Sustainable HandaPhos-ppm Palladium Technology for Copper-Free Sonogashira Couplings in Water under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.7b03621

Complexation of ca. 1000 ppm Pd(OAc)₂ with the ligand HandaPhos (1-1.5:1) leads to a precatalyst that efficiently mediates Sonogashira couplings in aqueous nanomicelles under very mild conditions. Neither copper nor organic solvent is required

Full text of DOI:10.1021/acs.orglett.7b03621

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sustainable HandaPhos-ppm Palladium Technology for Copper-Free
Sonogashira Couplings in Water under Mild Conditions
Sachin Handa,*,†,§ Justin D. Smith,†,§ Yitao Zhang,† Balaram S. Takale,† Fabrice Gallou,‡
and Bruce H. Lipshutz*,†
§Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292, United States
‡Novartis Pharma AG, 4002 Basel, Switzerland
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: Complexation of ca. 1000 ppm Pd(OAc)2 with
the ligand HandaPhos (1−1.5:1) leads to a precatalyst that
efficiently mediates Sonogashira couplings in aqueous nano-
micelles under very mild conditions. Neither copper nor organic
solvent is required in the reaction medium, and the product can
be isolated directly from the reaction flask, leaving behind a
reaction mixture that can be recycled without additional
additives.
ccording to the review in 2012 by Colacot and Snieckus
Atracing the history of the 2010 Nobel Prizes in
Chemistry,1 Sonogashira couplings rank third among the
most heavily used Pd-catalyzed “name” reactions over the
past decade, not far behind Heck couplings. The importance of
such processes, dating back to 1975, for introducing an alkynyl
unit onto an aromatic or heteroaromatic nucleus is underscored
by the continuing evolution of this time-honored reaction.2
Advances through the decades have led to elimination of
copper as a cocatalyst with palladium as well as copper-only-
based couplings.3 However, the use of copper only generally
requires more harsh reaction conditions and may lead to
difficulties in workup due to the formation of emulsions.
Furthermore, the selectivity may also be adversely affected,
especially if the coupling partner has an azide, amine, and/or
alkynyl group.4 In 2008, we disclosed that such valued C−C
bond constructions, in the absence of Cu, could be effected in
aqueous nanomicelles at room temperature, thereby eliminating
organic solvents as reaction media.5 These “green“ conditions
Figure 1. Micelles in water as nanoreactors together with the highly
(i.e., in reusable water at rt), could be utilized in other Pd-
catalyzed couplings (e.g., Negishi,6 Stille,7 aminations,8 etc.) as
well as in unrelated but equally valuable synthetic trans-
formations (e.g., SNAr, amide/peptide bonds, olefin metathesis,
etc.).9 Hence, both the solvent and reaction temperature no
longer require consideration, as newly engineered nanoreactors
serve admirably at ambient temperatures in water (Figure 1).
However, the crucial question regarding the extent to which the
loading of a Pd catalyst can be reduced had yet to be addressed,
lipophilic ligand HandaPhos for ppm-level Pd-catalyzed Sonogashira
couplings.
as typical usage in the 1−5 mol % range of a precious and/or
endangered metal is not sustainable.10
Received: November 21, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b03621
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Toward the goal of reducing the levels of transition metal
usage in catalysis, we recently introduced the new ligand
HandaPhos.11 This monodentate cyclic phosphine was
designed specifically as a match for micellar catalysis, where
the concentrations of all reaction components inside the
lipophilic cores of nanoparticles present in water may be in
excess of 2 M. Under such circumstances, ligand design takes
on a new meaning; that is, while the usual variables such as
steric and stereoelectronic effects, conformation, and donicity
remain integral,12 lipophilicity, a design feature of little
consequence in organic solvents, becomes an important
parameter.11,13 In essence, the longer the catalyst spends inside
the micelle, (i.e., the greater its binding constant), the more
catalysis takes place, and therefore, less catalyst is needed for
this purpose. Initial application of HandaPhos technology
documented this concept for especially useful Suzuki−Miyaura
cross-couplings, which can now be done in water at rt using
ppm levels of palladium monocomplexed by this ligand.11 In
this report, we illustrate how (HandaPhos)Pd can also be
applied, in an environmentally responsible manner and at the
ppm level, to Sonogashira couplings.
Scheme 1. Representative Sonogashira Couplings in Water
at Either RT or 45 °C
Previously, Sonogashira couplings were enabled by each of
the designer surfactants PTS, TPGS-750-M, and Nok (Figure
2).5,14 These were quite efficient processes at rt, and in no case
Figure 2. Previous conditions for Sonogashira couplings using
designer surfactants.
Routes to functionalized enynes using an enyne partner
presented no complications (11). Aryl-, heteroaryl-, and alkyl-
substituted alkynes readily undergo coupling. A number of
heteroaromatic halides were screened, including those in the
quinoline, thiophene, pyridyl, pyrimidine, uracil, and benzo-
thiophene series; all reacted smoothly to afford the desired
adducts. Likewise, carbamate (1, 2, 6), fluoro (3), pyrimidine-
dione (4), hydroxyl (5), bromo (6), thioether (7), tert-
butyldimethylsilyl (8), chloro (11), acetal (12), aldehyde (14),
trifluoromethyl (17), and bisimide (18) residues are all
amenable. Notably, multiple couplings could be effected within
was copper needed as a cocatalyst. However, a 1−3 mol %
loading of a Pd salt was involved. This investment of 10000−
30000 ppm Pd is far too high for a metal that is both expensive
and in limited supply. By switching to a ca. 1:1 complex of
Pd(OAc)2 and HandaPhos, couplings could be conducted
between rt and 45 °C typically using only 1000 ppm (0.10 mol
%) in 2 weight percent aqueous TPGS-750-M.
Several representative examples, as illustrated in Scheme 1,
attest to the generality of this method. Functional group
compatibility is high for the many educts examined to date.
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DOI: 10.1021/acs.orglett.7b03621
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the same substrate (e.g., 15−18). Overall, good to excellent
yields were obtained.
The coupling partners could also be inverted to arrive at the
same acetylenic materials, as documented in Scheme 2.
conditions led to little to no reaction upon attempted couplings
between partners 18 and 19 to arrive at alkyne 1. Using ligated
HandaPhos under micellar conditions, however, led to 1 in
excellent yield.
Typically, the use of micellar catalysis in synthesis at the
gram scale is questioned because of concerns over product
recovery. To further validate this technology, coupling partners
21 and 22 were reacted under micellar conditions (Scheme 4)
Scheme 2. Inversion of Polarity of Coupling Partners
Scheme 4. Gram-Scale Synthesis of 16 Using
(HandaPhos)Pd in Micellar Media
to initially cleanly afford product 15. Without purification,
further treatment with methanolic potassium carbonate gave >1
g of 16 in 78% overall yield. Both product extraction and
isolation proceeded uneventfully.
Among the many attractive features associated with micellar
catalysis, recycling of the aqueous reaction mixture that retains
the surfactant and the catalyst is particularly noteworthy.
Sonogashira couplings run under these conditions, notwith-
standing the low levels of palladium catalyst (HandaPhos)Pd
being used in each cycle, provide similar opportunities to
minimize waste generation (Scheme 5).18a Importantly, the
Although times to completion varied, similar reaction yields
were obtained. An initial triple displacement starting with 1,3,5-
tribromobenzene led to 1,3,5-triethynylbenzene (16) after in
situ TMS deprotection. Subsequent couplings with 3,5-
bis(trifluoromethyl)bromobenzene afforded 17 in 80% overall
yield. Triynes of this nature are particularly valuable en route to
organic light-emitting diodes (OLEDs),15 where related
couplings using traditional means in general lead to poor yields.
The effectiveness of HandaPhos technology under micellar
catalysis conditions relative to other state-of-the-art ligands
routinely used in organic solvents at the 1−5 mol % level can
be seen in comparison reactions, as shown in Scheme 3. Thus,
while the coupling shown can be catalyzed under very mild
conditions in water, equivalent amounts of palladium ligated by
either BI-DIME16 or XPhos17 under otherwise identical
Scheme 5. E Factor Determination and Recycling Study
Scheme 3. Comparisons between HandaPhos and Other
Ligands
amount of water invested in these couplings is minimal, as no
additional water is used in reaction processing. If an extraction
(rather than simple filtration of solid products) is anticipated,
this can be performed “in flask”. Moreover, Sheldon’s E
Factor18b associated with this process based on organic solvent
used and as a measure of greenness is minimal, in line with
prior observations based on this micellar catalysis strategy.18a
Since ppm levels of Pd are used in these C−C bond-forming
reactions, relatively low levels of residual metal are found in the
product alkynes. Thus, as reported recently in Suzuki−Miyaura
couplings,11 the amounts of residual Pd in the products are
approximately an order of magnitude below those typically seen
from reactions using catalysts in the 1−5 mol % range (Scheme
6). This characteristic alone, which is of considerable
C
DOI: 10.1021/acs.orglett.7b03621
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(2) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
consequence in the pharmaceutical industry, makes this
technology unique.19
1975, 16, 4467. (b) Chinchilla, R.; Naj
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(b) Thomas, A. M.; Sujatha, A.; Anilkumar, G. RSC Adv. 2014, 4,
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Scheme 6. ICP-MS Analyses for Residual Palladium in
Products 16 and 18
(4) Schilz, M.; Plenio, H. J. Org. Chem. 2012, 77, 2798.
(5) Lipshutz, B. H.; Chung, D. W.; Rich, B. Org. Lett. 2008, 10, 3793.
Also see: Bakherad, M. Appl. Organomet. Chem. 2013, 27, 125.
(6) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc.
2009, 131, 15592.
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2009, 351, 1717.
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(b) Lipshutz, B. H.; Ghorai, S. Green Chem. 2014, 16, 3660.
(10) (a) Davies, E.; Renner, R. Chem. World 2011, 1, 50. (b) Pitts, M.
New Sci. 2011, 209 (2799), 26.
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H. Angew. Chem., Int. Ed. 2016, 55, 4914; Angew. Chem. 2016, 128,
4998. For representative alternative processes that also involve both
Cu-free and ppm-level Pd Sonogashira couplings, see: Yu, L.; Han, Z.;
Ding, Y. Org. Process Res. Dev. 2016, 20, 2124. Sarkar, S. M.; Rahman,
M. L.; Yusoff, M. M. New J. Chem. 2015, 39, 3564.
(12) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685. (b) Martin, R.; Buchwald, S. L. Acc.
Chem. Res. 2008, 41, 1461. (c) Bruno, N. C.; Tudge, M. T.; Buchwald,
S. L. Chem. Sci. 2013, 4, 916. (d) Zhang, D.; Wang, Q. Coord. Chem.
Rev. 2015, 286, 1.
(13) (a) Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed.
2005, 44, 7174; Angew. Chem. 2005, 117, 7338. (b) Handa, S.;
Lippincott, D. J.; Aue, D. H.; Lipshutz, B. H. Angew. Chem., Int. Ed.
2014, 53, 10658; Angew. Chem. 2014, 126, 10834. (c) La Sorella, G.;
Strukul, G.; Scarso, A. Green Chem. 2015, 17, 644.
(14) (a) Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.;
Nishikata, T.; Duplais, C.; Krasovskiy, A.; Gaston, R. D.; Gadwood, R.
C. J. Org. Chem. 2011, 76, 4379. (b) Klumphu, P.; Lipshutz, B. H. J.
Org. Chem. 2014, 79, 888.
In summary, highly valued palladium-catalyzed Sonogashira
couplings can now be run not only in water under very mild
conditions but with ppm levels of palladium in the complete
absence of added copper. The parameters addressed by this
methodology are representative of the three prominent reaction
variables in synthetic chemistry from the green chemistry
perspective: (1) the organic solvent has been replaced by
minimal and reusable amounts of water; (2) the input of energy
for heating reaction mixtures has been reduced to between rt
and 45 °C; and (3) the amount of Pd catalyst involved has been
dramatically lowered from 10000−50000 ppm to ca. 1000 ppm
before recycling. Further advances based on HandaPhos
technology will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03621.
(15) (a) Adhikari, R. M.; Duan, L.; Hou, L.; Qiu, Y.; Neckers, D. C.;
Shah, B. K. Chem. Mater. 2009, 21, 4638. (b) Yamaguchi, Y.; Ochi, T.;
Miyamura, S.; Tanaka, T.; Kobayashi, S.; Wakamiya, T.; Matsubara, Y.;
Yoshida, Z.-i. J. Am. Chem. Soc. 2006, 128, 4504.
(16) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel, N.
D.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu, B. Z.;
Krishnamurthy, D.; Yee, N. K.; Senanayake, C. H. Angew. Chem., Int.
Ed. 2010, 49, 5879.
Reaction optimization; details of cryo-TEM, DLS, and
control experiments; analytical data of compounds; and
NMR data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(17) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42,
5993.
*lipshutz@chem.ucsb.edu
*sachin.handa@louisville.edu
ORCID
(18) (a) Lipshutz, B. H.; Isley, N. A.; Fennewald, J. C.; Slack, E. D.
Angew. Chem., Int. Ed. 2013, 52, 10952. (b) Sheldon, R. A.; Arends, I.
W. C. E.; Hanefeld, U. Green Chemistry and Catalysis; Wiley-VCH:
Weinheim, Germany, 2007.
(19) Koide, K. In New Trends in Cross-Couplings: Theory and
Applications; Colacot, T., Ed.; Royal Society of Chemistry: Cambridge,
U.K., 2014; pp 779−810.
Sachin Handa: 0000-0002-7635-5794
Bruce H. Lipshutz: 0000-0001-9116-7049
Notes
The authors declare the following competing financial
interest(s): The University of California has submitted a patent
application for the HandaPhos ligand and its derivatives.
ACKNOWLEDGMENTS
■
We thank Evan Landstrom (UCSB) for technical assistance.
We warmly acknowledge Novartis and the NSF (GOALI
SusChEM 1566212) for financial support.
REFERENCES
■
(1) Johansson-Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062; Angew. Chem.
2012, 124, 5150.
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DOI: 10.1021/acs.orglett.7b03621
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