One-Pot Synthesis of Indoles and Pyrazoles via Pd-Catalyzed Couplings/Cyclizations Enabled by Aqueous Micellar Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c02315

An effective one-pot synthesis of either indoles or pyrazoles can be achieved via Pd-catalyzed aminations followed by subsequent cyclizations facilitated by aqueous micellar catalysis. This new technology includes efficient couplings with low loadings of palladium, a more stable source of the required hydrazine moiety, greater atom economy for the initial coupling, and reduced reaction temperatures, all leading to environmentally responsible processes.

Full text of DOI:10.1021/acs.orglett.0c02315

pubs.acs.org/OrgLett
Letter
One-Pot Synthesis of Indoles and Pyrazoles via Pd-Catalyzed
Couplings/Cyclizations Enabled by Aqueous Micellar Catalysis
Evan B. Landstrom, Nnamdi Akporji, Nicholas R. Lee, Christopher M. Gabriel, Felipe C. Braga,
and Bruce H. Lipshutz*
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ABSTRACT: An effective one-pot synthesis of either indoles or
pyrazoles can be achieved via Pd-catalyzed aminations followed by
subsequent cyclizations facilitated by aqueous micellar catalysis.
This new technology includes efficient couplings with low loadings
of palladium, a more stable source of the required hydrazine
moiety, greater atom economy for the initial coupling, and reduced
reaction temperatures, all leading to environmentally responsible
processes.
MePhos),1 a limited number of examples were described and
required heating to 100 °C in amyl alcohol.
ndole represents a privileged structure that can be found in
Ia variety of organic molecules ranging from agrochemicals
and medicines to natural products. Due to its prevalence, the
search to synthesize indoles and derivatives has been an active
area of research since Bayer first produced indoles from the
decomposition of dyes in 1866.1 The first widely used method
for the synthesis of indoles was described by Fischer in 1883,2
derived from an aryl hydrazine and an aldehyde or ketone
under acidic conditions. The hydrazine intermediates are
typically prepared via diazotization of aniline derivatives that
are then reduced to the corresponding aryl hydrazines. Due to
their unstable nature, the aryl hydrazines oftentimes must be
used immediately. With recent advances in Pd-catalyzed cross-
coupling reactions, C−N bond formation involving aryl halide
reaction partners has become an important method for
preparing anilines and derivatives.3 One modification of an
indole synthesis disclosed in 19994 utilizes a Pd-catalyzed C−
N coupling between an aryl halide and benzophenone
hydrazone to introduce, after hydrolysis, the desired hydrazine.
This approach allows for enhanced flexibility since the initial
aryl hydrazone product could be isolated and stored for later
use. However, limitations associated with this method include
the initial coupling, run in hot toluene (80 °C), as well as the
need to effect a solvent switch to ethanol prior to cyclization
when run using a “one-pot” protocol. Moreover, loadings of
endangered palladium were up to 5 mol %, 2 equiv of p-
toluenesulfonic acid (PTSA) were invested, and from a
practical standpoint, the presence of liberated benzophenone
not only represented significant waste generation but also
complicated the purity profile of the final product. While more
recent conditions have been reported that involve a far lower
catalyst loading (0.1 mol % Pd(OAc)2, together with 0.2 mol %
Petroleum-derived organic solvents are the major source of
organic waste created by the chemical industry, while use of
such high reaction temperatures requires a significant invest-
ment in energy for both their use and removal. Herein, we
describe our efforts to develop a mild Pd-catalyzed coupling
that relies on tert-butyl carbazate, along with an aryl halide, that
can be easily telescoped into a one-pot tandem process for the
synthesis of indoles and pyrazoles, all performed in an aqueous
reaction medium (Scheme 1).
Initial studies focused on the use of both benzophenone
hydrazone and the analogous hydrazone derived from
Michler’s ketone as entries to the targeted indoles (Figure
1). However, purification and solubility issues led us to
investigate alternative methods and sources for the introduc-
tion of the hydrazine moiety. Earlier work investigating
palladium-catalyzed couplings of protected ammonia equiv-
alents5 suggested that tert-butyl carbazate (Boc-hydrazine)
could be used as the source of hydrazine. Jiang and co-workers
showcased Boc-hydrazine’s ability to couple smoothly under
related metal-catalyzed conditions, albeit in an organic solvent,
thereby demonstrating its viability as an alternative source of
the hydrazine moiety.6
Preliminary screening of palladium sources (see Supporting
Information (SI)) indicated that 0.5 mol % of [t-
Received: July 11, 2020
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© XXXX American Chemical Society
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Scheme 1. Syntheses of Indoles and Pyrazoles via C−N
Couplings
Scheme 2. Determination of Linear to Branched Ratio from
Initial C−N Coupling
chromatography methods (1-(4-(tert-butyl)phenyl)hydrazine-
1-carboxylate (3) and tert-butyl 2-(4-(tert-butyl)phenyl)-
hydrazine-1-carboxylate (4)); however, using 1H NMR
analysis, a 2:1 ratio of the linear/branched products had
been formed.
After optimization of the hydrazine coupling, the nature of
the reaction medium needed for the cyclization was examined
using PTSA as the proton source. In anticipation that the
presence of significant amounts of water would be deleterious
to the condensation of the aryl hydrazine with the desired
ketone, initial attempts to conduct the cyclization were
performed in absolute ethanol. As a test case, cyclization of a
hydrazine intermediate with cyclohexanone leading to adduct 5
(Scheme 3) was conducted in absolute ethanol and compared
with results obtained from the same reaction run in a mixture
of aqueous surfactant diluted with ethanol. Since isolated yields
of 5 were comparable, the initial coupling (at 0.5 M) under
aqueous conditions was then followed by simple dilution with
ethanol (to 0.2 M). Since sulfuric acid has long been known to
be an effective acid catalyst for the Fischer indole synthesis,9
final conditions of the one-pot process included the initial
coupling in nanomicelles formed from designer surfactant
TPGS-750-M,10 followed by addition of an enolzable ketone
(2 equiv), concentrated sulfuric acid (3 equiv), and dilution of
the reaction mixture with ethanol to give a global
concentration of 0.2 M relative to the starting halide, all at
reflux in a sealed reaction vial.
Under these conditions, a broad range of electron-rich as
well as electron-neutral substrates could be coupled smoothly
and subsequently used in the Fischer cyclization (Scheme 3).
Thus, 11 ketones were studied and led to the expected indoles
5−15 in very good to excellent yields (60%-quant). Overall,
results from this approach compare favorably with those
obtained using prior art.3 Products 5, 8, and 14 could be
isolated in 89%, 98%, and 91% yields vs previously reported
yields of 92%, 54%, and 81%, respectively. Formation of adduct
13 required use of absolute ethanol for the cyclization en route
to a key intermediate for the NSAID indomethacin (Figure 2),
prepared from 4-bromoanisole and levulinic acid in a five-step
coupling, deprotection, condensation, cyclization, and ester-
forming sequence.
Figure 1. Common sources of the hydrazine moiety.
BuBrettPhosPd-(allyl)]OTf7 was the most robust catalytic
system when applied to the coupling of 4-bromobiphenyl and
tert-butyl carbazate (1.1 equiv) under micellar conditions at 45
°C in the presence of triethylamine (1.5 equiv) as base.
Complete consumption of starting material was observed after
18 h (at 0.5 M) by TLC analysis. Increasing the amounts of
both base and nucleophile to 2.0 equiv led to complete
consumption of the aryl halide after 90 min. Although
triethylamine was an effective base for the coupling, it had to
be freeze−pump−thawed on a consistent basis to remove
oxygen. tert-Butoxide, a base that is widely employed in C−N
coupling reactions, showed similar reactivity to that of
triethylamine. Coupling with an electron-rich halide, such as
4-bromoanisole, under the same conditions yielded a
maximum conversion of 90% after 5 h. Increasing the reaction
temperature to 55 °C led to rapid formation of Pd-black while
only minimal conversion to the desired product was observed.
Based on previous experience with other ligands utilized in
Suzuki−Miyaura couplings and literature precedent,8 we
investigated increasing the ratio of ligand-to-Pd to 2:1. Initially,
adding free t-BuBrettPhos at the start of the reaction led to
complete conversion of 4-bromoanisole after 6 h with no
noticeable formation of Pd black. For this iteration, raising the
temperature from 45 to 55 °C unexpectedly resulted in
incomplete conversion, with noticeable Pd black formation
(see SI for details). Thus, optimized conditions settled on use
of an equivalent of ligand relative to the amount of Pd catalyst
(5000 ppm, or 0.5 mol %).
Although the ratio of branched-to-linear products of the
Boc-hydrazine intermediate is not relevant for this study, since
the Boc-deprotected intermediate ultimately involved in the
cyclization would be identical, we nonetheless determined the
ratio of products to gain insight into the overall efficacy of
bond formation and regioselectivity involved under these new
conditions (Scheme 2). 1-Bromo-4-tert-butylbenzene, there-
fore, was subjected to the optimized conditions leading to
complete consumption of starting material after 90 min. The
products were only partially separable under typical
The Fischer indole synthesis does have some recognized
limitations. For example, only electron-neutral or electron-rich
substrates undergo the required [3,3]-sigmatropic rearrange-
ment. Therefore, this excludes electron-deficient substrates
despite their being more favorable reaction partners for the
initial Pd-catalyzed C−N bond formation. Nonetheless, these
as well as all other types of ring substitutions are amenable
substrates to the Knorr pyrazole synthesis (Scheme 4).11
Consequently, the desired pyrazoles 16−21 were synthesized
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Scheme 3. Synthesis of Indoles via One-Pot Coupling/
Fischer Cyclization
Scheme 4. Pyrazole Synthesis under Mild Aqueous
a
a
Conditions
a
Reaction conditions unless otherwise noted: 1 mmol aryl halide, 2
mmol of Boc-hydrazine, 0.5 mol % of [Pd(allyl)(t-BuBrettPhos)]OTf,
0.5 mmol t-BuBrettPhos, 2 mmol of NaOt-Bu stirred in 2 wt %
TPGS-750-M/H2O at 45 °C for 16 h. Upon completion dilute with
ethanol to [0.2 M], 3 mmol of H2SO4 along with 2 mmol of diketone
at reflux for 24 h. Isolated yields reported.
Scheme 5. Two-Step, One-Pot Synthesis of Celecoxib
a
Reaction conditions unless otherwise noted: 1 mmol aryl halide, 2
mmol of Boc-hydrazine, 0.5 mol % of [Pd(allyl)(t-BuBrettPhos)]OTf,
0.5 mmol t-BuBrettPhos, 2 mmol of NaOt-Bu stirred in 2 wt %
TPGS-750-M/H2O at 45 °C for 16 h. Upon completion, dilution with
ethanol (to 0.2 M), addition of 3 mmol of H2SO4 along with 2 mmol
of ketone, at reflux for 24 h. Isolated yields reported. * Fischer
cyclization run in absolute ethanol.
unsymmetrical β-diketone 23 leading in 67% overall yield to
the desired drug, 24.
Recycling of the aqueous 2 wt % surfactant medium
(Scheme 6) was readily carried out for the formation of the
a
Scheme 6. Recycle Study
Figure 2. Synthesis of a key intermediate en route to indomethacin.
under mild aqueous conditions in excellent yields (79%-
quant). Notably, substrates bearing an o-nitrile group can
undergo cyclization to form a 3-aminoindazole such as 21.
However, use of unsymmetrical diketones, unless internally
biased, will lead to regioisomeric mixtures of products.
One representative example of the potential applications of
this new methodology to the pharmaceutical sector is the two-
step, one-pot synthesis of celecoxib (Celebrex),12 a common
nonsteroidal anti-inflammatory used to treat the symptoms of
acute pain or inflammation (Scheme 5). The sequence was
achieved by initial amination (with 1.1 equiv hydrazine) of
bromosulfonamide 22, followed by introduction of the
a
Isolated yields.
C
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initial product hydrazine, illustrating minimization of organic
waste produced as measured by the associated E Factor.13 Each
recycle involved an in-flask extraction of the reaction mixture
with ethyl acetate, followed by addition of fresh aryl halide,
Boc-hydrazine, palladium catalyst, ligand, and NaO-t-Bu (1
equiv). The low E Factor of 4.7 for hydrazine formation
showcases the limited quantity of waste generated from use of
recyclable water, especially when compared to the typical
conditions for this type of bond formation.1,3,4
In summary, an efficient, mild, and environmentally
responsible method has been developed for C−N couplings
between aryl halides and tert-butyl carbazate to yield protected
hydrazines. These, without isolation, readily undergo cycliza-
tions leading to nitrogen heterocycles, including indoles and
pyrazoles. This new technology, in the composite, provides a
solution to several important and timely issues associated with
prior methods, most notably including reduction in the loading
of endangered Pd as catalyst, as well as the significant
reduction in the amounts of newly generated organic waste.
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ASSOCIATED CONTENT
* Supporting Information
■
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Hydro-L-Proline as a More Effective Catalytic System for Coupling of
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Chem. 2009, 74, 4542−4546.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02315.
Experimental procedures, analytical data, and copies of
NMR spectra for all compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Bruce H. Lipshutz − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States; orcid.org/0000-0001-
9116-7049; Email: bhlipshutz@ucsb.edu
(9) Robinson, B. Studies on the Fischer Indole Synthesis. Chem. Rev.
1969, 69, 227−250.
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T.; Duplais, C.; Krasovskiy, A.; Gaston, R. D.; Gadwood, R. C. TPGS-
750-M: A Second-Generation Amphiphile for Metal-Catalyzed Cross-
Couplings in Water at Room Temperature. J. Org. Chem. 2011, 76,
4379−4391.
(11) (a) Knorr, L. Einwirkung von Acetessigester auf Phenyl-
hydrazin. Ber. Dtsch. Chem. Ges. 1883, 16, 2597−2599. (b) Knorr
Pyrazole Synthesis. In Comprehensive Organic Name Reactions and
Reagents; American Cancer Society: 2010; pp 1631−1633. (c) Kar-
rouchi, K.; Radi, S.; Ramli, S.; Taoufik, J.; Mabkhot, Y. N.; Al-aizari,
F.; Ansar, M. Synthesis and Pharmacological Activities of Pyrazole
Derivatives: A Review. Molecules 2018, 23, 134.
Authors
Evan B. Landstrom − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States; orcid.org/0000-0002-
5789-6106
Nnamdi Akporji − Department of Chemistry and Biochemistry,
University of California, Santa Barbara, California 93106,
United States
Nicholas R. Lee − Department of Chemistry and Biochemistry,
University of California, Santa Barbara, California 93106,
United States
Christopher M. Gabriel − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States
(12) (a) Gong, L.; Thorn, C. F.; Bertagnolli, M. M.; Grosser, T.;
Altman, R. B.; Klein, T. E. Celecoxib pathways: Pharmacokinetics and
Pharmacodynamics. Pharmacogenet. Genomics 2012, 22, 310−318.
(b) Sthalam, V. K.; Singh, A. K.; Pabbaraja, S. An Integrated
Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS)
for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors.
Org. Process Res. Dev. 2019, 23, 1892−1899.
Felipe C. Braga − Department of Chemistry and Biochemistry,
University of California, Santa Barbara, California 93106,
United States
(13) Sheldon, R. A. The E Factor: fifteen years on. Green Chem.
2007, 9, 1273−1283.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02315
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NSF (CHE 18-56406) is warmly
acknowledged.
D
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