R.R. Thakore, B.S. Takale, Y. Hu et al.
Tetrahedron 87 (2021) 132090
Combi-Blocks, Alfa Aeser, or Acros Organics and used without
further purification. Solvents were obtained from an Innovative
Technologies Solvent Purification System (SPS) and used immedi-
ately. Deuterated solvents were purchased from Cambridge Iso-
topes Laboratories. 1H and 13C NMR spectra were recorded on a
Varian Unity Inova 500 MHz (500 MHz for 1H, 125 MHz for 13C);
DMSO-d6, CD3OD, and CDCl3 were used as NMR solvents. The
chemical shifts are reported in parts per million (ppm), the
coupling constant J values are given in Hertz (Hz). The peak pat-
terns are indicated as follows: s, singlet; d, doublet; t, triplet; q,
quartet; p, pentet; m, multiplet. High-resolution mass analyses
were obtained using a 5975C Mass Selective S-3 Detector, coupled
with a 7890A Gas Chromatograph (Agilent Technologies). As
Scheme 3. 1-Pot tandem sequence.
capillary column,
a
HP-5MS cross linked 5% phenyl-
m,
methylpolysiloxanediphenyl column (30 m ꢁ 0.250 mm, 0.25
m
Agilent Technologies) was employed. Helium was used as carrier
gas at a constant flow of 1 mL/min. Thin layer chromatography
(TLC) was performed using Silica Gel 60 F254 plates (Merck,
0.25 mm thick). Flash chromatography was performed in glass
columns using Silica Gel 60 (EMD, 40e63 mm) and using Biotage
Isolera instruments. GC-MS data were recorded on a 5975C Mass
Selective Detector, coupled with a 7890A Gas Chromatograph
(Agilent Technologies). TPGS-750-M was either prepared or sup-
plied by PHT international (also available from Sigma-Aldrich,
catalog #733857), and 1 wt % Pd/C was purchased from Sigma-
Aldrich (#205672). The desired 2 wt % of surfactant solution in
HPLC water (which was degassed with argon prior to use) was
prepared by dissolving 2 g of surfactant together with 98 g of HPLC
water and stored under argon.
Scheme 4. Recycling of aqueous TPG-lite and E Factor.
2.7. Recycling and E factor determination
4.1. Preparation of TPG-lite
The potential for recycling of these aqueous reaction mixtures
containing surfactant 6 is illustrated in Scheme 4. Here, the solid
product 9 could be isolated simply via filtration, while the aqueous
reaction mixture, as usual, is readily recycled, thereby minimizing
waste water streams. The associated E Factor for this reaction in
TPG-lite, based on organic solvent usage was, therefore zero.
A 100 mL round-bottom flask with magnetic stir bar and septum
was charged with MPEG-750-COOH 7, (8.43 g, 11.00 mmol), DL-a-
tocopherol (4.9 g, 11.6 mmol), N-Ethyl-N0-(3-dimethylaminopropyl)
carbodiimide hydrochloride (EDCI) (2.8 g, 14.4 mmol), N,N-Dime-
thylpyridin-4-amine (DMAP) (270 mg, 20 mol%) and solvent (70 mL
DCM or 100 mL 2-Me THF). A rubber septum was put on, and the
reaction flask was placed in a pre-heat oil bath (45 or 65 ꢀC) until
the reaction reached completion (followed by TLC). The resulting
solution was allowed to attain rt, at which point ~55e60 mL of the
solvent was recovered via rotary evaporation. The concentrate in
vacuo was purified by flash column chromatography on silica gel
eluting with a 100% DCM to 7% MeOH/DCM gradient to afford TPG-
lite 6 (11.7 g, 88%) as very light yellowish white wax. 1H NMR
3. Conclusions
TPG-lite has been developed to function akin to established
TPGS-750-M as an enabling, nanomicelle-forming surfactant. Un-
like its precursor, this amphiphile is devoid of a linker between it
lipophilic (vitamin E) portion and its hydrophilic (MPEG-750) sec-
tion, thereby containing only a single ester linkage potentially
improving its economic footprint, and its stability due to the highly
hindered ester. It can be used interchangeably in all representative
reactions studied to date that feature direct comparisons, including
those involving ppm level Pd catalysis. Based on in silico evalua-
tions, TPG-lite appears, not unexpectedly given its otherwise close
relationship to TPGS-750-M, to be safe towards both human and
aquatic life. Its presence in water gives rise to nanomicelles that are
closely related to those of its precursor, as seen via both DLS and
cryo-TEM measurements. Recycling of such aqueous reaction
mixtures containing TPG-lite is straightforward, while its use in a
representative coupling indicates that low E Factors, attesting to its
extent of “greenness”, are to be expected. Additional, newly
designed, and unprecedented alternative surfactants to those in
this series are under development and will be disclosed in future
reports from these labs.
(500 MHz, CDCl3)
d 4.46 (s, 2H), 4.19 (s, 2H), 4.01e3.44 (m, 51H),
3.38 (s, 3H), 2.58 (t, J ¼ 6.8 Hz, 2H), 2.08 (s, 3H), 2.01 (s, 3H), 1.97 (s,
3H), 1.69 (dt, J ¼ 13.4, 4.1 Hz, 2H), 1.62e1.49 (m, 4H), 1.41e1.33 (m,
4H), 1.24 (d, J ¼ 9.6 Hz, 8H), 1.17e1.03 (m, 8H), 0.96e0.78 (m, 12H).
13C NMR (126 MHz, CDCl3)
d 71.9, 71.0, 70.6, 70.6, 70.6, 68.4, 59.0,
49.0, 39.4, 37.4, 37.4, 34.0, 32.8, 32.7, 28.0, 25.6, 25.0, 24.8, 24.4, 22.7,
22.6, 21.0, 20.6, 19.8, 19.7, 13.0, 12.2, 11.8.
4.2. Experimental procedure for stability studies of TPGS-750-M
and TPG-lite in Suzuki-Miyaura coupling
Into a 1-dram screw cap vial containing a PTFE coated magnetic
stir bar was added 0.5 mol% of PPh3-Pd-G3 (with respect to iodo-
benzenze), 0.6 mmol of 4-trifluoromethyl phenylboronic acid. The
vial was evacuated and backfilled with argon (this procedure was
repeated three times). Iodobenzene (0.5 mmol), triethylamine
(0.75 mmol), A 0.5 mL 2 wt % surfactant/H2O solution were added
under argon. The vial was quickly replaced with the screw cap and
stirred at 45 ꢀC for 3 h (GC-MS shows complete conversion). The
4. Experimental section
Reagents and chemicals were purchased from Sigma-Aldrich,
6