2-Aminophenyl-1H-pyrazole as a Removable Directing Group for Copper-Mediated C-H Amidation and Sulfonamidation

Article abstract of DOI:10.1021/acs.orglett.6b01105

2-Aminophenyl-1H-pyrazole was discovered as a removable bidentate directing group for copper-mediated aerobic oxidative C(sp²-H) bond amidation and sulfonamidation. When Cu(OAc)₂ was employed as the copper source and 1,1,3,3-tetramet

Full text of DOI:10.1021/acs.orglett.6b01105

Letter
pubs.acs.org/OrgLett
2‑Aminophenyl‑1H‑pyrazole as a Removable Directing Group for
Copper-Mediated C−H Amidation and Sulfonamidation
Wan-Chen Cindy Lee, Yuning Shen, David A. Gutierrez, and Jie Jack Li*
Department of Chemistry, University of San Francisco, 2130 Fulton Street, San Francisco, California 94117, United States
S
* Supporting Information
ABSTRACT: 2-Aminophenyl-1H-pyrazole was discovered as a removable
bidentate directing group for copper-mediated aerobic oxidative C(sp2−H)
bond amidation and sulfonamidation. When Cu(OAc)2 was employed as the
copper source and 1,1,3,3-tetramethylguanidine as an organic base, the
reaction, optimally carried out overnight in DMSO at 80 °C in open air,
produced a variety of amides and sulfonamides in moderate to excellent
yields. This directing group has proven to be particularly efficient in C−H sulfonamidation.
any transition metals are employed to catalyze/mediate
C−H activation. Among them, copper salts stand out
M
because they are inexpensive and nontoxic, and many of them are
commercially available. Furthermore, copper-mediated C−H
activation reactions generally do not require ligands or
cocatalysts. They often have good functional group tolerance as
well, thus increasing their synthetic utility.1 Copper-mediated C−
H arylation2 and C−H alkylation,3 especially for heterocycles,
havegained popularity during thepast decade although palladium
is still the most prevalent catalyst for such reactions. Meanwhile,
copper-mediated C−H halogenation,4 C−H oxygenation,5 and
C−H chalcogenation/sulfonylation6 have also appeared in the
literature.
Our interests have focused on Cu-mediated C−H amination7
and amidation4 8 because amide−sulfonamides and anthranilic
f,
amides have long been workhorses in medicinal chemistry,
serving in a variety of bioisosteres. For instance, anthranilic
sulfonamides have been discovered to be pharmacophores for
HCV (hepatitis C virus, Figure 1) NS5B (nonstructure protein
accomplished a Cu(II)-mediated C−H amidation and amination
of arenes and hetarenes [eq 3].12 In the former two cases, 8-
aminoquinoline was employed as a removable directing group
(DG), and the third used 2-(4,5-dihydrooxazol-2-yl)aniline as the
removable DG. While the mechanism has not been clearly
delineated, empirical comparison of these two DGs reveals that
the two N-atoms on both 8-aminoquinoline and 2-(4,5-
dihydrooxazol-2-yl)aniline, respectively, must work in concert
with the N-atom on the amide to form the N,N-bidentate
complex. This configuration can accommodate the Cu-atom to
form a bicyclic intermediate and facilitate subsequent C−H
cupration.
Figure 1. Bioactive anthranilic-sulfonamides and anthranilamides.
Similar to “rational drug design”, we proposed to rationally
design removable DGs. It was speculated that five-membered N-
containing heteroaryls attached to an aniline in place of the 8-
aminoquinoline and the 2-(4,5-dihydrooxazol-2-yl)aniline
should serve as efficient removable DGs so long as a basic
nitrogen atom occupies the strategic position to provide the
requisite N,N-bidentate complex with copper to form a bicyclic
complex [eq 4].13 To that end, we designed a series of 2-
5B) polymerase inhibitors,9a glycerol 3-phosphate acyltransferase
(GPAT) inhibitors,9b etc. Even more prevalent, anthranilamides
have served as pharmacophores for factor Xa inhibitors
(betrixaban),10a breast cancer resistance protein (BCRP)
inhibitors,10b etc.
In 2013, Daugulis described a directed amination of nonacidic
arene C−H bonds using a Cu−Ag catalytic system [eq 1].11a
During preparation of this manuscript, Daugulis published an
extension to sulfonamidation employing 1,1,3,3-tetramethyl-
guanidine (TMG) as the organic base [eq 2].11b In 2014, Yu
Received: April 15, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b01105
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Letter
Table 1. Optimization of Copper-Mediated Oxidative C(sp2−
H) Bond Amidation and Sulfonamidation
aminophenyl five-membered heteroaryls as removable DGs and
proceeded to test our hypothesis.
A total of six 2-aminophenyl five-membered heteroaryls were
synthesized. In thecase of 2-aminophenyl-1H-pyrazole (1), itwas
assembled in 87% yield in a two-step sequence involving an SNAr
reaction of 1-fluoro-2-nitrobenzene with pyrazole with the aid of
NaH in DMF,14 followed by a palladium-catalyzed hydro-
genation.15 In terms of cost, 1 is less expensive than commercially
available 8-aminoquinoline and is considerably less expensive
than 2-(4,5-dihydrooxazol-2-yl)aniline (see Supporting Informa-
tion for cost analysis).
Similar chemistry offered a series of substrates bearing 2-
aminophenyl-1H-heterocycle A−E (Scheme 1). Benzamide
substrates 2 were easily assembled by coupling aniline 1 with a
variety of benzoyl chlorides.
Scheme 1. Preparation and Screening of Removable DGs
a
Regrettably, under conventional Cu-mediated C−N formation
conditions in the literature including the ones described in eqs 1−
3, little amination or amidation product was observed despite
extensive experimentation with combinations of a variety of Cu
salts, bases, oxidizing agents, and N sources.
Isolated yields under reaction conditions: Substrate 2a (0.30 mmol),
primary amide or sulfonamide (1.5 equiv), Cu(OAc)2 (1 equiv), base
(4 equiv) in solvent at 80 °C overnight in open air. Hydroxylation
product phenol 5 was observed in ∼5% yield.
b
Scheme 2. Cu(OAc)2-Mediated Aerobic C(sp2−H)
Hydroxylation
As shown in Table 1, initial screening of substrate 2a16 did not
show much promise at first. Experimentation with a variety of
nitrogen sources (entries 1−7) including alkyl amines, anilines,
carbamates, alkylsulfonamides, alkylamides, and arylamides with
a combination of copper salts, oxidants, solvents, and bases at 80
°C came to no avail. Only when trifluoroacetamide was employed
as the nitrogen source did Cu(OAc)2-mediated amidation take
place smoothly with Cs2CO3 as the base and DMF as the solvent
to give anthranilamide 3a in 76% yield (entry 8). Switching the
solvent to DMSO boosted the yield an additional 5% (entry 9).
Encouraged, Cu(TFA)2 was chosen as the next “logical” choice of
copper salt, which surprisingly failed to produce any amidation
product (entry 10). An attemptusing N-methylpiperidine (NMP,
entry 11) as the solvent did not offer much advantage in terms of
yields either. Later, it was discovered that TMG provided the
highest yield, presumably due to its higher solubility in DMSO
than inorganic salts. Asevidence ofhow sensitive the reaction isto
the nitrogen source, even 2,2-difluoroacetamide only produced a
trace amount of the corresponding anthranilamide (entry 13).
Gratifyingly, the methodology worked smoothly for all primary
arylsulfonamides and alkylsulfonamides tested (entries14and 15,
and vide infra).
(94% based on recovered starting material; Scheme 2). While the
reaction is catalytic for the copper source, a stoichiometric
amount of copper salts was employed due to their low cost.
It was intriguing to notice that when trichloroacetamide was
employed as the nitrogen source, unexpectedly, no desired
anthranilamide was isolated. Surprisingly, Cu(OAc)2-mediated
aerobic C(sp2−H) dichlorination product 6 was isolated in good
yield (Scheme 3). To the best of our knowledge, this is the first
report using trichloroacetamide as the chlorination agent for C−
H halogenation.17
With reaction conditions optimized, the utility of Cu(OAc)2-
mediated C−H amidation using 2-aminophenyl-1H-pyrazole (1)
as the removable DG was explored. As shown in Table 2, the
reaction worked for a variety of substituted benzamide substrates
2a−2e when trifluoroacetamide was used as the nitrogen source.
The parent benzamide 2a afforded anthranilamide 3a in 94%
yield. The amidation reaction worked on benzamide 2b with an
When the amidation failed to work well (entries 4−7, 13), a
competing aerobic oxidation product, phenol 5, was isolated.
When the reaction was carried out without any nitrogen source,
hydroxylationtookplaceexclusively toofferphenol5in76%yield
B
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Scheme 3. Cu(OAc)2-Mediated Aerobic C(sp2−H)
substrate 2g and thiophene substrate 2h offered the desired
anthranilamides 3g and 3h in 67% and 69% yield, respectively.
As a highlight, all substrates 2a−2h were sulfonamidated in
consistently high yields using this method. Methanesulfonamide,
trifluoromethanesulfonamide, benzenesulfonamide, p-toluene-
sulfonamide, and p-methoxybenzenesulfonamide all worked
smoothly as the nitrogen source to produce amide−sulfonamides
4a−4h in 70−99% yield. Overall, 2-aminophenyl-1H-pyrazole
(1) appears to be superior to existing removable DGs in terms of
sulfonamidation, providing good yields for all primary
sulfonamides tested.
The utility of the resulting adducts is found in the following
transformations. Hydrolysis of adduct 4a using KOH in ethanol12
reveals the carboxylic acid 7 (which itself is an GPAT inhibitor;9b
see Figure 1) for further manipulations (Scheme 4). Yet,
treatment of adduct 3a with K2CO3 in refluxing methanol
exposesaniline8foradditionalderivatizations. Transformationof
Dichlorination
electron-donating substituent as well as benzamides 2c−2e with
electron-withdrawing substituents.
Attention was then focused toward heterocyclic substrates. For
the furan substrate 2f, the desired anthranilamide 3f was isolated
in only 27% yield (82% based on recovered starting material);
even elevated temperature (150 °C!) and additional Cu(OAc)2
did not drive the reaction to completion. Meanwhile, pyridine
a
Table 2. Copper-Mediated C−H Amidation and Sulfonamidation
a
Reaction conditions: Substrate 2 (0.30 mmol), primary amide or sulfonamide (1.5 equiv), Cu(OAc)2 (1 equiv), TMS (4 equiv) in DMSO at 80 °C
b
c
overnight in open air. Isolated yields. Based on recovered starting material.
C
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Letter
Notes
Scheme 4. Removal of the DG
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Weare indebtedtoDrs. Kewei XuandJoseph Pease atGenentech
for HRMS data acquisition.
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While the mechanism for copper-mediated C−N bond
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amidation employing our bidentate removable DG as shown in
Scheme 5. Therefore, chelation of Cu(OAc)2 with N,N-bidentate
substrate 2a affords Cu(II)-complex 9. With the aid of the base,
complex 9 undergoes C−H cupration to afford Cu(II)-complex
10, which is oxidized by Cu(OAc)2 to produce Cu(III)-complex
11. Ligand exchange with methanesulfonamide then gives rise to
intermediate 12, which subsequently undergoes a reductive
elimination to deliver amide−sulfonamide 4a.
In summary, we discovered inexpensive 2-aminophenyl-1H-
pyrazole as a removable bidentate DG for copper-mediated
aerobic oxidative C(sp2−H) bond amidation and sulfonamida-
tion. While amidation worked for only trifluoroacetamide,
sulfonamidation resulted in excellent yields for all sulfonamides
explored. While the scope of our removable DG is narrower than
those of 2-(4,5-dihydrooxazol-2-yl)aniline and 8-aminoquino-
line, we expanded the repertoire of removable DGs through
rational design. Its utility in other C−H activations will be
explored and extended.
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b01105.
(18) (a) Liu, J.; Yu, L.; Zhuang, S.; Gui, Q.; Chen, X.; Wang, W.; Tan, Z.
Chem. Commun. 2015, 51, 6418. (b) Sahoo, H.; Reddy, M. K.;
Ramakrishna, I.; Baidya, M. Chem. - Eur. J. 2016, 22, 1592. (c) Zhao,
S.; Yuan, J.; Li, Y.-C.; Shi, B.-F. Chem. Commun. 2015, 51, 12823.
(d) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196.
Experimental procedures and compound characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Author
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*E-mail: jjli@usfca.edu.
D
DOI: 10.1021/acs.orglett.6b01105
Org. Lett. XXXX, XXX, XXX−XXX