to rt
1 h
HN
O
NH2
10
94%
O
16
14
Table 1 Comparison of the Synthetic Routes for Imatinib Basea
Me
Br
1-methylpiperazine
Advantages
Noble-metal Free of genotoxic Free of genotoxic
free
6
15
reflux, 3 h
78%
N
HN
N
Zimmermann’s routes
Loiseleur’s routes
Wang’s routes
no
no
yes
Me
O
no
yes
no
yes
no
11
yes
yes
N
This work
yes
yes
N
N
12
NH2
a See Schemes 1–5 for details.
imatinib base 1
DMEDA, CuI, K2CO3
1,4-dioxane, 100 °C, N2, 24 h
62%
In conclusion, we developed a practical synthetic route
for the preparation of imatinib base, which is very practical
because of the concise procedures including the practical
isolation by recrystallization, the industrially available
starting materials and the avoidance of highly toxic transi-
tion-metal catalysts or reagents and the genotoxic impuri-
ties.
Scheme 4 Our routes for the synthesis of imatinib base 1
The price of compound 12 was expensive, but fortu-
nately, it could be synthesized from the industrially avail-
able materials through known methodologies:9 Refluxing
1-(pyridin-3-yl)ethan-1-one (17, ca. $72/kg in China) with
1,1-dimethoxy-N,N-dimethylmethanamine (18, ca. $16/kg
in China) in xylene led to the intermediate 19 in excellent
yield. Further reaction with guanidine nitrate gave 4-(pyri-
din-3-yl)pyrimidin-2-amine (12) in good yield (Scheme 5).9
Thus, in our procedures, all of the materials were industri-
ally available and their prices were below $100/kg (in Chi-
na).
Acknowledgment
We thank National Nature Science Foundation of China (21202141),
Yangzhou Nature Science Foundation (YZ2014040), the High Level
Talent Support Project of Yangzhou University, the Innovation Foun-
dation of Yangzhou University (2015CXJ009), the Open Project Pro-
gram of Jiangsu Key Laboratory of Zoonosis (R1509), and the Priority
Academic Program Development of Jiangsu Higher Education Institu-
tions for financial support. We also thank the analysis center of Yang-
zhou University for assistance and Prof. Rong Guo for suggestions.
O
O
O
xylene
reflux, 20 h
+
N
N
O
94%
N
N
17
19
18
Supporting Information
guanidine nitate
NaOH, n-BuOH
Supporting information for this article is available online at
N
http://dx.doi.org/10.1055/s-0035-1562498.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
N
N
reflux, 12 h
88%
NH2
12
References and Notes
Scheme 5 Synthesis of 4-(pyridin-3-yl)pyrimidin-2-amine (12)
(1) (a) Miura, M. Biol. Pharm. Bull. 2015, 38, 645. (b) Agulnik, M.;
Giel, J. L. Am. J. Clin. Oncol. 2014, 37, 417. (c) DeCaprio, J. A.;
Duensing, A. Curr. Opin. Oncol. 2014, 26, 415. (d) Blay, J.-Y.;
Rutkowski, P. Cancer Treat. Rev. 2014, 40, 242. (e) Signorovitch,
J.; Ayyagari, R.; Reichmann, W. M.; Wu, E. Q.; Chen, L. Cancer
Treat. Rev. 2014, 40, 285.
(2) Zimmermann, J.; Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N.
B.; Traxler, P. Bioorg. Med. Chem. Lett. 1996, 6, 1221.
(3) Loiseleur, O.; Kaufmann, D.; Abel, S.; Buerger, H. M.;
Meisenbach, M.; Schmitz, B.; Sedelmeier, G. WO 2003066613,
2003; Chem. Abstr. 2003, 139, 180080
In order to facilitate the readers to understand the ad-
vantages of our routes, we wish to compare them with pre-
viously reported works. As shown in Table 1,Zimmermann’s
routes avoid the genotoxic intermediate 15 generation step,
but require noble-metal catalyst and suffer from the geno-
toxic intermediate 6. Loiseleur’s routes do not undergo the
genotoxic intermediates 6 and 15 generation steps, but re-
quire both platinum and palladium catalysts, while Lee’s
improvement using polystyrene-supported CuO catalyst
failed and resulted in very low product yield. Free of noble-
(4) Amala, K.; Bhujanga Rao, A. K. S.; Venkaiah Chowdary, N. WO
2004108699, 2004; Chem. Abstr. 2004, 142, 56339
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
X. Zhang et al.
Letter
Synlett
(5) Szakács, Z.; Béni, S.; Varga, Z.; Örfi, L.; Kéri, G.; Noszál, B. J. Med.
Chem. 2005, 249.
(6) Szczepek, W.; Luniewski, W.; Kaczmare, L.; Zagrodzki, B.;
Samson-Lazinska, D.; Szelejewski, M.; Skarzynski, W. US
7674901, 2010; Chem. Abstr. 2010, 145, 103728
(7) Kompella, A.; Adibhatla, B. R. K.; Muddasani, P. R.; Rachakonda,
S.; Gampa, V. K.; Dubey, P. K. Org. Process Res. Dev. 2012, 16,
1794.
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Lett. 2012, 53, 6657.
H), 7.51 (d, J = 7.8 Hz, 2 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.22 (d, J =
8.4 Hz, 1 H), 4.63 (s, 2 H), 2.38 (s, 3 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 165.0, 141.4, 136.6, 134.6, 134.2, 130.9, 129.0, 127.5,
124.9, 123.9, 119.2, 45.3, 22.3 ppm. MS (EI, 70 eV): m/z (%) = 339
(10) [M+] (37Cl), 337 (7) [M+] (35Cl), 137 (100). Known com-
pound: CAS Reg. No. 1072105-05-5.7
(14) Procedure for the Synthesis of 11
To a 100 mL round-bottom flask, 16 (1.7 g, 5 mmol) and 1-
methylpiperazine (56 mL) were added. The mixture was
refluxed for 3 h and poured to 100 mL of water after cooling to
room temperature. The precipitated crystals were filtrated and
washed with water to give 1.57 g of 11 as the brown powder
(78% yield).
(9) Liu, Y.-F.; Wang, C.-L.; Bai, Y.-J.; Han, N.; Jiao, J.-P.; Qi, X.-L. Org.
Process Res. Dev. 2008, 12, 490.
(10) (a) Yu, L.; Chen, F.-L.; Ding, Y.-H. ChemCatChem 2016, 8, 1033.
(b) Yu, L.; Bai, Z.-B.; Zhang, X.; Zhang, X.-H.; Ding, Y.-H.; Xu, Q.
Catal. Sci. Technol. 2016, 6, 1804. (c) Zhang, X.; Sun, J.-J.; Ding,
Y.-H.; Yu, L. Org. Lett. 2015, 17, 5840. (d) Yu, L.; Luan, J.; Xu, L.;
Ding, Y.-H.; Xu, Q. Tetrahedron Lett. 2015, 56, 6116. (e) Yu, L.;
Huang, Y.-P.; Wei, Z.; Ding, Y.-H.; Su, C.-L.; Xu, Q. J. Org. Chem.
2015, 80, 8677. (f) Yu, L.; Ye, J.-Q.; Zhang, X.; Ding, Y.-H.; Xu, Q.
Catal. Sci. Technol. 2015, 5, 4830. (g) Zhang, X.; Ye, J.-Q.; Yu, L.;
Shi, X.-K.; Zhang, M.; Xu, Q. Adv. Synth. Catal. 2015, 357, 955.
(h) Yu, L.; Wu, Y.-L.; Cao, H.-E.; Zhang, X.; Shi, X.-K.; Luan, J.;
Chen, T.; Pan, Y.; Xu, Q. Green Chem. 2014, 16, 287. (i) Yu, L.; Li,
H.-Y.; Zhang, X.; Ye, J.-Q.; Liu, J.-P.; Xu, Q.; Lautens, M. Org. Lett.
2014, 16, 1346. (j) Yu, L.; Wu, Y.-L.; Chen, T.; Pan, Y.; Xu, Q. Org.
Lett. 2013, 15, 144. (k) Fan, L.; Yi, R.; Yu, L.; Wu, Y.-L.; Chen, T.;
Guo, R. Catal. Sci. Technol. 2012, 2, 1136.
(11) (a) Deng, S.-C.; Zhuang, K.; Xu, B.-L.; Ding, Y.-H.; Yu, L.; Fan, Y.-N.
Catal. Sci. Technol. 2016, 6, 1772. (b) Xu, L.; Huang, J.-J.; Liu, Y.-
B.; Wang, Y.-N.; Xu, B.-L.; Ding, K.-H.; Ding, Y.-H.; Xu, Q.; Yu, L.;
Fan, Y. RSC Adv. 2015, 5, 42178. (c) Wang, Y.-G.; Zhu, B.-C.; Xu,
Q.; Zhu, Q.; Yu, L. RSC Adv. 2014, 4, 49170. (d) Yu, L.; Wang, J.;
Zhang, X.; Cao, H.-E.; Wang, G.-L.; Ding, K.-H.; Xu, Q.; Lautens,
M. RSC Adv. 2014, 4, 19122. (e) Yu, L.; Wang, J.; Chen, T.; Wang,
Y.-G.; Xu, Q. Appl. Organomet. Chem. 2014, 28, 652. (f) Yu, L.;
Wang, J.; Cao, H.-E.; Ding, K.-H.; Xu, Q. Chin. J. Org. Chem. 2014,
34, 1986. (g) Yu, L.; Wang, J.; Chen, T.; Ding, K.-H.; Pan, Y. Chin. J.
Org. Chem. 2013, 33, 1096.
Characterization Data of Compound 11
Mp 140.8–141.3 °C. 1H NMR (600 MHz, DMSO-d6, TMS): δ =
10.28 (s, 1 H), 8.13 (s, 1 H), 7.90 (d, J = 7.8 Hz, 2 H), 7.67 (d, J =
8.4 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.32 (s, 1 H), 3.52 (s, 2 H),
2.51–2.35 (br s, 8 H), 2.32 (s, 3 H), 2.15 (s, 3 H) ppm. 13C NMR
(150 MHz, DMSO-d6): δ = 165.4, 142.4, 138.4, 133.2, 132.0,
130.8, 128.6, 127.6, 123.6, 123.2, 119.4, 61.6, 54.7, 52.6, 45.7,
21.7 ppm. Known compound: CAS Reg. No. 581076-59-7.4
(15) Procedure for the Coupling of 11 To Give Imatinib Base 1
3 mmol Scale Reaction
To a 100 mL round-bottom flask, 12 (0.57 g, 3.3 mmol), 11 (1.2
g, 3 mmol), CuI (0.14 g, 0.75 mmol), and K2CO3 (0.83 g, 6 mmol)
were added. Under N2 protection, a solution of DMEDA (66 mg)
in 1,4-dioxane (45 mL) was injected. The mixture was stirred at
100 °C for 24 h. After cooling to room temperature, it was
poured into a mixture of concentrated NH3 (12 mL) and sat.
NaCl solution (60 mL) and extracted by EtOAc (3 × 50 mL). The
combined organic layer was dried by Na2SO4 and gave 0.92 g of
imatinib base 1 as a white crystal (62% yield) after concentra-
tion.
1 mol Scale Reaction
To 20 L autoclave, 12 (189.4 g, 1.1 mol), 11 (402.3 g, 1 mol), CuI
(47.8 g, 0.25 mol), and K2CO3 (276.4 g, 2 mol) were added. The
autoclave was then charged with N2, and a solution of DMEDA
(26.8 mL) in 12 L of 1,4-dioxane was slowly dropped. The
mixture was mechanically stirred at 100 °C for 28 h. After
cooling to room temperature, it was poured into a mixture of
concentrated NH3 (3.5 L) and cold sat. NaCl solution (15 L, 0–5
°C) and extracted by EtOAc (3 × 14 L). The combined organic
layer was dried by Na2SO4 and led to white crystal after concen-
tration. The crystal was washed by PE and dried under vacuum
overnight to afford 350.5 g of imatinib base 1 in 71% yield.
Characterization Data of Compound 1
(12) General Methods
All of the chemicals were industrially pure and directly used
without special treatment. Melting points were measured by a
WRS-2A digital melting pointing instrument. IR spectra were
measured by a Bruker IFS66/S FTIR spectrophotometer. 1H NMR
(600 MHz) and 13C NMR NMR (150 MHz) spectra were recorded
by using CDCl3 or DMSO-d6 as the solvent with TMS as the
internal standard. Coupling constants (J) are given in Hz. Mass
spectra were measured on a Thermo Trace DSQ II spectrometer
(EI).
Mp 207.4–209.2 °C. IR (KBr): 3410, 3290, 2967, 2964, 2932,
2801, 1628, 1588, 1532, 1507, 1478, 1450, 1416, 1380, 1346,
(13) Procedure for the Synthesis of 16
1007, 829, 761, 700 cm–1 1H NMR (600 MHz, DMSO-d6, TMS):
.
3-Bromo-4-methylaniline (10, 1.86 g, 10 mmol), K2CO3 (1.38 g,
10 mmol), and DCE (40 mL) were first added into a 100 mL
round-bottom flask and stirred. 4-(Chloromethyl)benzoyl chlo-
ride (14, 1.89 g, 10 mmol) was then injected. After 1 h, the
product 16 precipitated as yellow crystals and could be isolated
by filtration and purified by washing with small amount of DCE.
About 3.18 g of 16 were obtained (94% yield).
δ = 10.22 (s, 1 H), 9.30 (d, J = 1.8 Hz, 1 H), 9.02 (s, 1 H), 8.71–8.70
(m, 1 H), 8.54–8.50 (m, 2 H), 8.12 (s, 1 H), 7.93 (d, J = 8.4 Hz, 2
H), 7.55–7.44 (m, 5 H), 7.23 (d, J = 8.4 Hz, 1 H), 3.53 (s, 2 H),
2.53–2.33 (br s, 8 H), 2.25 (s, 3 H), 2.16 (s, 3 H) ppm. 13C NMR
(150 MHz, DMSO-d6): δ = 165.3, 161.6, 161.2, 159.4, 151.3,
148.1, 142.1, 137.8, 137.2, 134.4, 133.7, 132.2, 130.0, 128.6,
127.5, 123.8, 117.2, 116.8, 107.5, 61.6, 54.7, 52.5, 45.7, 17.6
ppm. Known compound: CAS Reg. No. 152459-95-5.3
Characterization Data of Compound 16
IR (KBr): 3452, 3284, 2985, 2871, 1641, 1577, 1499, 1441, 1384,
1299, 1137, 1078, 1033, 849, 806, 665 cm–1. 1H NMR (600 MHz,
CDCl3, TMS): δ = 7.89 (s, 1 H), 7.85 (d, J = 7.8 Hz, 2 H), 7.75 (s, 1
(16) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.; Buchwald,
S. L. Chem. Sci. 2011, 2, 57.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D