Copper-Mediated sp 2 C-H Chlorination with Trichloroacetamide Using a Removable Directing Group

Article abstract of DOI:10.1055/s-0036-1590503

2-Aminophenyl-1 H -pyrazole was discovered as a removable, bidentate directing group for copper-mediated aerobic oxidative sp ² C-H bond chlorination employing trichloroacetamide as a new chlorine source. When Cu(OAc) ₂ was employed as the copper source, 1,1,3,3-tetramethylguanidine (TMG) as an organic base, the reaction, optimally carried out overnight in DMSO at 80 °C in open air, produced a variety of mono- and dichlorinated products in moderate to excellent yields. This directing group can be removed oxidatively with cerium ammonium nitrate (CAN).

Full text of DOI:10.1055/s-0036-1590503

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
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W.-C. C. Lee et al.
Feature
Synthesis
Copper-Mediated sp2 C–H Chlorination with Trichloroacetamide
Using a Removable Directing Group
Wan-Chen Cindy Lee
Arya Tehrani
Cl3CCONH2
O
O
Jie Jack Li*
0
0
0
0
0-
0
0
3
0-
9
9
1
2-
4
7
1
Cu(OAc)2, TMG, DMSO
air, 80 °C, overnight, 80%
NH
N
Cl
NH
N
H
Department of Chemistry, University of San Francisco,
2130 Fulton Street, San Francisco, CA 94117, USA
jjli@usfca.edu
unprecedented chlorine source
new removable directing group
N
N
compatible for aryl/heteroaryl substrates
Dedicated to Prof. David R. Williams at Indiana University
Received: 05.05.2017
Accepted: 08.05.2017
Published online: 15.05.2017
R
N
DOI: 10.1055/s-0036-1590503; Art ID: ss-2017-z0219-fa
R
N
O
N
O
H
Abstract 2-Aminophenyl-1H-pyrazole was discovered as a removable,
bidentate directing group for copper-mediated aerobic oxidative sp2
C–H bond chlorination employing trichloroacetamide as a new chlorine
source. When Cu(OAc)2 was employed as the copper source, 1,1,3,3-
tetramethylguanidine (TMG) as an organic base, the reaction, optimally
carried out overnight in DMSO at 80 °C in open air, produced a variety
of mono- and dichlorinated products in moderate to excellent yields.
This directing group can be removed oxidatively with cerium ammoni-
um nitrate (CAN).
1, R = Me, OPC-4392
2, R = Cl, aripiprazole
Cl
N
Me
OH
N
N
N
N
KN
Key words C–H chlorination, copper-mediated, trichloroacetamide,
removable directing group, 2-aminophenyl-1H-pyrazole
3, losartan (Cozarr)
Before the resurgence of fluorine chemistry in the last
decade, chlorine was the atom of choice to block metabo-
lism sites in medicinal chemistry. A case in point is the suc-
cess of aripiprazole (Abilify).1 As an agonist for dopamine
D2 autoreceptor and an antagonist of postsynaptic dopa-
mine receptors, OPC-4392 (1) was rapidly metabolized
with an ED50 value of 16.6 mg/kg when given p.o. (orally).
However, replacing the methyl groups with chlorine atoms
afforded aripiprazole (2) (Figure 1), which has a vastly im-
proved ED50 value of 0.6 mg/kg because the two Cl atoms
blocked the CYP-450 oxidation of the methyl groups. An-
other conspicuous example of chlorine atom’s role in me-
tabolism is losartan (3, Cozarr),2 which demonstrated for
the first time that 4-chloroimidazole is a viable pharmaco-
phore. Before losartan (3), the conventional wisdom was
that the α-chlorine atom on imidazole would be labile to
nucleophilic substitution in vivo.
Figure 1 Bioactive chlorinated compounds
trichloroacetamide as the nitrogen source, unexpectedly,
instead of the amidation product, Cu(OAc)2-mediated aero-
bic sp2 C–H dichlorination product 5 was isolated as the
sole product (Scheme 1). To the best of our knowledge, this
is the first report of using trichloroacetamide as the chlo-
rine source for C–H chlorination.4
Many transition metals, most conspicuously palladium5
and copper,6 have been employed to catalyze/mediate C–H
halogenation. In 2004, Sanford achieved a palladium-cata-
Cl
H
O
O
CCl3CONH2
NH Cl
NH
N
H
Cu(OAc)2, TMG, DMSO
air, 80 °C, overnight
77%
N
N
N
During our pursuit of copper-mediated aerobic oxida-
tive C–H amidation using 2-aminophenyl-1H-pyrazole as a
new removable bidentate directing group (DG),3 we made a
fortuitous discovery. When substrate 4 was treated with
4
5
Scheme 1 Cu(OAc)2-mediated aerobic C(sp2–H) dichlorination
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
W.-C. C. Lee et al.
Feature
Synthesis
lyzed C–H electrophilic chlorination of benzo[h]quinoline
(6) to give chloride 7,5a and in 2011, Bedford similarly chlo-
rinated amide 8 to afford chloride 9 employing Pd(OAc)2 as
the catalyst utilizing pivaloylamide as the removable DG
(Scheme 2).5b
Meanwhile, copper salts have emerged as worthy com-
petitors thanks to their low cost, better tolerance of func-
tional groups, and no pre-requisites of ligands or co-cata-
lysts. Both nucleophilic C–H chlorination using chloride as
the chlorine source7 and electrophilic C–H chlorination us-
ing chloronium ion equivalence as the chlorine source8
have been successful. In 2006, Yu ortho-chlorinated phen-
ylpyridine using Cu(OAc)2 as the catalyst and tetrachlo-
roethane as the chlorine source.7a In 2011, Cheng achieved
the same feat employing Cu(OAc)2 as the catalyst and ben-
zoyl chloride as the electrophilic chlorine source.8a More
important, taking the advantage of removable DGs, as
shown in Scheme 3, Carretero carried out a C–H electro-
philic chlorination of 10 bearing a removable N-(2-pyr-
idyl)sulfonyl auxiliary to make chloride 11 [Scheme 3 (1)]
in 2013.8b In 2015, Shi used 2-(pyridine-2-yl)isopropyl-
amine (PIPamine) as the removable DG to accomplish an
electrophilic C–H chlorination of benzamide 12 to give
chloride 13 [Scheme 3 (2)].8d Encouraged by our accidental
Sanford, 2004:
Pd(OAc)2 1–5 mol%
2 equiv NCS
MeCN, 70–100 °C
1–3 d, 95%
N
N
H
Cl
6
7
Bedford, 2011:
Pd(OAc)2 15 mol%
1 equiv NCS
0.5 equiv PTSA
H
N
H
N
EtO2C
EtO2C
O
toluene, 50 °C
24 h, 80%
O
H
Cl
8
9
Scheme 2 Palladium-catalyzed C–H Chlorination
Biographical Sketches
Wan-Chen Cindy Lee was
born in Taipei, Taiwan. She
earned her B.S. degree in chem-
istry from the National Taiwan
Normal University in 2014. At
present, she is a graduate stu-
dent at the University of San
Francisco in the group of Prof.
Jie Jack Li, working on the devel-
opment of organometallic cata-
lytic methodologies for C–H
bond functionalization with
novel
removable
directing
groups.
Arya Tehrani is a senior at the
University of San Francisco. He
is studying chemistry with a fo-
cus on biochemistry. He is high-
ly interested in the application
of chemistry to the process of
drug discovery. After comple-
tion of his degree in December
2017, he aims to continue his
education in the form of
Pharm.D./Ph.D. program.
a
Jie Jack Li received his B.S. and
M.S. degrees in 1983 and 1988,
respectively, from Nanjing Uni-
versity in China and earned his
Ph.D. in organic chemistry in
1995 at Indiana University. After
a stint as a postdoctoral fellow
at MIT, he worked as a medicinal
chemist at Pfizer and Bristol-
Myers Squibb from 1997 to
2012. Since then he has been an
Associate Professor of Chemis-
try at the University of San Fran-
cisco, teaching organic and
medicinal chemistry. He has
published 25 books ranging
from organic and medicinal
chemistry, to the history of drug
discovery. His book ‘Name Re-
actions: A Collection of Detailed
Mechanisms and Synthetic Ap-
plications’ is now in its fifth edi-
tion. Research in the Li group
focuses on two areas: C–H bond
functionalization and medicinal
chemistry in the therapeutic
area of oncology.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
W.-C. C. Lee et al.
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observation of transformation 4 → 5, we set out to explore
the scope and the limitation of copper-mediated ortho-
chlorination of benzamides 14 using trichloroacetamide as
the chlorine source to prepare the corresponding chlorides
15 [Scheme 3 (3)].
lower than open to air. Furthermore, no C–H bromination
took place under similar reaction conditions using several
bromine sources.Once optimal reaction conditions were se-
cured, we proceeded to explore the scope and limitation for
the substrates 14. Similar to what we observed previously
for copper-mediated C–H amidation reactions,3 a compet-
ing Cu(OAc)2-mediated aerobic C(sp2–H) hydroxylation
sometimes takes place concurrently along with the C–H
chlorination, giving rise to phenol 16 as a by-product (see
footnote c in Figure 2). For instance, when the fluorine sub-
strate 14b was subjected to the optimized Cu(OAc)2-medi-
ated C–H chlorination conditions, 16% of the corresponding
phenol was isolated in addition to the expected ortho-chlo-
rination product 15b. Further scrutiny revealed that
Cu(OAc)2-mediated C–H hydroxylation takes place more
readily on electron-deficient substrates. Nitro substrate 14i
furnished 6% of the corresponding mono-hydroxylation
product in addition to 20% of the chlorination product 15i
(see Supporting Information).
Carretero, 2013:
(1)
O2
S
O2
S
N
N
HN
HN
CuCl2 (10 mol%)
1.2 equiv NCS
O2 (1 atm)
H
Cl
MeCN, 100 °C
8 h, 86%
NO2
NO2
10
11
(2)
Shi, 2015:
O
CuCl (20 mol%)
1.4 equiv NCS
1 equiv Zn(OAc)2
O
N
N
N
H
N
H
DCE, 120 °C, 24 h
40% mono-; 25% di-
O2N
Cl
O2N
H
12
13
(3)
This work:
R
R
Table 1 Optimization of Copper-Catalyzed sp2 C–H Chlorination
O
O
CCl3CONH2
NH
N
H
NH Cl
Cu(OAc)2, TMG, DMSO
air, 80 °C, overnight
N
N
N
O
O
Cl source, Cu salt
NH Cl
NH
N
H
14
15
solvent, base
N
air, 80 °C, overnight
N
N
Scheme 3 Copper-mediated C–H chlorination using removable DGs
14a
15a
Employing benzamide 14a as our substrate, the validity
of trichloroacetamide as a new chlorine source was investi-
gated in comparison to other chlorine sources in the con-
text of C–H chlorination using a removable DG, 2-amino-
phenyl-1H-pyrazole. As shown in Table 1, 2,2,2-trichloro-
acetonitrile failed to chlorinate the substrate when
Cu(OAc)2 was used as the copper salt and TMG as the or-
ganic base (Table 1, entry 1), so did tetrachloroethane with
CuI (entry 2). Switching the copper salt to Cu(OAc)2, tetra-
chloroethane provided the desired chlorinated product 15a
in 11% yield when the reaction was run at 55 °C (entry 3).
Since much left in the reaction was unreacted benzamide
14a, it was logical to raise the temperature to 80 °C, and the
reaction was driven to completion to afford 15a in 77% yield
(entry 4). Trichloroisocyanuric acid (TCA), hexachloroace-
tone (HCA), and N-chlorosuccinimide (NCS) all proved to be
viable chlorine sources with different degrees of success
(entries 5–9). We then turned our attention to trichloroac-
etamide as a new chlorine source fortuitously discovered in
our laboratory.3 Experimentation (entries 10–14) revealed
that the optimal conditions for the C–H chlorination of 14a
are as follows: Cu(OAc)2 as the copper salt and TMG as the
organic base. Trichloroacetamide was superior to other
chlorine sources when the reaction was run overnight in
DMSO at 80 °C and open to air (entry 12). When the reac-
tion was run in nitrogen, the yields were generally 3–5%
Entry Cl source
Cu salt
Solvent
Base
Yield
(%)a
1
2
CCl3CN
Cu(OAc)2
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1,4-dioxane
DMSO
DMSO
DMSO
NMP
TMG
0
Cl2CHCHCl2
Cl2CHCHCl2
Cl2CHCHCl2
TCA
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
Cs2CO3
TMG
0
3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
11b
77
38
54
0
4
5
6
HCA
7
NCS
8
NCS
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
44b
76
0c
9
NCS
10
11
12
13
14
CCl3CONH2
CCl3CONH2
CCl3CONH2
CCl3CONH2
CCl3CONH2
48b,c
80
53c
76c
a Isolated yields under reaction conditions: Substrate 14a (0.30 mmol),
chlorine source (1.5 equiv), copper salt (1 equiv), base (4 equiv) in solvent
at 80 °C overnight in open air.
b Run at 55 °C.
c Hydroxylation product phenol was observed in ~6–16% yield (see text).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
W.-C. C. Lee et al.
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More interestingly, when bromophenyl substrate 14d
was subjected to the C–H chlorination conditions, the Cl–Br
halogen exchange reaction also took place to afford bis-
chlorinated product 5 in 60% yield, along with debrominat-
ed and hydroxylated product 17d in 10% yield (Scheme 4).
This method adds one additional example to the small rep-
ertoire of copper-mediated Cl–Br halogen exchange reac-
tions in the literature.8 In addition, instead of the Cl–Br hal-
ogen exchange, the copper-mediated C–H hydroxylation
product 17d lost its halogen atom. It is likely that a protona-
tion reaction with the complex PhCuBr took place before
the reductive elimination step. While the ramification on
deciphering the detailed mechanism is not immediately
clear, the Br–Cl and Br–H exchanges strongly suggest the
participation of the DG in the processes of generating
both 5 and 17d. This is further evidenced by the fact that no
Br–Cl and Br–H exchange products were observed from the
meta-bromo-substrate 14e, as the DG may affect the con-
certed metalation-deprotonation (CMD)9 with the aid of
copper only on the ortho positions.
F
Cl
O
O
O
NH Cl
NH Cl
NH Cl
N
N
N
N
N
N
15a, 80%
Br
15b, 80 (16c)%
5, 83%
Cl
Cl
Cl
O
O
O
NH Cl
NH Cl
NH Cl
N
N
N
N
N
N
15e, 57%
Cl
15f, 43%
15g, 44%
O
Cl
NO2
OMe
O
Cl
O
O
O
NH Cl
NH Cl
NH Cl
N
N
N
N
N
N
Cl
Br
O
O
O
15h, 32%
15i, 20 (6c)%
15j, 47%
NH Cl
NH
H
NH OH
CCl3CONH2
Cl
O
N
S
N
+
N
N
N
N
Cu(OAc)2, TMG, DMSO
air, 80 °C, overnight
N
N
O
O
O
O
Cl
Cl
NH
N
NH
NH Cl
14d
5 (60%)
17d (10%)
NH Cl
N
N
N
N
Scheme 4 Copper-mediated Cl–Br halogen exchange
N
N
When there was no ortho-substituent to block one of
the two ortho positions, bis-chlorination products were the
major products as shown by meta-substituted substrates
14e and 14f, as well as para-substituted substrates 14g–i.
As shown in Figure 2, the methylenedioxy substrate 14j af-
forded the bis-chlorination product 15j in 47% isolated
yield (62% based on recovered starting material). Naphtha-
lenyl substrate 14k gave an excellent isolated yield (90%) of
the mono-chlorinated product 15k, which has a very low
solubility, presumably because of an increased π-stacking
effect.
We then turned our attention to heteroaryl substrates.
The chlorination reactions for both of the furan and thio-
phene substrates 14l and 14m could not be driven to com-
pletion even with elevated temperature and elongated reac-
tion time. Mono-chlorinated furan product 15l was isolated
in 32% yield (72% based on recovered starting material).
Similarly, mono-chlorinated thiophene product 15m was
isolated in 68% yield (91% based on recovered starting ma-
terial). Finally, pyridyl substrate 14n gave rise to bis-chloro
product 15n in 54% yield (Figure 2).
15k, 90%
15l, 32%
15m, 68%
15n, 54%
Figure 2 Copper-mediated C–H chlorinationa,b a Reaction conditions:
Substrate 14 (0.30 mmol), trichloroacetamide (1.5 equiv), Cu(OAc)2 (1
equiv), TMG (4 equiv) in DMSO at 80 °C overnight in open air. b Isolated
yields. c An additional 6–16% of the corresponding hydroxylation prod-
uct 16 was also isolated.
hydrolysis of substrate 15a using KOH in ethanol10a and
LiOH/H2O2 in THF,10b and acidic hydrolysis11 using HCl or
H2SO4 failed. Methylation12 of the amide functional group
on 15a was successful, but the subsequent basic hydrolysis
only resulted in recovered starting material. Regrettably,
treatment of 15a with (Boc)2O13 did not produce the de-
sired Boc product, either. Eventually, after extensive experi-
mentation, we succeeded in removing the 2-aminophenyl-
1H-pyrazole DG under oxidative conditions by refluxing
15a with cerium ammonium nitrate (CAN)14 in acetonitrile
to deliver the primary amide 18 in 73% isolated yield
(Scheme 5). A perusal of literature indicated that extreme
measures have been taken for removing a recalcitrant DG.
For instance, Yu et al. removed the aminophenyloxazoline
DG by forming the Boc adduct, followed by thioester forma-
tion, and hydrolysis.15 Recently, Maulide’s team removed 8-
aminoquinoline DG via a sequence involving ozonolysis,
Unmasking the removable DG was not as straightfor-
ward as in the case of our amidation products.3 Both basic
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
W.-C. C. Lee et al.
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Technologies), with visualization by UV or I2. Flash chromatography
was performed using standard grade silica gel (60 Å, 230–400 mesh;
SORBENT Technologies). Melting points were taken using Vernier
Melt Station LabQuest 2 and are not corrected. NMR spectra were ac-
quired using an Agilent VNMRS spectrometer equipped with one
NMR probe (500 MHz for 1H, 126 MHz for 13C, 470 MHz for 19F). Spec-
tra were processed using MNova software (Mestrelab). Chemical
shifts are reported in parts per million (ppm), coupling constants (J)
in Hz and are calibrated to residual protonated solvent. IR spectra of
neat samples were acquired using a PerkinElmer Spectrum 100 FT-IR
spectrometer, with solid samples analyzed using a Universal ATR (at-
tenuated total reflectance) sampling accessory. GC-MS was per-
formed on a Hewlett Packard HP6890 Series GC System and a 5973
Mass Selective Detector.
O
(NH4)2Ce(NO3)6
NH Cl
O
MeCN, 80 °C, 12 h
73%
N
N
NH2 Cl
15a
18
Scheme 5 Removal of the DG
treatment with dimethyl sulfide, followed by an oxidative,
basic hydrolysis with H2O2/LiOH.16
As far as the mechanism for the nucleophilic C–H chlori-
nation is concerned, Yu proposed a SET pathway involving a
radical cation intermediate7a and Stahl forwarded an or-
ganometallic mechanism involving Cu(III) species.17 For our
copper-mediated eletrophilic C–H chlorination, few prece-
dents exist. Based on relevant literature, a plausible mecha-
nism is proposed as follows: Chelation of Cu(OAc)2 with
N,N-bidentate substrate 14a affords Cu(II)-complex 19.
With the aid of the base TMG, complex 19 undergoes con-
certed metalation-deprotonation (CMD) to afford the cyclo-
cupration product as Cu(II)-complex 20. In the presence of
trichloroacetamide as an electrophile, Cu(II)-complex 20
may serve as an organocuprate and attack trichloroacet-
amide directly, giving rise to the chlorination product 15a
(Scheme 6).
Preparation of starting benzamide substrates 14 is provided in the
Supporting Information.
C–H Chlorination; General Procedure
A 10 mL microwave vial was charged with the substrate 14 (0.38
mmol), followed by 2,2,2-trichloroacetamide (123 mg, 0.76 mmol),
Cu(OAc)2 (69 mg, 0.38 mmol), and 1,1,3,3,-tetramethylguanidine
(TMG; 88 mg, 0.76 mmol). After adding the solvent DMSO (3 mL), the
reaction mixture was heated at 80 °C open to air. After stirring at
80 °C for 12 h, the reaction was judged complete by TLC, and the mix-
ture was filtered. The filtrate was washed with sat. aq NH4Cl and
brine, the organic layer was dried (MgSO4), filtered, and concentrated
in vacuo. The residue was purified by flash chromatography to give
the desired chlorinated product (Figure 2).
2,6-Dichloro-N-[2-(1H-pyrazol-1-yl)phenyl]benzamide (5)
White solid; yield: 0.19 g (77% yield); mp 139.6–141.2 °C. Flash chro-
matography solvent system: CH2Cl2/hexane (3:1); Rf = 0.56 (CH2Cl2).
N
N
base
CMD
FTIR (neat, ATR): 3258 (NH), 1670 (amide carbonyl), 1454, 1429,
CuII(OAc)2
– AcOH
1393, 1308, 938, 776 cm–1
.
14a
N
CuII
H
OAc
1H NMR (500 MHz, CDCl3): δ = 10.56 (s, 1 H, NH), 8.54 (dd, J = 8.3, 1.4
Hz, 1 H), 7.82 (d, J = 2.4 Hz, 1 H), 7.66 (d, J = 1.8 Hz, 1 H), 7.43 (td,
J = 7.8, 1.5 Hz, 1 H), 7.40–7.31 (m, 2 H), 7.31–7.21 (m, 3 H), 6.46 (t,
J = 2.2 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 162.63, 141.20, 136.07, 132.25,
130.73, 130.70, 130.10, 129.90, 128.11, 128.02, 125.12, 124.04,
122.39, 107.16.
O
19
N
N
Cl
Cl
Cl
N
CuII
CuII
NH2
15a
+
O
O
GC-MS (ESI): m/z calcd for C16H11Cl2N3O: 331.0279; found: 331.
20
Scheme 6 A plausible mechanism
2-Chloro-6-methyl-N-[2-(1H-pyrazol-1-yl)phenyl]benzamide
(15a)
White solid; yield: 0.10 g (80%; 88% based on recovered starting ma-
terial). Flash chromatography solvent system: CH2Cl2/hexane (4:1);
Rf = 0.48 (EtOAc/hexane, 1:2).
1H NMR (500 MHz, CDCl3): δ = 10.34–10.30 (m, 1 H, NH), 8.56 (dd,
J = 8.3, 1.4 Hz, 1 H), 7.81 (d, J = 2.3 Hz, 1 H), 7.66 (d, J = 1.8 Hz, 1 H),
7.49–7.40 (m, 1 H), 7.36 (dd, J = 8.1, 1.4 Hz, 1 H), 7.28–7.17 (m, 3 H),
7.12 (q, J = 4.4 Hz, 1 H), 6.47 (s, 1 H), 2.30 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 165.53, 141.21, 137.02, 136.70,
131.05, 130.60, 130.16, 129.94, 129.89, 128.63, 128.09, 126.89,
124.88, 123.93, 122.57, 107.15.
In summary, we have developed a copper-mediated
eletrophilic sp2 C–H chlorination with trichloroacetamide
as the chlorine source using 2-aminophenyl-1H-pyrazole as
a new removable directing group. In comparison to other
removable directing groups employed for C–H chlorination,
2-aminophenyl-1H-pyrazole is less expensive.18 The direct-
ing group may be removed oxidatively using CAN.
HRMS (ESI): m/z calcd for C17H15ClN3O [M + 1]: 312.0904; found:
312.0895.
All reactions were performed in anhydrous solvents, which were pur-
chased and utilized without further purification. Analytical TLC was
carried out using Silica G TLC plates, 200 μM with UV254 (SORBENT
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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W.-C. C. Lee et al.
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2-Chloro-6-fluoro-N-[2-(1H-pyrazol-1-yl)phenyl]benzamide (15b)
2,6-Dichloro-3-methyl-N-[2-(1H-pyrazol-1-yl)phenyl]benzamide
(15f)
White solid; yield: 0.09 g (80%); mp 135.2–136.1 °C. Flash chromato-
graphy solvent system: EtOAc/hexane (1:6); Rf = 0.46 (CH2Cl2).
Yellow solid; yield: 0.06 g (43%; 46% based on recovered starting ma-
terial); mp 133.6–135.1 °C. Flash chromatography solvent system:
EtOAc/hexane (1:6); Rf = 0.43 (EtOAc/hexane, 1:2).
1H NMR (500 MHz, CDCl3): δ = 10.47 (s, 1 H, NH), 8.54 (d, J = 8.2 Hz, 1
H), 7.81 (d, J = 2.5 Hz, 1 H), 7.65 (d, J = 1.9 Hz, 1 H), 7.42 (d, J = 7.3 Hz,
1 H), 7.39–7.33 (m, 1 H), 7.28–7.23 (m, 1 H), 6.46 (t, J = 2.2 Hz, 1 H),
2.34 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 163.17, 141.18, 136.09, 135.74,
132.08, 131.87, 130.79, 130.09, 129.94, 129.15, 128.03, 127.62,
125.05, 124.10, 122.43, 107.12, 19.94.
1H NMR (500 MHz, CDCl3): δ = 10.72 (s, 1 H, NH), 8.62 (d, J = 8.3 Hz, 1
H), 7.82 (d, J = 2.5 Hz, 1 H), 7.67 (d, J = 1.9 Hz, 1 H), 7.45–7.38 (m, 1 H),
7.34 (ddd, J = 20.0, 8.2, 1.9 Hz, 2 H), 7.27–7.19 (m, 2 H), 7.05 (t, J = 8.5
Hz, 1 H), 6.46 (t, J = 2.2 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 160.56, 158.55, 141.18, 132.34,
131.28, 131.13, 130.84, 129.48, 127.95, 125.68, 124.93, 124.87,
123.46, 122.32, 122.28, 114.65, 107.12.
19F NMR (470 MHz, CDCl3): δ = –112.8.
HRMS (ESI): m/z calcd for C16H11ClFN3O [M + 1]: 316.0575; found:
316.0643.
HRMS (ESI): m/z calcd for C17H14Cl2N3O [M + 1]: 346.0514; found:
346.0505.
2-Fluoro-6-hydroxy-N-[2-(1H-pyrazol-1-yl)phenyl]benzamide
(16c)
2,6-Dichloro-4-methyl-N-[2-(1H-pyrazol-1-yl)phenyl]benzamide
(15g)
See Supporting Information for structure.
White solid; yield: 0.04 g (44%; 79% based on recovered starting ma-
terial). Flash chromatography solvent system: CH2Cl2/hexane (4:1);
Rf = 0.58 (CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 10.47 (s, 1 H), 8.54 (dd, J = 8.2, 1.3 Hz, 1
H), 7.81 (d, J = 2.5 Hz, 1 H), 7.67 (d, J = 1.8 Hz, 1 H), 7.43 (t, J = 7.9 Hz, 1
H), 7.36 (dd, J = 8.1, 1.4 Hz, 1 H), 7.32–7.21 (m, 1 H), 7.14 (s, 2 H), 6.46
(s, 1 H), 6.46 (d, J = 4.5 Hz, 1 H), 2.34 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 162.83, 141.56, 141.20, 141.18,
133.25, 131.84, 131.83, 130.86, 130.10, 130.08, 129.86, 128.66,
128.64, 128.05, 128.03, 124.98, 124.97, 123.98, 123.96, 122.42,
122.40, 107.12, 107.10, 20.94, 20.92.
White solid; yield: 0.03 g (16%). Flash chromatography solvent sys-
tem: EtOAc/hexane (1:6); Rf = 0.50 (CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 12.91 (s, 1 H, OH), 11.04 (d, J = 16.5 Hz,
1 H, NH), 8.40 (d, J = 8.3 Hz, 1 H), 7.83 (s, 1 H), 7.77 (d, J = 2.3 Hz, 1 H),
7.43 (t, J = 7.9 Hz, 1 H), 7.37 (d, J = 7.9 Hz, 1 H), 7.36–7.25 (m, 2 H),
6.79 (d, J = 8.4 Hz, 1 H), 6.60 (dd, J = 12.4, 8.2 Hz, 1 H), 6.50 (s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 166.49, 163.88, 141.38, 134.14,
130.99, 130.64, 129.93, 127.97, 125.44, 124.96, 123.53, 114.55,
107.38, 105.90, 105.70, 104.24.
19F NMR (470 MHz, CDCl3): δ = –110.05.
HRMS (ESI): m/z calcd for C16H13FN3O2 [M + 1]: 298.0992; found:
HRMS (ESI): m/z calcd for C17H14Cl2N3O [M + 1]: 346.0514; found:
298.0981.
346.0506.
2-Hydroxy-N-[2-(1H-pyrazol-1-yl)phenyl]benzamide (17d)
2,6-Dichloro-4-methoxy-N-[2-(1H-pyrazol-1-yl)phenyl]ben-
(Scheme 4)
zamide (15h)
White solid; yield: 0.003 g (10%). Flash chromatography solvent sys-
tem: CH2Cl2/hexane (4:1); Rf = 0.83 (CH2Cl2).
White solid; yield: 0.03 g (32%; 68% based on recovered starting ma-
terial); mp 181.1–183.5 °C. Flash chromatography solvent system:
CH2Cl2/hexanes (4:1); Rf = 0.43 (CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 10.45 (s, 1 H, NH), 8.54 (d, J = 8.2 Hz, 1
H), 7.81 (d, J = 2.4 Hz, 1 H), 7.68 (d, J = 1.8 Hz, 1 H), 7.42 (s, 1 H), 7.36
(d, J = 7.8 Hz, 1 H), 7.25 (d, J = 8.1 Hz, 1 H), 6.85 (s, 2 H), 6.46 (t, J = 2.0
Hz, 1 H), 3.81 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 162.73, 160.38, 141.20, 132.96,
130.94, 130.92, 130.13, 129.83, 128.79, 128.06, 124.94, 123.90,
122.45, 114.05, 107.12, 55.86, 29.68.
1H NMR (500 MHz, CDCl3): δ = 12.23 (s, 1 H, OH), 11.63 (s, 1 H, NH),
8.54 (d, J = 8.2 Hz, 1 H), 7.92–7.86 (m, 2 H), 7.65 (d, J = 8.0 Hz, 1 H),
7.42 (td, J = 8.2, 7.7, 2.8 Hz, 3 H), 7.25 (d, J = 6.4 Hz, 2 H), 7.00 (d,
J = 8.3 Hz, 1 H), 6.93 (s, 1 H), 6.54 (q, J = 1.9 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 168.69, 162.16, 141.22, 134.47,
130.57, 130.15, 129.48, 127.90, 126.01, 124.69, 123.49, 122.07,
118.94, 118.66, 114.90, 107.46.
GC-MS (ESI): m/z calcd for C16H13N3O2: 279.1008; found: 279.
HRMS (ESI): m/z calcd for C17H14Cl2N3O2[M + 1]: 362.0463; found:
362.0454.
3-Bromo-2,6-dichloro-N-[2-(1H-pyrazol-1-yl)phenyl]benzamide
(15e)
2,6-Dichloro-4-nitro-N-[2-(1H-pyrazol-1-yl)phenyl]benzamide
White solid; yield: 0.03 g (57%); mp 124.7–126.1 °C. Flash chromato-
(15i)
graphy solvent system: CH2Cl2/hexane (4:1); Rf = 0.70 (CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 10.66 (s, 1 H), 8.53 (d, J = 8.2 Hz, 1 H),
7.85 (t, J = 1.9 Hz, 1 H), 7.69 (d, J = 2.1 Hz, 1 H), 7.62 (dd, J = 8.6, 1.5 Hz,
1 H), 7.47–7.37 (m, 3 H), 7.32–7.19 (m, 4 H), 6.49 (q, J = 2.0 Hz, 1 H),
1.27 (s, 2 H).
13C NMR (126 MHz, CDCl3): δ = 162.02, 141.28, 137.57, 134.55,
132.75, 131.13, 130.44, 130.04, 129.90, 129.02, 128.01, 125.31,
124.10, 122.25, 121.94, 107.25.
Yellow solid; yield: 0.02 g (20%). Flash chromatography solvent sys-
tem: CH2Cl2/hexane (4:1); Rf = 0.56 (CH2Cl2).
1H NMR (500 MHz, DMSO-d6): δ = 11.14 (s, 1 H, NH), 8.40 (d, J = 8.3
Hz, 1 H), 8.19 (d, J = 2.3 Hz, 1 H), 8.11 (d, J = 9.2 Hz, 1 H), 7.80 (d,
J = 1.7 Hz, 1 H), 7.75–7.69 (m, 2 H), 7.53–7.44 (m, 2 H), 7.30 (d, J = 7.6
Hz, 1 H).
13C NMR (126 MHz, DMSO-d6): δ = 162.64, 156.99, 150.36, 141.59,
132.82, 132.11, 131.75, 131.34, 128.65, 125.45, 125.43, 125.11,
124.06, 114.21, 111.80, 107.74.
HRMS (ESI): m/z calcd for C16H11BrCl2N3O [M + 1]: 409.9463; found:
409.9457.
GC-MS (ESI): m/z calcd for C16H10Cl2N4O3: 376.0130; found: 376.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
W.-C. C. Lee et al.
Feature
Synthesis
4,6-Dichloro-N-[2-(1H-pyrazol-1-yl)phenyl]-1,3-benzodioxole-5-
3,5-Dichloro-N-[2-(1H-pyrazol-1-yl)phenyl]isonicotinamide (15n)
carboxamide (15j)
White solid; yield: 0.080 g (55%); mp 235.8–236.4 °C. Flash chroma-
tography solvent system: CH2Cl2/acetone (10:1); Rf = 0.37 (EtOAc/
hexane, 1:2).
1H NMR (500 MHz, CDCl3): δ = 10.92 (s, 1 H), 8.54 (d, J = 15.4 Hz, 3 H),
7.85 (d, J = 2.4 Hz, 1 H), 7.67 (d, J = 1.8 Hz, 1 H), 7.47–7.37 (m, 2 H),
7.28 (t, J = 7.7 Hz, 1 H), 6.48 (t, J = 2.2 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 160.11, 147.87, 142.10, 141.28,
130.03, 129.99, 129.67, 128.94, 127.98, 125.53, 123.88, 122.05,
107.33.
White solid; yield: 0.04 g (47%; 62% based on recovered starting ma-
terial); mp 149.2–150.6 °C. Flash chromatography solvent system:
CH2Cl2/hexane (4:1); Rf = 0.53 (CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 10.54 (s, 1 H), 8.55 (dd, J = 8.3, 1.4 Hz, 1
H), 7.83 (d, J = 2.4 Hz, 1 H), 7.70 (d, J = 1.8 Hz, 1 H), 7.43 (td, J = 7.9, 1.5
Hz, 2 H), 7.37 (dd, J = 8.0, 1.5 Hz, 2 H), 7.29–7.22 (m, 1 H), 6.79 (s, 1 H),
6.48 (t, J = 2.2 Hz, 1 H), 6.10 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 162.13, 148.91, 144.06, 141.27,
130.81, 130.12, 129.81, 129.71, 128.04, 125.05, 124.58, 123.87,
122.42, 112.35, 108.79, 107.19, 102.78, 77.30, 77.04, 76.79.
HRMS (ESI): m/z calcd for C15H11Cl2N4O [M + 1]: 333.0310; found:
333.0303.
HRMS (ESI): m/z calcd for C17H12Cl2N3O3[M + 1]: 376.0256; found:
376.0248.
2-Chloro-6-methylbenzamide (18)
To a solution of 15a (120 mg, 0.38 mmol) and CAN (2.08 g, 3.80
mmol) was added MeCN (5 mL). After stirring at 80 °C for 12 h, the
reaction was judged complete by TLC. The filtrate was washed with
brine, the organic layer was dried (MgSO4), filtered, and concentrated
in vacuo. The residue was purified by flash chromatography eluting
with EtOAc/hexane (1:6) to give the desired amide 18 as a white sol-
id; yield: 0.046 g (73%); Rf = 0.40 (EtOAc/hexane, 1:1).
1H NMR (500 MHz, CDCl3): δ = 7.40–6.96 (m, 3 H), 6.53–6.28 (m, 1 H),
5.89 (s, 1 H), 2.39 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 169.53, 136.86, 135.91, 130.10,
2-Chloro-N-[2-(1H-pyrazol-1-yl)phenyl]-1-naphthamide (15k)
White solid; yield: 0.14 g (90%); mp > 280 °C. Flash chromatography
solvent system: CH2Cl2/hexane (4:1); Rf = 0.46 (CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 10.66 (s, 1 H), 8.74 (d, J = 8.2 Hz, 1 H,
NH), 7.89–7.79 (m, 4 H), 7.53–7.41 (m, 5 H), 7.38 (d, J = 7.9 Hz, 1 H),
7.27 (s, 1 H), 6.42 (d, J = 2.2 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 165.03, 141.03, 140.11, 139.26,
136.67, 135.42, 131.25, 129.91, 129.44, 129.32, 129.04, 128.33,
128.15, 127.96, 127.38, 127.00, 124.32, 123.30, 122.71, 107.02.
129.89, 128.60, 126.79, 19.36.
HRMS (ESI): m/z calcd for C20H15ClN3O [M + 1]: 348.0904; found:
348.0896.
HRMS (ESI): m/z calcd for C8H8ClNO [M + 1]: 170.0294; found:
170.0301.
3-Chloro-N-[2-(1H-pyrazol-1-yl)phenyl]-2-furamide (15l)
White solid; yield: 0.03 g (32%; 78% based on recovered starting ma-
terial); mp 128.8–129.2 °C. Flash chromatography solvent system:
CH2Cl2/hexane (3:1); Rf = 0.50 (CH2Cl2).
1H NMR (500 MHz, CDCl3): δ = 11.05 (s, 1 H, NH), 8.62 (d, J = 8.3 Hz, 1
H), 7.82 (d, J = 14.4 Hz, 2 H), 7.45 (s, 1 H), 7.41–7.31 (m, 2 H), 7.19 (t,
J = 7.7 Hz, 1 H), 6.51 (d, J = 8.0 Hz, 2 H).
Acknowledgment
We are indebted to Dr. Joseph Pease and Kewei Xu at Genentech for
HRMS data acquisition.
13C NMR (126 MHz, CDCl3): δ = 155.38, 143.48, 141.59, 141.16,
131.13, 130.10, 129.34, 128.10, 124.35, 123.09, 122.60, 121.32,
114.83, 107.28.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1590503.
S
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p
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rmoaitn
HRMS (ESI): m/z calcd for C14H11ClN3O2[M + 1]: 288.0540; found:
288.0532.
References
3-Chloro-N-[2-(1H-pyrazol-1-yl)phenyl]thiophene-2-carboxam-
ide (15m)
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H