Checked by David J. Mathre, Khateeta M. Emerson, and Ichiro Shinkai.
1. Procedure
C.
(R)-(−)-2,2-Diphenylcyclopentanol 1. In a
500-mL, three-necked, round-bottomed flask, equipped with a
125-mL graduated, pressure-equalizing addition funnel,
30-mm, egg-shaped magnetic stir bar, nitrogen/vacuum adapter, and an internal temperature probe is placed
1.76 g (6.34 mmol) of the B-methyloxazaborolidine catalyst (Note
1), (Note
19), (Note
20). The apparatus is evacuated, flushed with
nitrogen, charged with
86 mL of dry THF and
6.34 mL (63.4 mmol) of borane-methyl sulfide complex, and then warmed to 40°C (internal temperature) (Note
21). In a
250-mL, three-necked, round-bottomed flask, equipped with a nitrogen/vacuum adapter and magnetic stirrer is placed
15 g (63.4 mmol) of 2,2-diphenylcyclopentanone. The flask is evacuated, flushed with
nitrogen, and charged with
111 mL of dry THF. After dissolution, the ketone solution is transferred to the addition funnel via
cannula and added dropwise over 8 hr to the stirred catalyst solution maintained at 40°C (Note
22). After complete addition, the funnel is rinsed into the reaction vessel with
10 mL of dry THF, and the resulting reaction mixture is stirred at 40°C for an additional 30 min. Finally, the reaction mixture is cooled to 0–5°C and carefully quenched by the dropwise addition of
100 mL of methanol (
CAUTION: considerable hydrogen evolution occurs after a short induction period) (Note
23). The cold bath is removed and the reaction is stirred until gas evolution ceases (Note
24). The resulting solution is poured into a
1-L, round-bottomed flask and the reaction vessel is rinsed with
50 mL of methanol. A simple distillation head is attached to the
1-L flask and 100 mL of solvent is distilled (
CAUTION: the distillate contains malodorous methyl sulfide). An additional
100 mL of fresh methanol is added and 100 mL of solvent is again distilled. The residue is cooled to room temperature and concentrated on a rotary evaporator to afford a slightly yellow oil. The oil is dissolved in
MTBE (250 mL), washed with aqueous 0.1 N aqueous
hydrochloric acid (3 × 100 mL), and the combined acidic, aqueous phases are back-extracted with
MTBE (100 mL). The combined organic phases are washed with water (100 mL) and
brine (100 mL), dried (Na
2SO
4), filtered, and concentrated on a rotary evaporator to afford
15.1 g of an off-white solid. The solid is purified by bulb-to-bulb distillation (bp
180°C/0.2 mm) to afford
14.7 g (
97%) of
(R)-(−)-2,2-diphenylcyclopentanol (92% ee) as an analytically-pure, white solid (Note
25), (Note
26). Multiple recrystallizations of the product from
hexane afford
11.3 g (
75%) of
(R)-(−)-2,2-diphenylcyclopentanol (>97% ee) (Note
26), (Note
27), (Note
28). To recover the catalyst precursor,
(S)-α,α-diphenyl-2-pyrrolidinemethanol, the acidic, aqueous phase is made basic (blue to litmus) by addition of
25 mL of aqueous 25% sodium hydroxide solution. The aqueous phase is extracted with
dichloromethane (3 × 100 mL), and the combined organic phases are washed with
brine (100 mL), dried (Na
2SO
4), filtered, and concentrated on a rotary evaporator to afford a clear oil that crystallizes under high vacuum (0.1 mm, several hours). The solid is recrystallized from
hexane to afford
1.5 g (93% recovery) of (S)-α,α-diphenyl-2-pyrrolidinemethanol as a white crystalline solid (Note
29).
2. Notes
1. All glassware was dried in an
oven (140°C) and after assembly was allowed to cool under an atmosphere of dry
nitrogen.
5.
4-Bromobutyronitrile was purchased from Aldrich Chemical Company, Inc., and was freshly distilled (bp
95–98°C, 15 mm).
6.
4-Iodobutyronitrile may also be used as a less expensive alternative available from
4-chlorobutyronitrile3 by a modification of the above procedure. The increased reactivity of the iodide, however, requires a more tedious procedure, but is provided as follows:
A.
4-Iodobutyronitrile. To a
1-L, three-necked, round-bottomed flask equipped with a mechanical stirrer and a reflux condenser is placed a solution of
70 mL (0.77 mol) of 4-chlorobutyronitrile in
420 mL of acetone. To the solution is added
123.4 g (0.82 mol) of sodium iodide, and the resulting clear solution is heated to reflux for 23 hr. Over time, the formation of large amounts of a white precipitate is observed. The resulting suspension is cooled to room temperature, filtered, and the filter cake is washed with
dichloromethane (200 mL). The combined organic layers are concentrated on a rotary evaporator. The residue is redissolved into
dichloromethane (200 mL), washed with saturated aqueous
sodium thiosulfate (Na2S2O3, 50 mL) and
brine (50 mL), dried (Na
2SO
4), and concentrated on a rotary evaporator. The resulting oil is distilled (bp
80–92°C/0.8 mm) to afford
141.6 g (
92%) of
4-iodobutyronitrile as a clear colorless oil.
B.
2-Amino-3,3-diphenyl-1-cyclopentene-1-carbonitrile. In a 1-L, three-necked, round-bottomed flask, a solution of
53.8 mL (0.38 mol) of diisopropylamine in
250 mL of dry THF is cooled to −70°C. To the solution is slowly added
118 mL of butyllithium (2.95 M in
hexane, 0.34 mol) at such a rate that the internal temperature never exceeds −50°C. The resulting solution is cooled to −70°C, and a solution of
67.5 g (0.34 mol) of diphenylacetonitrile in
250 mL of dry THF is added over 30 min forming a black solution that is stirred an additional 20 min. In a 2-L, three-necked, round-bottomed flask, a solution of
4-iodobutyronitrile (74.9 g, 0.38 mol) in
250 mL of dry THF is cooled to −77°C. Using a
Teflon cannula (0.5-cm diameter) the anion of
diphenylacetonitrile is added very rapidly to the
4-iodobutyronitrile solution (internal temperature rose by only 3°C). The resulting light-yellow solution is stirred for 80 min at −78°C, warmed to 0°C for 60 min, and allowed to stir at room temperature for 30 min. The reaction mixture is quenched with water (34 mL), diluted with
MTBE (500 mL), and washed with water (2 × 250 mL) and
brine (250 mL). The aqueous layers are back-extracted with
MTBE (200 mL), and the combined organic layers are dried (Na
2SO
4) and concentrated on a rotary evaporator. The resulting crude dinitrile is dissolved in a mixture of
tert-butyl alcohol (540 mL) and
THF (270 mL). To the solution is added
31.0 g (0.28 mol) of potassium tert-butoxide, and the suspension is heated at 60°C (internal temperature) for 2 hr. After the reaction mixture is cooled to room temperature, it is diluted with
MTBE (600 mL), and washed with water (150 mL) and
brine (3 × 150 mL). The aqueous layers are back-extracted with
MTBE (150 mL), and the combined organic layers are dried (MgSO
4) and concentrated on a rotary evaporator. The crude product is suspended in
MTBE (75 mL), cooled, filtered, and recrystallized from absolute
ethanol (600 mL) to afford
67.5 g of pure ketone. The mother liquor is concentrated on a rotary evaporator, purified by column chromatography [hexane/EtOAc (8/1, 4/1)], and crystallized from absolute
ethanol to afford
8.6 g (
9.5%) of additional material for a combined yield of
76.1 g (
84%) of analytically pure enaminonitrile as a white solid giving identical spectral data to that reported above (Anal. Calcd for C
18N
16N
2: C, 83.04; H, 6.20; N, 10.76. Found: C, 83.06; H, 6.20; N, 10.74).
7. The following reverse-phase HPLC assay was developed to monitor steps A-C. Column: YMC J'Sphere H80 (4.6 × 250 mm); eluent: 45:55 H
2O (20 mM H
3PO
4)/MeCN; flow rate: 1.0 mL/min; column temp.: 45°C; detection: UV (210 nm). Retention times: "diphenylprolinol" (1.85 min, with solvent front);
4-bromobutyronitrile (4.0 min); "enaminoamide" (6.1 min); "dinitrile" (11.4 min);
diphenylacetonitrile (12.0 min); "cyanoketone" (12.5 min);
diphenylcyclopentanol (13.1 min); "enaminonitrile" (14.4 min); "diphenylcyclopentanone" (19.5 min).
8. Kieselgel 60 (230–400 mesh) was purchased from EM Science.
9. Rather than purifying the mother liquors by column chromatography, the checkers obtained a second crop of crystals for a combined yield of
57.3 to 60.3 g (
85–89%). The checkers also note that the crude product can be used "as is" in the next step after being suspended and washed with cold MTBE.
10. The physical properties are as follows: mp
145–148°C; 1H NMR (400 MHz, CDCl
3) δ: 2.46 (dd, 2 H, J = 6.8, 5.6), 2.63 (dd, 2 H, J = 7.6, 6.3), 4.38 (br, 2 H, NH
2), 7.23–7.37 (m, 10 H);
13C NMR (100 MHz, CDCl
3) δ: 27.94, 41.48, 62.76, 76.19, 118.77, 127.08, 128.19, 128.40, 142.82, 164.78; IR (CCl
4) cm
−1: 3490 (w), 3395 (w), 3063 (w), 2954 (w), 2863 (w), 2197 (m), 1643 (s), 1595 (m); MS (EI, 70 eV) 260 (M
+, 100), 259 (31), 183 (49), 182 (36); TLC R
f = 0.38 (hexane/EtOAc, 4/1). Anal. Calcd for C
18H
16N
2: C, 83.05; H, 6.19; N, 10.76. Found: C, 83.34; H, 6.07; N, 10.84.
11. The product may sublime into the condenser causing it to become clogged. This can be prevented by periodically washing down the solids with 6 N
HCl.
12. To ensure complete consumption of the intermediate cyano ketone, the ratio of enaminonitrile to solvent volume cannot be altered.
13. Efficient stirring and heating to a vigorous reflux is crucial for complete consumption of the intermediate cyano ketone.
14. The reaction progress can be monitored by
1H NMR integration of the signals of the ketone (dt, 1.95 ppm, 2 H) and the cyano ketone intermediate (t, 3.43 ppm, 1 H) determined from a crude reaction sample following the same work-up as reported above. Spectral data for
2-cyano-5,5-diphenylcyclopentanone are as follows:
1H NMR (400 MHz, CDCl
3) δ: 2.22 (m, 1 H), 2.47 (m, 1 H), 2.70 (ddd, 1 H, J = 12.5, 9.8, 6.1), 2.90 (dt, 1 H, J
d = 12.5, J
t = 6.1), 3.43 (t, 1 H, J = 9.0), 7.15–7.40 (m, 10 H). Alternatively, high pressure liquid chromatography (HPLC) analysis may be used employing a Supelco LC-Si (5μ, 250 × 4.5 mm) column (hexane/EtOAc, 9/1, 1.5 mL/min, detector λ = 254 nm); R
t: "ketone" (4.6 min, response factor = 1.50), R
t: "cyano ketone" (16.8 min, response factor = 0.76).
15. The progress of the reaction was monitored by HPLC. The checkers found the reaction to take from 4 to 7 days to reach > 99% completion.
16. Yields ranged from 84% to 92%.
17. Rather than purifying the mother liquors by column chromatography, the checkers obtained a second crop of crystals for a combined yield of
87–95%.
18. The physical properties are as follows: mp
85–88°C; 1H NMR (400 MHz, CDCl
3) δ: 1.95 (dt, 2 H, J
d = 13.4, J
t = 7.3) 2.46 (t, 2 H, J = 7.7), 2.73 (t, 2 H, J = 6.6), 7.21–7.32 (m, 10 H);
13C NMR (100 MHz, CDCl
3) δ: 18.79, 38.07, 38.16, 62.44, 126.69, 127.96, 128.31, 142.02, 217.77; IR (CCl
4) cm
−1: 3061 (m), 3033 (m), 2969 (m), 2886 (m), 1744 (s), 1494 (s), 1446 (m), 1406 (m), 1143 (m), 1104 (m); MS (EI, 70 eV) 236 (M
+, 47), 208 (11), 180 (100), 179 (37), 178 (25), 165 (43); TLC R
f = 0.48 (hexane/EtOAc, 8/1). Anal. Calcd for C
17H
16O: C, 86.41; H, 6.82. Found: C, 86.57; H, 6.75.
19. A Baxter Diagnostics Inc. Type K Thermo-Couple Thermometer was used to monitor the internal temperature of the reaction solution.
20.
(S)-Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole was prepared from
(S)-proline in two steps according to the literature procedure
4 and purified by bulb-to-bulb distillation (170°C, 0.2 mm). The enantiomeric purity of the intermediate,
(S)-α,α-diphenyl-2-pyrrolidinemethanol, was determined to be >99% ee by chiral HPLC analysis of its corresponding
N-p-toluenesulfonamide derivative (DIACEL Chiralcel OD column;
hexane/
ethanol, 92/8; 1.0 mL/min; R
t(S) 8.6 min; R
t(R) 12.8 min). The checkers used the crystalline
β-methyloxazaborolidine-borane complex (1.84 g, 6.34 mmol) as the catalyst.
21.
Borane-methyl sulfide complex was purchased from Aldrich Chemical Company, Inc., and was used without purification.
22. Addition of the ketone solution over a 6-hr period affords almost identical results. However, variation of the reaction temperature can have a dramatic effect on product ee.
5
23. Anhydrous,
reagent-grade methyl alcohol was purchased from Mallinckrodt Inc. and used without purification.
24.
Hydrogen evolution stops after 2–3 hr; however, for convenience the reaction can be allowed to stand at room temperature overnight with no deleterious effect on yield or enantioselectivity.
25. Anal. Calcd for C
17H
18O: C, 85.67; H, 7.61. Found: C, 85.65; H, 7.63.
26. Enantiomeric excess is determined by chiral HPLC analysis (DIACEL Chiralcel OJ column;
hexane/
ethanol, 70/30; 1.0 mL/min; R
t: S-isomer (8.8 min); R
t: R-isomer (17.9 min).
27. The checkers determined enantiomeric purity by supercritical fluid chromatography (SFC) using a Chiralpak AD (4.6 × 250 mm) column. Eluent:
carbon dioxide (300 Bar); modifier:
methanol (24%); flow rate: 1.5 mL/min; detection: UV (210 nm). Retention times were as follows: "diphenylcyclopentanone" (3.9 min);
(R)-diphenylcyclopentanol (5.9 min);
(S)-diphenylcyclopentanol (10.4 min).
28. The product is recrystallized two times by dissolution in boiling
hexane (60 mL and 50 mL) and cooling to room temperature to provide 9.8 g of material with greater than 97% ee. The mother liquors are then combined, concentrated and recrystallized four times from
hexane (20 mL, 15 mL, 10 mL and 10 mL) to provide
1.5 g of additional
(R)-(−)-2,2-diphenylcyclopentanol with greater than 97% ee. The physical properties are as follows: mp
76–77°C; 1H NMR (CDCl
3, 400 MHz) δ: 1.28 (dd, 1 H, J = 4.9, 0.7), 1.55–1.75 (m, 2 H), 1.93 (m, 1 H), 2.10 (m, 1 H), 2.32 (ddd, 1 H, J = 12.9, 8.7, 3.3), 2.66 (dt, 1 H, J
t = 12.9, J
d = 8.9), 4.88 (dd, 1 H, J = 9.7, 4.8), 7.14–7.33 (m, 10 H);
13C NMR (100 MHz, CDCl
3) δ: 19.95, 31.67, 34.60, 59.71, 77.57, 125.89, 126.33, 126.92, 128.17, 128.44, 128.53, 144.26, 146.87; MS (EI, 70 eV) 239 (8), 238 (M
+, 44), 78 (12), 167 (100), 115 (16), 91 (11); IR (CCl
4) cm
−1: 3585 (m), 3061 (m), 3025 (w), 2967 (s), 2916 (w), 1495 (s), 1446 (s), 1288 (w), 1094 (m), 1074 (m), 1034 (m), 1015 (m);
[α]D26 −114.8° (EtOH,
c 1.17). Anal. Calcd for C
17H
18O: C, 85.67; H, 7.61. Found: C, 85.65; H, 7.59.
29. The solid is recrystallized by dissolution in boiling
hexane (20 mL) and cooling to 0°C to afford
1.37 g of (S)-α,α-diphenyl-2-pyrrolidinemethanol. The mother liquor is then concentrated and recrystallized from
hexane (10 mL) to afford an additional
0.13 g of material. The physical properties are as follows: mp
75–76°C; 1H NMR (400 MHz, CDCl
3) 1.58–1.74 (m, 4 H), 2.96 (m, 1 H), 3.02 (m, 1 H), 4.26 (t, 1 H, J = 7.6), 7.14–7.59 (m, 10 H).
3. Discussion
The oxazaborolidine-catalyzed
borane reduction of
2,2-diphenylcyclopentanone provides an efficient and useful alternative for the asymmetric synthesis of (R)-
1 on a preparative scale. Variation of several reaction parameters such as catalyst loading, solvent, temperature, and addition order, have led to the development of an optimized procedure for this reduction. To achieve a selectivity of >90% ee, the reaction requires the use of
10 mol% of the oxazaborolidine catalyst, which is easily prepared in two steps from natural
proline4 or in one step from commercially available
(S)-α,α-diphenylpyrrolidinemethanol. When using a smaller catalyst loading a significant decrease in selectivity is observed [5 mol% cat. provides 87% ee (R)-
1]. The
oxazaborolidine catalyst used in these experiments was purified by bulb-to-bulb distillation prior to use and quickly weighed in the open atmosphere. Examination of the purified catalyst by
1H NMR confirmed the presence of
B-methyloxazaborolidine as well as varying amounts of the hydrated adduct (approximately 7–20%).
4 Unfortunately, it is not clear whether the hydrated adduct was the result of trace amounts of water in the NMR solvent, exposure to atmospheric moisture, or simply insufficient purification. Regardless, the use of different batches of the catalyst provided reproducible results that are within experimental error [(R)-
1 with 91–94% ee]. Several solvents such as
toluene,
dichloromethane and THF have been reported to be useful in
oxazaborolidine reductions;
19 however, for the reduction of
2,2-diphenylcyclopentanone the use of THF was found to provide the highest enantioselectivity. An extremely important parameter in this reaction is temperature. The reaction displays an inverse temperature effect with respect to enantioselectivity, where decreased selectivity is observed at lower temperatures. This interesting phenomenon in oxazaborolidine-catalyzed reductions has precedents,
5 and can be attributed to the slow breakdown of the catalyst-product complex at low temperatures. The catalyst-product complex is a highly active but less selective catalyst for the reduction of the starting ketone.
20 Accumulation of this undesired intermediate can be avoided by running the reaction at higher temperatures (40°C) as well as using a slow inverse addition of the ketone to the catalyst-borane mixture.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
(+)-β-chlorodiisopinocampheylborane
β-chlorodiisopinocampheylborane
brine
(R)-(−)-2,2-DIPHENYLCYCLOPENTANOL
Methylaluminum bis-2,6-diphenylphenoxide
β-methyloxazaborolidine
ethanol (64-17-5)
hydrochloric acid,
HCl (7647-01-0)
ammonia (7664-41-7)
ethyl acetate (141-78-6)
methyl alcohol,
methanol (67-56-1)
hydrogen (1333-74-0)
sodium hydroxide (1310-73-2)
sodium bicarbonate (144-55-8)
sodium sulfate (7757-82-6)
sodium thiosulfate (7772-98-7)
nitrogen (7727-37-9)
carbon dioxide (124-38-9)
acetone (67-64-1)
carbon (7782-42-5)
pyridine (110-86-1)
toluene (108-88-3)
Benzophenone (119-61-9)
sodium (13966-32-0)
4-chlorobutyronitrile (628-20-6)
Diphenylacetic acid (117-34-0)
sodium iodide (7681-82-5)
dichloromethane (75-09-2)
borane (7440-42-8)
methyl sulfide (75-18-3)
sodium amide (7782-92-5)
butyllithium (109-72-8)
proline,
(S)-proline (147-85-3)
Tetrahydrofuran (109-99-9)
4-bromobutyronitrile (5332-06-9)
Diphenylacetonitrile (86-29-3)
DIPHENYLIODONIUM IODIDE (2217-79-0)
hexane (110-54-3)
tert-butyl alcohol (75-65-0)
cyano ketone (1115-12-4)
lithium diisopropylamide (4111-54-0)
diisopropylamine (108-18-9)
Cyclopentanol, 2,2-diphenyl-, (R)- (126421-67-8)
2-Amino-3,3-diphenyl-1-cyclopentene-1-carbonitrile (3597-67-9)
tert-butyl methyl ether (1634-04-4)
potassium tert-butoxide (865-47-4)
2,2-Diphenylcyclopentanone (15324-42-2)
B-methyloxazaborolidine
1,1-dicyano-4,4-diphenylbutane
4-Iodobutyronitrile (6727-73-7)
diphenylcyclopentanol
2-cyano-5,5-diphenylcyclopentanone (2674-76-2)
(S)-Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (112022-81-8)
N-p-toluenesulfonamide (70-55-3)
2-(acetoxy)vinyl ether
5,5-diphenyl-2-cyclopentenone
diphenyliodonium fluoride
oxazaborolidine
(S)-α,α-diphenyl-2-pyrrolidinemethanol
(R)-diphenylcyclopentanol
(S)-diphenylcyclopentanol
(R)-2,2-diphenyl-1-ethenoxycyclopentane
(S)-α,α-diphenylpyrrolidinemethanol
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