Piyatida
Klumphu
a,
Camille
Desfeux
b,
Yitao
Zhang
a,
Sachin
Handa
*c,
Fabrice
Gallou
d and
Bruce H.
Lipshutz
*a
aDepartment of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, USA. E-mail: lipshutz@chem.ucsb.edu
bChimie Paris Tech, Paris, France
cDepartment of Chemistry, University of Louisville, Kentucky 40292, USA. E-mail: sachin.handa@louisville.edu
dNovartis Pharma, Basel, Switzerland
First published on 20th July 2017
Several ppm level gold-catalyzed reactions enabled by the ligand HandaPhos can be performed at room temperature in aqueous nanoreactors composed of the surfactant Nok. Variously substituted allenes undergo cycloisomerization leading to heterocyclic products in good yields. Likewise, cyclodehydration is also illustrated under similar conditions, as is an intermolecular variant, hydration of terminal alkynes. Recycling of the catalyst and reaction medium is also illustrated. A low E factor associated with limited solvent use and therefore, waste generation, documents the greenness of this process.
One approach to lowering the required levels of precious metals involved in catalytic processes is to take advantage of the higher concentrations of both water-insoluble reactants and catalysts preferentially found within the inner cores of nanomicelles in water (Fig. 1).5 The extent to which the occupants reside within these nanoreactors, as opposed to their dynamic exchange between nanomicelles, depends upon their binding constants. The greater the binding constant for a given ligated gold catalyst, the more time spent within each micelle and hence, the less needed for catalysis. This requires that in addition to consideration of the common elements fundamental to ligand design, such as steric, stereoelectronic, and conformational effects, as well as donicity, lipophilicity may be an important consideration,6 which is otherwise meaningless for catalysis run in organic solvents.1b
Fig. 1 Formation of a HandaPhos-Au catalyst for use at the ppm level under micellar catalysis conditions. |
These considerations have led to the design of the recently introduced ligand (racemic) HandaPhos6 (Scheme 1), shown to function in the form of a 1:1 complex with palladium as a means of effecting Suzuki–Miyaura cross-couplings at the ppm level of metal in water at room temperature. To determine if HandaPhos technology applies to other precious metal chemistry, we have turned to cationic gold in an effort to provide not only ppm level catalysis of several typical Au-catalyzed reactions, but to make such a process relatively environmentally benign. It was anticipated that both the electron-rich and bulky nature of this ligand would contribute to its effectiveness in gold catalysis, especially for intramolecular cyclizations where protodeauration is known to be rate-determining.7 In this report, we disclose technology that, indeed, provides a new Au(I) catalyst that can be used, and recycled, at the ≤1000 ppm (0.1 mol%)8 level under aqueous micellar conditions.
Scheme 1 Formation of a HandaPhos-Au catalyst for use at the ppm level under micellar catalysis conditions. |
Entry | Conditions | Result |
---|---|---|
1 | LAuCl (1000 ppm) + AgBF4 (1000 ppm) | NR |
2 | LAuCl (1000 ppm) + AgOTf (1000 ppm) | NR |
3 | LAuCl (1000 ppm) + AgSbF6 (1000 ppm) | NR |
4 | LAuCl (1000 ppm) + AgBF4 (1000 ppm) + TFA (1 equiv.) | 56% (5 d) |
5 | LAuCl (1000 ppm) + AgOTf (1000 ppm) + TFA (1 equiv.) | Trace |
6 | LAuCl (1000 ppm) + AgSbF6 (1000 ppm) + TFA (1 equiv.) | 71% (4 d) |
7 | LAuCl (1000 ppm) + AgSbF6 (2000 ppm) + TFA (2 equiv.) | 98% |
Additional screening as to the choice of surfactant included the background reaction “on water” (Table 2). Clearly, cyclization could be achieved under such micelle-free conditions; however, the extent of conversion was low.
Switching from Nok to the alternative, vitamin E-based derivative, TPGS-750-M,17 afforded roughly comparable results. Poor conversions were noted in both organic solvents DCM and toluene even after four days.
Application of these newly established conditions to three additional allenic alcohols led to the corresponding dihydropyrans as shown in Scheme 2. In all cases, cyclization took place smoothly and gave the expected products in high isolated yields. Both di- and tri-substituted allenes are amenable to this Au-catalyzed process in water. Use of small percentages of co-solvent (toluene, 10% v/v)18 was found to have a beneficial effect on the extent of conversion and hence, yield.
Scheme 2 Representative examples of cyclizations of allenic alcohols catalyzed by ppm Au ligated by HandaPhos (L). |
These optimized conditions are also applicable to aminoallenes, as illustrated in Scheme 3. No conversion was observed with free amines, where the high affinity of an amino group for gold can inhibit the reaction as can its potential protonation by TFA. Derivatization as the sulfonamide (with TsCl) was sufficient to overcome this undesirable association, leading to smooth cyclization. Both α- and β-aminoallenes 7 and 9 were reactive and the corresponding cyclized 5- and 6-membered rings 8 and 10 were obtained in good-to-excellent yields. Moreover, mono- and di-substituted aminoallenes readily participated.
Scheme 3 Representative examples of cyclizations of allenic sulfonamides catalyzed by ppm Au ligated by HandaPhos (L) [conditions: see Scheme 2]. |
A γ-aminoallene was also cyclized, this example serving as a direct comparison with known literature conditions.19 By contrast, cyclization under micellar conditions reflects a significant drop in the amount of gold catalyst and associated silver salt, as well as avoidance of a chlorinated reaction solvent (Scheme 4).
In 2014, asymmetric gold-catalyzed lactonization was reported by us wherein 3 mol% of a gold complex was employed, also enabled by micellar catalysis in water at room temperature.20 Cyclizations of the same type of allenic acids were re-examined using ppm levels of a (racemic) gold catalyst (Fig. 2). Although longer reaction times were required, the expected products (13–16) were obtained in comparable yields.
Fig. 2 Representative examples of cyclizations of allenic acids catalyzed by ppm Au ligated by HandaPhos. |
Gold-catalyzed cyclodehydrations of variously function-alized hydroxy- and amino-allenes in water were pioneered by the Krause group, first reported back in 2009, which utilized chloroauric acid (HAuCl4) as catalyst.11d Limitations due to substrate insolubility in water led to their switch to amphiphiles under aqueous micellar conditions.21 The catalyst of choice was AuBr3 (2–5 mol%), used in the presence of 2 M NaCl. Advantages noted included a significant reaction rate acceleration, as well as minimization of organic waste via elimination of organic solvents. The same type of ring formation leading to substituted furans could be accomplished using HandaPhos technology where 200–500 times less gold need be used (i.e., 100 ppm, before recycling) to realize the same outcome, in 15 minutes at rt (Scheme 5).
Hydration of alkynes represents a fundamental route to methyl ketones.22 Nolan's approach,3 as illustrated in Fig. 3, employed low levels of an NHC Au complex, with added AgSbF6, typically between 100–1000 ppm, although these were performed in refluxing aqueous dioxane over an 18 hour time frame. Alternatively, use of our standard conditions on terminal alkynes led to functionalized methyl ketones in aqueous nanomicelles at rt over 24 h in high yields (Scheme 6).
Scheme 6 Application of HandaPhos technology to ppm level Au-catalyzed hydration of terminal alkynes. |
Among the virtues of this technology is the opportunity to recycle the entire reaction mixture following an “in flask” extraction of the product using a minimum of a single (recyclable) organic solvent. Moreover, the same reaction need not be used in each recycling step. As shown in Scheme 7, initial hydration of a sulfonamide could be followed by a cyclodehydration, followed by two successive, albeit distinct, cyclizations. After the first two reactions, additional catalyst (500 ppm Au and 1000 ppm Ag) was required, presumably due to deactivation from earlier processing. Nonetheless, the total investment of gold for these four reactions was 0.2 mol%.
Cyclization of an allenic alcohol as a representative substrate (Scheme 8) led to a calculated E factor of 7.6 on the basis of organic solvent used (see ESI†). This signifies a considerable improvement over values (25–100) typically associated with the pharmaceutical industry23 and is in line with numbers seen previously for related reactions in micellar media.24
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc02405c |
This journal is © The Royal Society of Chemistry 2017 |