A.
Cedrol lithium oxalate (2).
A 100 mL one-necked (24/40 joint) round-bottomed flask equipped with a Teflon-coated magnetic stir bar (oval, 25 mm x 10 mm) is charged with
cedrol (
1) (2.22 g, 10.0 mmol, 1.0 equiv) (
Note 1),
4-dimethylaminopyridine (1.34 g, 11.0 mmol, 1.1 equiv) (
Note 2), and
dichloromethane (40 mL) (
Note 3). The flask, which is open to air, is immersed in a room temperature water bath, and the mixture is rapidly stirred under ambient atmosphere. A disposable plastic syringe is used to add
methyl chlorooxoacetate (960 µL, 10.5 mmol, 1.05 equiv) (
Note 4) drop-wise over the course of 2 min (
Note 5). The resulting pale yellow solution is maintained for 2 h at room temperature (Figure 1). A fritted glass funnel (6 cm diameter x 10 cm height) with a vacuum adapter is packed with 35 g of silica gel (
Note 6) as a slurry in
dichloromethane. The crude reaction mixture is poured onto the silica gel plug (Figure 1). A mild vacuum (~10 mmHg) is applied, and the filtrate is collected. The 100 mL round-bottomed flask is rinsed with
dichloromethane (2 x 10 mL), and the washings are also poured onto the silica gel plug. The silica gel plug is washed with additional
dichloromethane (4 x 50 mL), and the combined organic washes are concentrated under reduced pressure (23 ºC, 12 mmHg) in a 500 mL round-bottomed flask to yield the crude
methyl oxalate as a clear oil (2.85-3.00 g).
Figure 1. Left: reaction turns pale yellow following the addition of methyl chlorooxoacetate; Right: reaction mixture is filtered over the silica gel plug
B. Cedrol benzyl acrylate addition product (3). On the bench under ambient atmosphere, six 8-mL scintillation vials (Note 13), each equipped with a magnetic stir bar (oval, 12 mm x 2 mm), are charged with benzyl acrylate (97 mg, 0.60 mmol, 1.0 equiv) (Note 14), cedrol lithium oxalate 2 (198 mg, 0.660 mmol, 1.1 equiv), and [Ir{dF(CF3 )ppy}2(dtbbpy)]PF6 (7 mg, 0.006 mmol, 0.01 equiv) (Note 15). A 3:1 mixture of dimethoxy-ethane/dimethylformamide (6 mL, 0.1 M) (Note 16) is added, followed by deionized water (110 µL, 6.0 mmol, 10 equiv) (Note 17), (Note 18). The vials are then sealed with screw caps bearing Teflon septa. Each septum of the sealed vials is pierced with a 21 gauge x 1.5'' needle that is inserted just barely through the septum with the tip of the needle kept above the fluid level inside the vial (Figure 2). A separate 21 gauge x 3'' needle attached to a flow of argon is also pierced through the septum, and the tip of the needle is pushed to the bottom of the vial and submersed in the fluid. The reaction mixtures are deoxygenated by sparging with argon for 15 min (Note 19).
Both needles are removed, and the sealed vials are then placed on a stir plate equipped with 2 x 34 W blue LED lamps (Notes
20 and
21) and a rack to hold the vials inside of a cardboard box to block light pollution from entering the lab (Figure 3). The vials are placed in two parallel rows of 3 vials approximately 4 cm from the lamps and stirred vigorously. The samples are irradiated by the lamps for 24 h inside the closed box, and the air inside the box rises to 40-45 ºC because of heat given off from the LEDs (Notes
22,
23, and
24).
Figure 2. Left: reaction mixture is being sparged with argon. Right: reaction mixture before (right) and after (left) being sparged with argon
The reactions are allowed to cool to rt, then all six are opened and poured into the same 500 mL separatory funnel. The vials are each rinsed with 5 mL of
diethyl ether, and the washings are also added to the separatory funnel. The mixture is further diluted with 200 mL of additional
diethyl ether. The organic solution is washed with an aqueous mixture of 2:1 saturated aqueous
LiCl/deionized
water (150 mL) (
Note 25). The layers are separated and the organic phase is washed with deionized
water (100 mL). The combined aqueous phases are extracted again with fresh
diethyl ether (100 mL). The layers are separated, and the organic phase is washed with deionized
water (100 mL). The combined ethereal extracts are dried with
MgSO4 (s) (4 g). The mixture is vacuum filtered through a fritted glass funnel (5 cm OD x 6 cm height), and the solids washed with
diethyl ether (2 x 30 mL). The filtrate is concentrated under reduced pressure on a rotary evaporator (23 °C, 12 mmHg). The crude material is charged on a column (3 cm OD x 12.5 cm height) of 45 g of silica gel (
Note 26) and eluted with 500 mL of 98:2 hexanes/Et
2O solvent mixture. The eluent is collected over 25 fractions, with the desired product obtained in fractions 13-22 (
Note 27). The fractions containing the product are concentrated under reduced pressure (23 °C, 12 mmHg) to give the desired product
3 as a yellow oil (1.04 g, 78% yield, 99% purity) (Notes
28,
29, and
30).
Figure 3. Visible light reaction set-up
2. Notes
1.
Cedrol (98%) was purchased from TCI America and used as received. "Redistilled Cedrol" is commercially available in cheap, bulk quantities, but the purity (~60%) is not sufficient for these studies.
2. DMAP (99%) was purchased from Oakwood Chemical and used as received.
3.
Dichloromethane (99.9%) was purchased from Fisher Scientific Company and used as received.
4.
Methyl chlorooxoacetate was purchased from Alfa Aesar and used as received. The batch used by the submitters was from a bottle without an air-free septum and was used periodically over the course of a year before being used in the reported procedure.
5. The reaction is mildly exothermic. A clear, pale yellow homogeneous solution is observed after addition of all reagents.
6. Geduran Si 60 (40-63 mm) silica gel was purchased from EMD Millipore Corporation.
7. Tetrahydrofuran (99.9%) was purchased from Fisher Scientific Company and used as received.
8.
LiOH monohydrate was purchased from Sigma-Aldrich and used as received. The salt is dissolved in deionized
water to form a stock solution. The stock solution was titrated with 1 N HCl (aq) using phenolphthalein as an indicator to determine the exact concentration of this stock solution. More than 0.9 equiv
LiOH (aq) can be judiciously used to consume all of the
methyl oxalate, but adding too much is detrimental to the purity of the product. The use of other alkali hydroxides is possible, and the resulting oxalates couple with similar efficiency.
2 In general, lithium and cesium oxalates have the most favorable physical properties (i.e., non-hygroscopic, non-deliquescent, and stable solid compounds) and perform well in the photoredox-catalyzed coupling reaction.
9. Hexanes (98.5%) was purchased from Fisher Scientific Company and used as received.
10. The lithium oxalate is not completely soluble in the aqueous phase because of the large hydrophobic backbone of
cedrol, so some insoluble product is observed at the interface of the layers. The second aqueous extraction dissolves this insoluble material. This poor solubility is not generally observed for lithium oxalates derived from other alcohols, but is in fact specific to
cedrol.
11. The use of a 1 L round bottom is highly recommended, as the mixture tends to bump during concentration. It is also advised to dry the sample on the rotary evaporator for at least an hour to remove as much
water as possible before placing it under high vacuum. After drying, the material can either be scraped out of the vessel or transferred to a smaller vessel by dissolving in methanol. It is important to thoroughly dry the salt under high vacuum to remove all methanol before use.
12. A reaction performed on half scale provided 1.27 g (85%) of product
2pdf. The lithium oxalate
2 is 98% pure as measured by
1H NMR using 1,3,5-trimethoxybenzene as internal standard. No melting or decomposition apparent at 360 ºC.
1H NMR
pdf(400 MHz, CD
3OD) d 0.87 (d,
J = 7.1, 3H), (1.00, (s, 3H), 1.23 (s, 3H), 1.27-1.35 (m, 1H), 1.40-1.59 (m, 5H), 1.60 (s, 3H), 1.66-1.73 (m, 2H), 1.85-1.95 (m, 2H), 2.08-2.12 (m, 2H), 2.52 (d,
J = 5.2 Hz, 1H);
13C NMR
pdf(101 MHz, CD
3OD) d: 15.8, 26.2, 26.3, 27.7, 28.9, 32.3, 34.2, 38.0, 42.1, 42.8, 44.5, 55.2, 58.1, 58.2, 88.8, 165.9, 166.7; IR (ATR) 2950, 1701, 1663, 1249 cm
-1; HRMS (ESI-TOF) (
m/
z) calculated for C
17H
25 LiO
4 [M − Li]
- 293.1753; found 293.1761; [α]
23D +27.9 (
c 1.0, MeOH).
13. The 8-mL vials (Kimble Glass Screw-Thread Sample Vials with PTFE/Silicone Septa and Open-Top Polypropylene Closure, 60942A8) were purchased from Fisher Scientific Company. The dimensions of the reaction vessel are important for maximizing surface area exposed to the light source.
14.
Benzyl acrylate was purchased from Alfa Aesar and used as received. Commercial Michael acceptors often contain ppm concentration of various radical inhibitors that are generally not detrimental to the reaction. This is consistent with the proposed photoredox mechanism that does not involve radical chain reactions.
15.
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 may be purchased from Sigma Aldrich or Strem Chemicals in high purity. The complex can alternatively be synthesized for a fraction of the price.
8a An
Organic Syntheses procedure is also available for the preparation of
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6.
8b
16.
Dimethoxyethane (99%) and
dimethylformamide (99.8%) were purchased from Fisher Scientific Company and used as received.
17. The addition of deionized
water is highly beneficial. Presumably, the
water both assists in solubilizing the oxalate salt and provides a proton source to quench the intermediate lithium enolate after radical coupling and reduction. The exact equiv of
water used is an important but is not an absolutely critical variable. A diminished isolated yield (59%) was obtained for a reaction run with 50 equiv of
water, which corresponds to a reaction solution that is roughly 10%
water by volume. As a corollary, the use of rigorously dried solvents and flame-dried glassware is generally not necessary.
18. It is important to add the deionized
water last. If the
water is added to the oxalate before the other solvents, a gel may form that impedes stirring in the reactions.
19. The reaction is moderately air sensitive. A 46%
1H NMR yield was observed when the reaction was run under an air atmosphere with no attempt to deoxygenate the reaction mixture at all.
21. Blue light from high-intensity LEDs can be damaging to eyesight. It is important that the reaction setup be surrounded by an appropriate shield to protect researchers from exposure to the light from the LED lamps. Researchers should wear blue-light blocking safety glasses when the lamps are in operation. The Submitters used Uvex Skyper Blue Computer Blocking Glasses (model #: S1933X).
22. The temperature of the reaction mixture after 24 h was measured by the use of a thermocouple to be 62 ºC, which is roughly 20 ºC warmer than the ambient air inside the cardboard box.
23. The increased temperature is generally beneficial to the reaction provided that the Michael acceptor is not particularly sensitive. If the reactions are cooled to rt by blowing a stream of rt air over them during irradiation, a 71% yield is observed by
1H NMR after 24 h.
24. As the rate of the reaction is proportional to the amount of light exposure, it is important that each vial has maximum exposure to the light source. The reactions turn brown-black within 5 minutes, then become greenish-brown after 24 h. The lithium oxalate is not completely soluble in the reaction mixture and may collect near the surface of the solution. It is helpful to briefly shake the vials once or twice during the 24 h course of the reaction to dislodge this material; all of this material should be dissolved to ensure complete reaction and to allow maximum light flux into solution. The low solubility of the lithium oxalate is not a general feature of lithium oxalates and seems unique to the cedrol-based lithium oxalate
2.
25. The purpose of the aqueous
LiCl wash is to remove traces of DMF from the product. There are some solids at the interface between the phases during the
LiCl (aq) wash. These dissolve during the subsequent wash with deionized
water.
26. Geduran Si 60 (40-63 mm) silica gel was purchased from EMD Millipore Corporation.
27. The course of the chromatography can be monitored by TLC. Coupled product
3: R
f = 0.42, 98:2 hexanes/EtOAc, visualized with KMnO stain.
Benzyl acrylate: R
f = 0.37, 98:2 hexanes/EtOAc, visualized with KMnO
4 stain.
28. A reaction performed on half scale provided 0.52 g (78%) of product
3pdf. The coupled product
3 is 99% pure as measured by
1H NMR using 1,2,4,5-tetrachlorobenzene as internal standard.
1H NMR
pdf(400 MHz, CDCl
3) δ: 0.83 (d,
J = 7.1, 3H), 0.98 (s, 3H), 1.03 (s, 3H), 1.20 (s, 3H), 1.22-1.40 (m, 6H), 1.46-1.57 (m, 4H), 1.60-1.69 (m, 2H), 1.73 (t,
J = 8.2 Hz, 1H), 1.86 (dq,
J = 11.8, 5.8 Hz, 1H), 2.08-2.17 (m, 1H), 2.23-2.32 (m, 2H), 5.11 (s, 2H), 7.40-7.30 (m, 5H);
13C NMR
pdf(101 MHz, CDCl
3) d: 15.6, 25.6, 26.9, 29.3, 29.4, 30.1, 30.4, 34.2, 36.9, 37.2, 37.6, 39.9, 42.0, 44.3, 53.9, 56.4, 57.7, 66.3, 128.3, 128.4, 128.7, 136.2, 174.7; IR (thin film): 2943, 2869, 1738, 1455, 1161 cm
-1; HRMS (FAB-TOF) (
m/
z) calculated for C
25H
36O
2 [(M+H)-H
2]
+ 367.2637; found 367.2645; [α]
23D +25.6 (
c 1.0, CHCl
3).
29. Trace amounts of
benzyl acrylate may be present in the sample. The impurity can be removed via concentration on a vacuum manifold (0.2 mmHg, 23 °C) overnight.
30. Due to the reaction's requirement for a large surface area to volume ratio for efficient exposure to visible light, the gram-scale procedure detailed here is appropriate mainly for academic research or medicinal chemistry applications. Flow-chemistry has been utilized to great effect for photoredox-catalyzed reactions
11 and should be employed for large-scale preparations.
3. Discussion
The reported method, which was developed in collaboration with the MacMillan group, allows for redox-neutral construction of quaternary carbon stereocenters by the coupling of tertiary radicals, generated from tertiary alcohol-derived oxalate salts, with electron-deficient alkenes under visible-light photoredox catalysis.
2 The most common alternative to the reported method for the generation of tertiary alkyl radicals from tertiary alcohols is the use of Barton's alkyl
N -hydroxypyridine-2-thionyl oxalates.
3 While useful for primary and secondary alcohols, Barton oxalate derivatives of tertiary alcohols are fairly unstable, which prevents their isolation, and their light sensitivity makes their use challenging. Inspired by this Barton chemistry, the Overman group described the use of
tert-alkyl
N -phthalimidoyl oxalates as precursors of tertiary radicals.
4 These radical precursors are relatively stable to visible light and can be stored at -20 ºC in a freezer indefinitely. However, the
N -phthalimidoyl oxalate moiety presents complications during purification, resulting in decomposition upon silica gel chromatography or aqueous extraction. Other synthetically useful methods for generation of tertiary radicals utilize precursor functional groups such as alkenes,
5 carboxylic acids,
6 or
N-(acyloxy)phthalimides.
7
In the example detailed here, a commercially available, sterically congested tertiary alcohol, cedrol 1, is coupled to a prototypical Michael acceptor, benzyl acrylate, to illustrate the efficiency and diastereoselective nature of the reaction in a complex setting. The resulting product is obtained as a single epimer at the newly formed quaternary carbon stereocenter in good yield using nearly equimolar amounts of the two coupling partners. The conditions reported are general and expected to be similarly efficient for a wide scope of coupling partners.
As shown in Scheme 1, the proposed mechanism of the coupling reaction involves irradiation of the heteroleptic photocatalyst
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (
4) [dF(CF
3)ppy = 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine, dtbbpy = 4,4'-di-
tert-butyl-2,2′-bipyridine] with visible light to generate a long-lived (
t = 2.3
ms) excited state *Ir
III 5, which is a strong oxidant (
E1/2red [*Ir
III/Ir
II] = +1.21 V vs. SCE in CH
3CN)8 capable of oxidizing
cedrol lithium oxalate 2 (
E1/2red = +1.28 V vs. SCE in CH
3CN for
t-BuOCOCO
2Cs)
2 via single-electron transfer (SET). After oxidation, the oxalate radical spontaneously extrudes two molecules of CO
2 in a stepwise fashion to form the tertiary alkyl radical
6. This nucleophilic carbon-centered radical
6 reacts with the electron-deficient alkene
benzyl acrylate. Finally, the reduction of the resulting adduct radical
7 (
E1/2 red = −0.59 to −0.73 V vs. SCE in MeCN)
9 by SET from the available Ir
II species
8 (
E 1/2red [Ir
III/Ir
II] = -1.37 V vs. SCE in CH
3CN)
8 followed by protonation yields coupled product
3 and regenerates ground state photocatalyst
4.