Ligand- and Brønsted Acid/Base-Switchable Reaction ...
Transcript of Ligand- and Brønsted Acid/Base-Switchable Reaction ...
S1
Ligand- and Brønsted Acid/Base-Switchable Reaction Pathways in
Gold(I)-Catalyzed Cycloisomerizations of Allenoic Acids
Sachin Handa,a Sri S. Subramanium,a Aaron A. Ruch,a,b Joseph M. Tanskic and LeGrande M. Slaughter*a,b
aDepartment of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078
bDepartment of Chemistry, University of North Texas, Denton, TX 76203
cDepartment of Chemistry, Vassar College, Poughkeepsie, New York 12604
SUPPLEMENTARY INFORMATION
Synthesis of allenoic acid substrates p. S2
X-ray crystallographic data and procedures p. S12
References p. S16
Kinetic plots P. S17
1H and 13C NMR spectra p. S27
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2015
S2
SYNTHESIS OF ALLENOIC ACID SUBSTRATES (1a-k)
Substrates 1a and 1j were synthesized by literature procedures.1 Substrates 1b and 1c
were synthesized by a modified procedure starting from the corresponding cycloalkanones
(Schemes S1 and S2).2 Substrates 1d-i and 1k were synthesized according to Scheme S2,2,3
starting from allenic esters 14a1a or 14b. Pd(PPh3)4 (min. 99.5%, min. 9% wt/wt Pd) was
purchased from Chem-Impex International, Inc.
Scheme S1. Synthesis of precursors to allenoic acid substrates.
Scheme S2. Synthesis of allenoic acid substrates.
1-(3-((tert-Butyldimethylsilyl)oxy)prop-1-yn-1-yl)cyclopentanol (10b). To a well-
dried two neck round-bottom flask equipped with a septum and nitrogen balloon, 70 mL dry
THF and tert-butyldimethyl(prop-2-yn-1-yloxy)silane (5.0 g, 29 mmol) were added. The
reaction mixture was cooled to −78 °C, and then 11.7 mL of nBuLi (2.5 M in hexanes; 29 mmol)
S3
was added slowly over 5 min via syringe. The reaction mixture was stirred for 10 min at −78 °C.
Cyclopentanone (2.60 mL, 29.4 mmol) was then slowly added to the reaction mixture over 2
min. The reaction mixture was stirred for 30 min at −78 °C and then for an additional 50 min at
25 °C. The reaction mixture was quenched with 0.5 M aqueous NH4Cl and then extracted twice
with 100 mL of diethyl ether. The organic layer was separated and dried over anhydrous sodium
sulfate. The solvent was removed on a rotary evaporator to obtain a viscous oil, which was
purified by flash column chromatography on silica. Rf 0.45 (1:9 diethyl ether/hexanes); colorless
oil, yield 7.0 g (94%). 1H NMR (400 MHz, CDCl3): δ 4.35 (s, 2H), 2.04 (br. s, 1H, OH), 1.89-
1.82 (m, 2H), 1.72-1.59 (m, 2H), 1.58-1.46 (m, 4H), 0.90 (s, 9H), 0.12 (s, 6H) ppm. 13C NMR
(101 MHz, CDCl3): δ 88.6, 81.9, 74.6, 51.9, 42.4, 26.0, 23.5, −4.9 ppm. IR (neat): ν 3274, 2359,
1104, 1070 cm-1. HRMS (ESI-orbitrap, [C14H26O2Si + H]+) calcd 255.1780, found m/z
255.1784.
1-(3-((tert-Butyldimethylsilyl)oxy)prop-1-yn-1-yl)cycloheptanol (10c). To a well-
dried two neck round-bottom flask equipped with a septum and nitrogen balloon, 50 mL dry
THF and tert-butyldimethyl(prop-2-yn-1-yloxy)silane (5.0 g, 29 mmol) were added. The
reaction mixture was cooled to −78 °C, and then 11.7 mL of nBuLi (2.5 M in hexanes; 29 mmol)
was added slowly over 5 min via syringe. The reaction mixture was stirred for 45 min at −78 °C.
Cycloheptanone (3.50 mL, 29.7 mmol) was then slowly added to the reaction mixture over 2
min. The reaction mixture was stirred for 1 h at −78 °C and then for an additional 2 h at 25 °C.
The reaction mixture was quenched with 0.5 M aqueous NH4Cl and then extracted twice with
100 mL of diethyl ether. The organic layer was separated and dried over anhydrous sodium
sulfate. The solvent was removed on a rotary evaporator to obtain a viscous oil. After further
drying under high vacuum, an analytically pure white solid was obtained. White solid, m.p. 62-
63 °C, yield 7.40 g (89%). 1H NMR (400 MHz, CDCl3): δ 4.35 (s, 2H), 2.01 (d, J = 8.0 Hz, 1H),
1.98 (d, J = 8.0 Hz, 1H), 1.85-1.77 (m, 3H), 1.67-1.49 (m, 7H), 0.91 (s, 9H), 0.12 (s, 6H). 13C
NMR (101 MHz, CDCl3): δ 89.7, 82.1, 71.8, 51.9, 43.2, 28.3, 25.9, 22.3, −4.9. IR (neat): ν
3272, 2358, 1101, 1071 cm-1. HRMS (ESI-orbitrap, [C16H30O2Si + H]+) calcd 283.2093, found
m/z 283.2101.
tert-Butyldimethyl[(3-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)prop-2-yn-1-
yl)oxy]silane (11b). To a solution of 10b (3.17 g, 12.4 mmol) in 5 mL of dry dichloromethane
was added TsOH·H2O (12 mg, 0.063 mmol), and the reaction mixture was stirred for 10 min at 0
S4
°C. 3,4-Dihydro-2H-pyran (8.8 mL, 96 mmol) was then added, and the reaction mixture was
stirred for 12 h at 25 °C. The reaction mixture was quenched with 5 mL of NEt3 and then stirred
for an additional 20 min at 25 °C. The solvent was evaporated to obtain a viscous yellow oil.
The crude material was dissolved in 200 mL of diethyl ether and then washed sequentially with
0.5 M NaHCO3, 0.05 M cold HCl, and water. The organic layer was separated and dried over
anhydrous sodium sulfate. The solvent was again removed, and the crude product was purified
by flash chromatography on silica. Rf 0.55 (1:19 diethyl ether/hexanes); viscous yellow oil, yield
3.37 g (80%). 1H NMR (400 MHz, CDCl3): δ 5.04 (dd, J = 5.6, 3.2 Hz, 1H), 4.35 (s, 2H), 3.94-
3.89 (m, 1H), 3.53-3.47 (m, 1H), 2.24-2.18 (m, 1H), 2.00-1.47 (m, 13H), 0.91 (s, 9H), 0.12 (s,
6H). 13C NMR (101 MHz, CDCl3): δ 96.7, 86.6, 83.3, 81.0, 63.6, 52.0, 41.4, 40.0, 32.1, 25.9,
25.6, 23.4, 23.0, 20.5, 18.4, −4.9. IR (neat): ν 3276, 2368, 1111, 1070 cm-1. HRMS (ESI-
orbitrap, [C19H34O3Si + H]+) calcd 339.2355, found m/z 339.2361.
tert-Butyldimethyl[(3-(1-((tetrahydro-2H-pyran-2-yl)oxy)cycloheptyl)prop-2-yn-1-
yl)oxy]silane (11c). This compound was synthesized from 10c (10.0 g, 35.4 mmol) by the same
procedure used to prepare 11b. Rf 0.67 (1:19 diethyl ether/hexanes); viscous yellow oil, yield
9.34 g (72%). 1H NMR (400 MHz, CDCl3): δ 5.05 (dd, J = 6.4, 3.6 Hz, 1H), 4.36 (s, 2H), 3.96-
3.91 (m, 1H), 3.50-3.46 (m, 1H), 2.02-1.95 (m, 3H), 1.89-1.82 (m, 2H), 1.71-1.45 (m, 13H), 0.90
(s, 9H), 0.12 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 96.0, 87.4, 83.8, 78.4, 63.7, 51.9, 42.2,
40.8, 32.4, 28.8, 25.9, 25.6, 22.2, 22.0, 20.7, 18.3, −4.9. IR (neat): ν 3277, 2357, 1101, 1076 cm-
1. HRMS (ESI-orbitrap,[C21H38O3Si + H]+) calcd 367.2668, found m/z 367.2667.
3-[1-((Tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl]prop-2-yn-1-ol (12b). To a
solution of 11b (3.94 g, 11.6 mmol) in 50 mL of THF was added [nBu4N]F (3.34 g, 12.8 mmol),
and the reaction mixture was stirred for 12 h at 25 °C. After complete consumption of the
starting material as monitored by TLC, the reaction mixture was diluted with 100 mL of ethyl
acetate and then washed thoroughly with water. The organic layer was separated and dried over
anhydrous sodium sulfate. The crude material was purified by column chromatography on silica.
Rf 0.48 (1:4 acetone/hexanes); viscous yellow oil, yield 1.8 g (69%). 1H NMR (400 MHz,
CDCl3): δ 5.05 (dd, J = 4.8, 3.2 Hz, 1H), 2.28 (d, J = 6.4 Hz, 2H), 3.95-3.89 (m, 1H), 3.54-3.49
(m, 1H), 2.37-2.30 (m, 1H), 2.22-2.15 (m, 1H), 2.01-1.88 (m, 2H), 1.85-1.75 (m, 4H), 1.74-1.64
(m, 3H), 1.58-1.48 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 96.3, 87.4, 83.0, 80.7, 63.3, 51.2,
S5
41.2, 40.3, 32.0, 25.5, 23.4, 23.0, 20.1. IR (neat): ν 3312, 3257, 2359, 1103, 1066 cm-1. HRMS
(ESI, [C13H20O3 + Na]+) calcd 247.1310, found m/z 247.1313.
3-[1-((Tetrahydro-2H-pyran-2-yl)oxy)cycloheptyl]prop-2-yn-1-ol (12c). This
compound was synthesized from 11c (11.6 g, 31.7 mmol) by the same procedure used to prepare
12b. Rf 0.50 (1:4 acetone/hexanes); viscous yellow oil, yield 6.0 g (75%). 1H NMR (400 MHz,
CDCl3): δ 5.08 (dd, J = 5.2, 3.6 Hz, 1H), 4.30 (s, 2H), 3.98-3.92 (m, 1H), 3.53-3.47 (m, 1H),
2.11 (br. s, 1H, OH), 2.06-1.95 (m, 2H), 1.96 (d, J = 7.6 Hz, 1H), 1.90-1.79 (m, 2H), 1.72-1.57
(m, 3H), 1.56-1.46 (m, 10H). 13C NMR (101 MHz, CDCl3): δ 95.7, 88.6, 83.5, 78.1, 63.3, 51.3,
42.0, 41.2, 32.3, 28.7, 28.2, 25.6, 22.3, 22.1, 19.3. IR (neat): ν 3311, 3258, 2358, 1101, 1066
cm-1. HRMS (ESI-orbitrap, [C15H24O3 + Na]+) calcd 275.1623, found m/z 275.1630.
3-Cyclopentylideneprop-2-en-1-ol (13b). A well-dried 500 mL two-neck round bottom
flask was fitted with a condenser topped with a nitrogen balloon, and 200 mL of dry THF was
added by syringe. The flask contents were cooled to 0 °C under inert atmosphere, and LiAlH4
(2.33 g, 61.6 mmol) was added under nitrogen counterflow. The slurry was stirred for 5 min,
and then a solution of 12b (6.9 g, 31 mmol) in 20 mL of dry THF was added dropwise via
syringe. The reaction mixture was allowed to warm to 25 °C and then heated at reflux for 45
min. The mixture was then cooled to 0 °C, and the unreacted LiAlH4 was quenched with 5.0 M
NaOH. The quenched mixture was stirred for 30 min at 25 °C and then diluted with 200 mL of
diethyl ether and filtered through celite. The organic layer was dried over anhydrous sodium
sulfate. The solvent was removed on a rotary evaporator to obtain analytically pure material as a
colorless oil. Rf 0.38 (1:4 acetone/hexanes); colorless oil, yield 2.8 g (73%). 1H NMR (400
MHz, CDCl3): δ 5.33-5.26 (m, 1H), 4.08 (d, J = 5.2 Hz, 2H), 2.40-2.36 (m, 4H), 1.71-1.65 (m,
4H), 1.55 (br s, 1H, OH). 13C NMR (151 MHz, CD2Cl2): δ 196.4, 107.1, 92.7, 61.3, 31.7, 27.4.
IR (neat) ν 3311 (m), 1961 (w), 1901 (w) cm-1. HRMS (ESI, [C8H12O + H]+) calcd 125.0966,
found m/z 125.0954.
3-Cycloheptylideneprop-2-en-1-ol (13c). This compound was synthesized from 12c
(4.0 g, 16 mmol) by the same procedure used to prepare 13b. Rf 0.39 (1:4 acetone/hexanes);
colorless oil, yield 1.8 g (75%). 1H NMR (400 MHz, CDCl3): δ 5.20-5.16 (m, 1H), 4.06 (t, J =
6.0 Hz, 2H), 2.27-2.24 (m, 4H), 1.65-1.51 (m, 8H). 13C NMR (101 MHz, CDCl3): δ 200.7,
108.0, 89.7, 61.2, 32.6, 29.4, 28.6. HRMS (ESI-orbitrap, [C10H16O + Na]+) calcd 175.1099,
found m/z 175.1101.
S6
3-Cyclopentylideneallyl benzoate (14b). This compound was prepared by a
modification of literature procedures used to prepare 14a.1a Under dry conditions, a solution of
allenol 13b (1.90 g, 15.2 mmol) in 50 mL of dry CH2Cl2 was placed in a two-necked round
bottom flask. The solution was cooled to 0 °C, and pyridine (1.4 mL, 17 mmol) and a catalytic
amount of DMAP (186 mg, 1.52 mmol) were added followed by slow syringe addition of
benzoyl chloride (2.6 mL, 22 mmol). The reaction mixture was then warmed to RT and stirred
for an additional 12 h. After complete consumption of starting material as monitored by TLC,
the solvent was evaporated under reduced pressure. The resulting oily residue was dissolved in
50.0 mL CH2Cl2 and then sequentially washed with cold 0.5 M HCl (2 x 50 mL) and saturated
aqueous NaHCO3. The organic layer was separated and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure to obtain a pale yellow viscous oil, which was
purified by flash column chromatography on silica. Rf 0.52 (8:92 diethyl ether/hexanes); yellow
oil, yield 3.13 g (90%). 1H NMR (400 MHz, CDCl3): δ 8.08-8.05 (m, 2H), 7.57-7.53 (m, 1H),
7.35 (dt, J = 7.6, 1.6 Hz, 2H), 5.35-5.28 (m, 1H), 4.79 (d, J = 6.8 Hz, 2H), 2.40-2.36 (m, 4H),
1.67-1.61 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 198.8, 166.5, 133.0, 130.1, 129.7, 128.4,
106.1, 87.4, 63.8, 31.3, 27.1. IR (neat): 2958 (m), 2867 (m), 1972 (w), 1715 (s), 1450 (m) cm-
1. HRMS (ESI-orbitrap, [C15H16O2 + H]+) calcd 229.1229, found m/z 229.1222.
3-Cycloheptylideneallyl benzoate (14c). This compound was prepared from 13c (1.30
g, 8.51 mmol) by the same procedure used to synthesize 14b. The compound was highly
unstable over silica and was used immediately after moderate purification. Rf 0.56 (8:92 diethyl
ether/hexanes); colorless oil, yield 1.95 g (89%). 1H NMR (400 MHz, CDCl3): δ 8.08-8.06 (m,
2H), 7.55-7.53 (m, 1H), 7.43 (dt, J = 8.0, 1.6 Hz, 2H), 5.24-5.19 (m, 1H), 4.77 (d, J = 6.4 Hz,
2H), 2.29-2.24 (m, 4H), 1.63-1.57 (m, 4H), 1.54-1.49 (m, 4H). 13C NMR (101 MHz, CDCl3): δ
203.3, 166.5, 132.9, 130.6, 129.8, 128.4, 106.9, 84.7, 63.9, 32.3, 29.4, 28.4. IR (neat): 3068
(w), 2923 (m), 2850 (m), 1960 (w), 1717 (s), 1601 (w), 1584 (w), 1451 (m). HRMS (ESI-
orbitrap, [C17H20O2 + H]+) calcd 257.1542, found m/z 257.1551.
General procedure for the synthesis of 2,2-diaryl allene methyl esters (15b-i,k). A
modification of literature procedures was used.1a,4 Into an oven-dried 100 mL, two-neck round
bottom flask containing the corresponding methyl diarylacetate56 (1.0 equiv relative to 14) was
added 50.0 mL of dry THF via vacuum distillation. The reaction mixture was cooled to −78 °C,
and lithium hexamethyldisilazide (1.18 g, 7.08 mmol) was added under argon counterflow. The
S7
reaction mixture was stirred at −78 °C under argon for approximately 2 h. Meanwhile, 100 mL
of dry THF was distilled under vacuum into another oven-dried 250 mL two-neck round bottom
flask, and a solution of 14 (3.0-5.0 mmol) in dry THF was added via syringe followed by
addition of Pd(PPh3)4 (5 mol%). This mixture was stirred at room temperature for 2 h, then
cooled to −78 °C and transferred via cannula into the vessel containing the cold (−78 °C)
solution of lithiated methyldiaryl acetate. The resulting mixture was allowed to warm slowly to
room temperature and stirred for 12 h. The mixture was then diluted with 100 mL of ethyl
acetate and sequentially washed with 0.5 M NaHCO3 and water. The organic layer was
separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure to obtain the crude product, which was purified by flash column chromatography on
silica.
Methyl-5-cyclopentylidene-2,2-diphenylpent-4-enoate (15b). Because of inseparable
impurities, compound was used as obtained for the next step without further purification.
Viscous oil, yield 1.12 g (82%). 1H NMR (400 MHz, CDCl3): δ 7.34-7.23 (m, 10H), 7.87-7.79
(m, 1H), 3.70 (s, 3H), 3.10 (d, J = 7.2 Hz, 2H), 2.15-2.11 (m, 4H), 1.59-1.54 (m, 4H).
Methyl-5-cycloheptylidene-2,2-diphenylpent-4-enoate (15c). Rf 0.55 (1:9
acetone/hexanes); yellow viscous oil, yield 0.95 g (89%). 1H NMR (400 MHz, CDCl3): δ 7.32-
7.22 (m, 10H), 4.75-4.69 (m, 1H), 3.70 (s, 3H), 3.10 (d, J = 7.2 Hz, 2H), 2.12-1.99 (m, 4H),
1.55-1.46 (m, 8H). 13C NMR (101 MHz, CDCl3): δ 203.9, 174.7, 142.6, 129.2, 127.9, 126.8,
103.8, 84.3, 60.7, 52.5, 39.6, 32.2, 29.4, 28.5. HRMS (ESI-orbitrap, [C25H28O2 + H]+) calcd
361.2167, found m/z 361.2165.
Methyl-2,2-bis(4-chlorophenyl)-5-cyclohexylidenepent-4-enoate (15d). Rf 0.59 (1:9
acetone/hexanes); yellow viscous oil, yield 1.20 g (78%). 1H NMR (400 MHz, CDCl3): δ 7.28-
7.24 (m, 4H), 7.21-7.18 (m, 4H), 4.68-4.63 (m, 1H), 3.70 (s, 3H), 3.03 (d, J = 7.2 Hz, 2H), 1.88-
1.87 (m, 4H), 1.53-1.44 (m, 6H). 13C NMR (101 MHz, CDCl3): δ 200.8, 173.9, 140.8, 133.1,
130.6, 128.2, 102.3, 83.83, 59.9, 52.7, 39.5, 31.2, 27.4, 26.1. HRMS (ESI, [C24H24Cl2O2 + H]+)
calcd 415.1232, found m/z 415.1228.
Methyl-2,2-bis(4-chlorophenyl)-5-cyclopentylidenepent-4-enoate (15e). Rf 0.56 (1:9
acetone/hexanes); yellow viscous oil, yield 1.10 g (79%). 1H NMR (400 MHz, CDCl3): δ 7.27-
7.23 (m, 4H), 7.19-7.15 (m, 4H), 4.79-4.72 (m, 1H), 3.68 (s, 3H), 3.01 (d, J = 7.6 Hz, 2H), 2.15-
2.08 (m, 4H), 1.58-1.55 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 199.6, 173.9, 140.8, 133.1,
S8
130.5, 128.2, 103.7, 86.5, 59.8, 52.7, 39.2, 31.0, 27.1. HRMS (ESI, [C23H22Cl2O2 + Na]+) calcd
423.0895, found m/z 423.0889.
Methyl-5-cyclohexylidene-2,2-bis(2,3-dihydrobenzofuran-5-yl)pent-4-enoate (15f).
Rf 0.49 (3:7 ethyl acetate/hexanes); yellow viscous oil, yield 1.75 g (82%). 1H NMR (400 MHz,
CDCl3): δ 7.12-7.11 (m, 2H), 7.01 (dd, J = 8.8, 1.6 Hz, 2H), 6.69 (d, J = 8.4, Hz, 2H), 4.71-4.67
(m, 1H), 4.55 (t, J = 8.8 Hz, 4H), 3.69 (s, 3H), 3.16 (t, J = 8.8 Hz, 4H), 3.02 (d, J = 7.6 Hz, 2H),
1.94-1.92 (m, 4H), 1.55-1.44 (m, 6H). 13C NMR (101 MHz, CDCl3): δ 200.5, 175.4, 158.9,
135.1, 129.0, 126.5, 125.8, 108.5, 101.8, 84.9, 71.5, 59.7, 52.4, 40.2, 31.3, 30.0, 27.5, 26.3.
HRMS (ESI, [C28H30O4 + Na]+) calcd 453.2042, found m/z 453.2036.
Methyl-5-cyclopentylidene-2,2-bis(2,3-dihydrobenzofuran-5-yl)pent-4-enoate (15g).
Rf 0.45 (3:7 ethyl acetate/hexanes); yellow viscous oil, yield 1.12 g (79%). 1H NMR (400 MHz,
CDCl3): δ 7.12-7.11 (m, 2H), 7.01 (dd, J = 8.4, 1.6 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 4.84-4.78
(m, 1H), 4.56 (t, J = 8.8 Hz, 4H), 3.69 (s, 3H), 3.17 (t, J = 8.8 Hz, 4H), 3.02 (d, J = 7.6 Hz, 2H),
2.20-2.16 (m, 4H), 1.61-1.57 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 199.3, 175.4, 158.9,
135.1, 128.9, 126.5, 125.8, 108.4, 103.1, 87.5, 71.5, 59.7, 52.4, 39.8, 30.9, 30.0, 27.1. HRMS
(ESI, [C27H28O4 + Na]+) calcd 439.1885, found m/z 439.1880.
Methyl-9-(3-cyclohexylideneallyl)-9H-xanthene-9-carboxylate (15h). Rf 0.48 (1:9
acetone/hexanes); yellow viscous oil, yield 1.20 g (87%). 1H NMR (400 MHz, CDCl3): δ 7.24-
7.20 (m, 2H), 7.16 (dd, J = 7.6, 1.2 Hz, 2H), 7.07-7.01 (m, 4H), 4.41-4.36 (m, 1H), 3.59 (s, 3H),
2.95 (d, J = 7.6 Hz, 2H), 1.61-1.53 (m, 4H), and 1.36-1.27 (m, 6H). 13C NMR (101 MHz,
CDCl3): δ 201.2, 174.5, 150.8, 134.0, 133.8, 128.6, 127.3, 123.2, 121.4, 116.7, 101.9, 82.5, 52.9,
50.5, 42.1, 31.1, 27.3, 26.1. HRMS (ESI, [C24H24O3 + Na]+) calcd 383.1623, found m/z
383.1622.
Methyl-9-(3-cyclopentylideneallyl)-9H-xanthene-9-carboxylate (15i). Rf 0.46 (1:9
acetone/hexanes); yellow viscous oil, yield 1.20 g (89%). 1H NMR (400 MHz, CDCl3): δ 7.24-
7.16 (m, 4H), 7.06-7.01 (m, 4H), 4.61-4.53 (m, 1H), 3.58 (s, 3H), 2.99 (d, J = 6.8 Hz, 2H), 1.92-
1.83 (m, 2H), 1.71-1.62 (m, 2H), 1.45-1.41 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 199.7,
174.4, 150.8, 134.0, 133.8, 128.6, 127.2, 123.3, 121.5, 116.7, 103.8, 85.3, 52.9, 50.2, 41.0, 30.7,
26.9. HRMS (ESI, [C23H22O3 + Na]+) calcd 369.1467, found m/z 369.1464.
Methyl-5-cyclohexylidene-2-(3-methoxyphenyl)-2-phenylpent-4-enoate (15k). Due to
inseparable impurities, the compound was only moderately purified by flash column
S9
chromatography and was used as such for the next step. Rf 0.55 (3:7 diethyl ether/hexanes);
yellow viscous oil, yield 1.12 g (70%; per 1H NMR). 1H NMR (400 MHz, CDCl3): δ 7.33-7.18
(m, 6H), 6.86-6.75 (m, 3H), 4.74-4.68 (m, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.11-3.01 (m, 2H),
1.88-1.86 (m, 4H), 1.51-1.41 (m, 6H).
2-(3-Methoxyphenyl)-2-phenylacetic acid (16). This compound was prepared
according to the literature procedure via the corresponding diaryl acetonitrile.6a,6b Full
characterization data of 16 have not been previously reported. Rf 0.39 (4:19 diethyl
ether/hexanes); colorless oil, yield 1.98 g (93%). 1H NMR (400 MHz, CDCl3): δ 11.1 (br. s, 1H,
COOH), 7.34-7.23 (m, 6H), 6.92 (dd, J = 7.6, 0.8 Hz, 1H), 6.88 (t, J = 2.0 Hz, 1H), 6.82 (ddd, J
= 8.0, 2,8, 0.8 Hz, 1H), 5.02 (s, 1H), 3.77 (s, 3H). 13C NMR (101 MHz, CDCl3): δ177.8, 159.9,
139.5, 137.9, 129.8, 129.5, 128.8, 127.7, 121.2, 114.8, 112.9, 57.0, 55.4. IR (neat): 3045, 2955
cm-1. HRMS (ESI, [C15H14O3 + Na]+) calcd 265.0841, found m/z 265.0844.
Methyl-2-(3-methoxyphenyl)-2-phenylacetate (17). The compound was prepared from
16 via Fischer esterification. Analytical data were in agreement with the literature.6c,7
General procedure for synthesis of allenoic acid substrates (1b-i,k). Into a 100 mL
two-neck round bottom flask fitted with a condenser was added a solution of allene ester 15 (2.1
– 2.9 mmol) in 30 mL of ethanol. Aqueous 2.0 M NaOH (30 mL) was added, and the reaction
mixture was heated at reflux for 12 h. The reaction mixture was then cooled to 25 °C and diluted
with 20 mL of water. This mixture was washed with 50 mL of hexanes. The aqueous layer was
separated and washed twice more with 10 mL portions of hexanes. The aqueous layer was
neutralized with 0.5 M HCl to obtain a turbid solution containing the desired compound. The
aqueous layer was extracted twice with CH2Cl2 (15 mL). The organic layer was separated and
dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to
obtain the crude product, which was purified by flash column chromatography on silica.
5-Cyclopentylidene-2,2-diphenylpent-4-enoic acid (1b).3 Rf 0.35 (1:4 ethyl
acetate/hexanes); white crystalline solid, m.p. 153-154 °C (reported1b 129-132 °C), yield 0.80 g
(89%). Spectroscopic data were in agreement with the literature.1b
5-Cycloheptylidene-2,2-diphenylpent-4-enoic acid (1c). Rf 0.55 (1:4 ethyl
acetate/hexanes); white crystalline solid, m.p. 68-69 °C, yield 0.78 g (81%). 1H NMR (400
MHz, CDCl3): δ 11.1 (br s, 1H, COOH), 7.34-7.23 (m, 10H), 4.74-4.69 (m, 1H), 3.08 (d, J = 7.6
Hz, 2H), 2.09-1.95 (m, 4H), 1.51-1.43 (m, 8H). 13C NMR (101 MHz, CDCl3): δ.204.1, 179.3,
S10
142.1, 129.4, 129.2, 128.0, 127.1, 104.0, 84.0, 60.6, 39.4, 32.1, 29.5, 28.5. IR (neat): ν 2919
(m), 2952 (m), 1960 (w), 1759 (s) 1689 (s), 1495 (m) cm-1. HRMS (ESI-orbitrap, [C24H26O2 +
Na]+) calcd 369.1830, found m/z 369.1820.
2,2-Bis(4-chlorophenyl)-5-cyclohexylidenepent-4-enoic acid (1d). Rf 0.57 (1:4 ethyl
acetate/hexanes); white crystalline solid, m.p. 157-158 °C, yield 0.80 g (87%). 1H NMR (400
MHz, CDCl3): δ 11.4 (br. s, 1H, COOH), 7.27-7.20 (m, 8H), 4.67-4.63 (m, 1H), 3.00 (d, J = 7.2
Hz, 2H), 1.90-1.78 (m, 4H), 1.46-1.39 (m, 6H). 13C NMR (101 MHz, CDCl3): δ 201.0, 179.1,
140.2, 133.4, 130.7, 128.3, 102.6, 83.6, 59.8, 39.3, 31.1, 27.3, 26.1. IR (neat): ν 3062 (br), 2918
(m), 2851 (w), 1965 (w), 1690 (s), 1490 (s) cm-1. HRMS (ESI-orbitrap, [C23H22Cl2O2 + Na]+)
calcd 423.0894, found m/z 423.0896.
2,2-Bis(4-chlorophenyl)-5-cyclopentylidenepent-4-enoic acid (1e).3 Rf 0.53 (1:4 ethyl
acetate/hexanes); white crystalline solid, m.p. 122-124 °C (decomp), yield 0.80 g (88%). 1H
NMR (400 MHz, CDCl3): δ 11.1 (br. s, 1H, COOH), 7.27-7.19 (m, 8H), 4.79-4.73 (m, 1H), 3.00
(d, J = 7.2 Hz, 2H), 2.12-2.05 (m, 4H), 1.57-1.51 (m, 4H). 13C NMR (101 MHz, CDCl3): δ
199.8, 178.8, 140.2, 133.4, 130.7, 128.3, 103.9, 86.3, 59.7, 39.1, 30.9, 27.0. IR (neat): ν 3060
(br), 2917 (m), 2853 (w), 1962 (w), 1691 (s), 1491 (s) cm-1. HRMS (ESI-orbitrap, [C22H20Cl2O2
+ Na]+) calcd 409.0738, found m/z 409.0738.
5-Cyclohexylidene-2,2-bis(2,3-dihydrobenzofuran-5-yl)pent-4-enoic acid (1f). Rf
0.33 (3:2 ethyl acetate/hexanes); viscous yellow oil, yield 0.70 g (66%). 1H NMR (400 MHz,
CDCl3): δ 10.5 (br. s, 1H, COOH), 7.21-7.05 (m, 4H), 6.71-6.66 (m, 2H), 4.73-4.68 (m, 1H),
4.59-4.51 (m, 4H), 3.23-3.13 (m, 4H), 3.03-2.88 (m, 2H), 1.97-1.89 (m, 4H), 1.52-1.41 (m, 6H). 13C NMR (101 MHz, CDCl3): δ.200.7, 159.1, 134.5, 129.1, 126.6, 125.9, 108.5, 102.0, 84.6,
71.5, 59.5, 40.1, 31.3, 30.0, 27.5, 26.3. IR (neat): ν 3033 (br), 2919 (m), 2855 (w), 1969 (w),
1699 (s), 1491 (s) cm-1. HRMS (ESI-orbitrap, [C27H28O4 + Na]+) calcd 439.1885, found m/z
439.1883.
5-Cyclopentylidene-2,2-bis(2,3-dihydrobenzofuran-5-yl)pent-4-enoic acid (1g). Rf
0.36 (3:2 ethyl acetate/hexanes); viscous yellow oil, yield 0.55 g (65%). 1H NMR (400 MHz,
CDCl3): δ 11.2 (br. s, 1H, COOH), 7.16-7.12 (m, 2H), 7.06 (dt, J = 8.4, 2.0 Hz, 2H), 6.70 (d, J =
8.8, Hz, 2H), 4.84-4.79 (m, 1H), 4.56 (t, J = 8.8 Hz, 4H), 3.17 (t, J = 8.8 Hz, 4H), 3.02 (d, J = 7.2
Hz, 2H), 2.16 (sextet, J = 3.2 Hz, 4H), 1.61-1.56 (m, 4H). 13C NMR (101 MHz, CDCl3): δ
199.5, 159.1, 134.5, 129.1, 126.6, 126.0, 126.0, 108.5, 103.3, 87.3, 71.5, 59.5, 39.7, 30.9, 30.0,
S11
27.1. IR (neat): ν 2959 (br), 2921 (m), 2856 (w), 1968 (w), 1697 (s), 1490 (s) cm-1. HRMS
(ESI-orbitrap, [C26H26O4 + Na]+) calcd 425.1729, found m/z 425.1730.
9-(3-Cyclohexylideneallyl)-9H-xanthene-9-carboxylic acid (1h).3 Rf 0.53 (1:4 ethyl
acetate/hexanes); white solid, m.p. 64-65 °C, yield 0.80 g (80%). 1H NMR (400 MHz, CDCl3): δ
11.2 (br s, 1H, COOH), 7.24-7.20 (m, 4H), 7.06-7.00 (m, 4H), 4.43-4.39 (m, 1H), 2.92 (d, J =
6.8 Hz, 2H), 1.61-1.49 (m, 4H), 1.38-1.24 (m, 6H). 13C NMR (101 MHz, CDCl3): δ 201.2,
179.0, 150.9, 128.9, 127.6, 123.3, 120.8, 116.8, 102.1, 82.5, 50.2, 40.8, 31.0, 27.2, 26.1. IR
(neat): ν 3055 (br), 2971(m), 2919 (m), 2865 (w), 1965 (w), 1901(w) 1698 (s), 1481 (m) cm-1.
HRMS (ESI-orbitrap, [C23H22O3 + Na]+) calcd 369.1467, found m/z 369.1465.
9-(3-Cyclopentylideneallyl)-9H-xanthene-9-carboxylic acid (1i).3 Rf 0.55 (1:4 ethyl
acetate/hexanes); white solid, m.p. 62-63 °C, yield 0.55 g (76%). 1H NMR (400 MHz, CDCl3): δ
10.8 (br. s, 1H, COOH), 7.27-7.21 (m, 4H), 7.07-7.03 (m, 4H), 4.61-4.54 (m, 1H), 2.99 (d, J =
6.8 Hz, 2H), 1.88-1.82 (m, 2H), 1.63-1.57 (m, 2H), 1.45-1.40 (m, 4H). 13C NMR (101 MHz,
CDCl3): δ 199.8, 178.5, 150.9, 129.0, 127.4, 123.3, 120.7, 116.8, 104.1, 85.2, 49.9, 39.5, 30.7,
26.9. IR (neat): ν 3053 (br), 2970 (m), 2921 (m), 2866 (w), 1961 (w), 1901 (w) 1696 (s), 1480
(m) cm-1. HRMS (ESI, [C22H20O3 + Na]+) calcd 355.1310, found m/z 355.1313.
5-Cyclohexylidene-2-(3-methoxyphenyl)-2-phenylpent-4-enoic acid (1k). Rf 0.41 (1:4
ethyl acetate/hexanes); white solid, m.p. 134-135 °C, yield 0.78 g (84%). 1H NMR (400 MHz,
CDCl3): δ 10.7 (br. s, 1H, COOH), 7.32-7.18 (m, 6H), 6.90 (ddd, J = 8.4, 2.4 Hz, 1H), 6.86 (t, J
= 2.0 Hz, 1H), 6.77 (ddd, J = 8.4, 2.4, 0.8 Hz, 1H), 4.73-4.69 (m, 1H), 3.72 (s, 3H), 3.11-3.01
(m, 2H), 1.89-1.81 (m, 4H), 1.49-1.39 (m, 6H). 13C NMR (101 MHz, CDCl3): δ 200.8, 179.3,
159.3, 143.7, 141.9, 129.3, 128.9, 127.9, 127.1, 121.8, 115.9, 112.0, 102.1, 84.3, 60.6, 55.3, 39.5,
31.2, 27.4, 26.2. IR (neat): ν 2918 (br), 2589 (w), 1699 (s), 1750 (s), 1612 (m) cm-1. HRMS
(ESI, [C24H26O3 + H]+) calcd 363.1960, found m/z 363.1956.
S12
X-RAY CRYSTALLOGRAPHIC DATA AND PROCEDURES
General Considerations. X-ray diffraction data were collected on Bruker single crystal
diffractometers equipped with CCD detectors (APEX or APEX II) using a combination of and
scans. Unit cell determination and data collection utilized the Bruker SMART8 and APEX29
software packages. Data integration employed SAINT.10 Multiscan absorption corrections were
implemented using SADABS.11 Structures were solved by direct methods and refined by full-
matrix least-squares on F2 using the SHELXTL software suite.12 Non-hydrogen atoms were
assigned anisotropic temperature factors, and hydrogen atoms were included in calculated
positions (riding model) with isotropic U fixed at 1.5 times the Ueq of the attached atom for -CH3
groups and 1.2 times the Ueq of the attached atom for other hydrogen atoms. CCDC 997310-
997312 contain the supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
Figure S1. X-ray structure of 2a, with displacement ellipsoids drawn at the 50% probability
level
X-ray Crystallographic Analysis of 2a. Colorless blocks were obtained by slow diffusion of
pentane into a Et2O/CH2Cl2 (98:2) solution of 2a. A sample measuring 0.40 x 0.25 x 0.25 mm
was placed on the goniometer of an APEX II DUO diffractometer, and reflection data were
collected using radiation from a Cu IS microfocus X-ray source (=1.54178 Å). The sample
was cooled to 125(1) K during data collection using an Oxford Cryostream liquid nitrogen
cooling device. C23H24O2, Mr = 332.42 g mol-1, monoclinic, space group P21/c, a = 10.2882(1),
S13
b = 10.0834(1), c = 17.6278(2) Å, = 100.1728(4)°, V = 1799.96(3) Å3, Z = 4, Z´ = 1, calcd =
1.227 g cm-3, = 0.598 mm-1, T = 125(2) K, 2max = 133.19°, 26227 total reflections, 3169
independent (Rint = 0.024), 3122 observed [I > 2(I)]. Final R1 [I > 2(I)] = 0.0345, wR2 (all
data) = 0.0844, largest difference peak (hole) 0.284 (-0.203) e Å-3. CCDC 997310.
(a) (b)
(c)
Figure S2. Views of the X-ray structure of 4a, showing the two crystallographically
independent molecules (a,b) and the asymmetric unit (c). Displacement ellipsoids are drawn at
the 50% probability level
X-ray Crystallographic Analysis of 4a. Colorless needles were obtained by slow diffusion of
pentane into a CH2Cl2/Et2O solution (98:2) of 4a. A sample measuring 0.24 x 0.07 x 0.02 mm
was placed on the goniometer of an APEX II DUO diffractometer, and reflection data were
collected using graphite-monochromated radiation from a Mo sealed-tube X-ray source
(=0.71073 Å) equipped with a MonoCap waveguide collimator. The sample was cooled to
125(1) K during data collection using an Oxford Cryostream liquid nitrogen cooling device. By
analyzing reflection data with CELL_NOW13 and TWINABS,14 the crystal was modeled as a
two-component nonmerohedral twin. Final refinement was performed on both twin components
S14
using data in HKLF5 format. The refined proportion of twin components was 0.477(1):0.523(1),
with a twin law corresponding to a 180 degree rotation about reciprocal axis 0.031 1.000 -0.005
and real axis 0.003 1.000 0.000. The asymmetric unit contains two crystallographically
independent molecules. C23H24O2, Mr = 332.42 g mol-1, triclinic, space group Pī, a = 7.1469(5),
b = 15.303(1), c = 16.4534(10) Å, = 73.1224(1), = 89.797(1), = 88.864(1)°, V = 1799.96(3)
Å3, Z = 4, Z´ = 2, calcd = 1.282 g cm-3, = 0.080 mm-1, T = 125(2) K, 2max = 61.02°, 22822
total reflections, 10426 independent (Rint = 0.086), 9443 observed [I > 2(I)]. Final R1 [I >
2(I)] = 0.0626, wR2 (all data) = 0.1600, largest difference peak (hole) 0.382 (-0.335) e Å-3.
CCDC 997311.
Figure S3. X-ray structure of 9, with displacement ellipsoids drawn at the 50% probability
level. Only the major orientation of the disordered phenyl group (C17-C21) is shown.
X-ray Crystallographic Analysis of 9. Colorless plates were obtained by slow diffusion of
pentane into a Et2O/CH2Cl2 (9:1) solution of 9. A sample measuring 0.52 x 0.40 x 0.02 mm was
placed on the goniometer of a SMART APEX diffractometer, and reflection data were collected
using graphite-monochromated radiation from a Mo sealed-tube X-ray source (=0.71073 Å)
equipped with a MonoCap waveguide collimator. The sample was cooled to 100(1) K during
data collection using an Oxford Cryostream liquid nitrogen cooling device. The phenyl group
showed slight rotational disorder, which was treated with a two-part disorder model. The
occupancies for atoms C17 – C22 refined to 0.60(2) and 0.40(2) for the two phenyl ring
orientations indicated by unprimed and primed atoms, respectively. Restraints on the positional
S15
and displacement parameters of the disordered atoms were required. The COOH hydrogen
bonded to O25 was located on a difference map, and its position was allowed to refine freely.
C24H26O3, Mr = 362.45 g mol-1, triclinic, space group Pī, a = 9.7954(4), b = 9.8427(4), c =
11.0909(5) Å, = 78.548(2), = 77.234(2), = 64.389(2)°, V = 933.94(7) Å3, Z = 2, Z´ = 1,
calcd = 1.289 g cm-3, = 0.083 mm-1, T = 100(2) K, 2max = 50.5°, 17614 total reflections, 4626
independent (Rint = 0.015), 4139 observed [I > 2(I)]. Final R1 [I > 2(I)] = 0.0431, wR2 (all
data) = 0.1243, largest difference peak (hole) 0.422 (-0.182) e Å-3. CCDC 997312.
S16
REFERENCES
1. (a) J. L. Arbour, H. S. Rzepa, A. J. P. White and K. K. Hii, Chem. Commun., 2009, 7125; (b) J. L. Arbour, H. S. Rzepa, J. Contreras-García, L. A. Adrio, E. M. Barreiro and K. K. Hii, Chem. Eur. J., 2012, 18, 11317.
2. (a) S. Handa, Ph.D. Thesis, Oklahoma State University, 2013; (b) S. Handa, D. J. Lippincott, D. H. Aue and B. H. Lipshutz, Angew. Chem. Int. Ed., 2014, 53, 10658.
3. Syntheses of substrates 1b, 1e, 1h, and 1i by the same procedures were recently reported (ref 2b).
4. J. Löfstedt, J. Franzén and J. E. Bäckvall, J. Org. Chem., 2001, 66, 8015. 5. Methyldiarylacetates with Ar = Ph and Ar2 = 9H-xanthen-9-yl were obtained from
commercial sources. Those with 4-chlorophenyl and 2,3-dihydrobenzofuran-5-yl substituents were prepared from the commercially available acids via Fischer esterification and used without chromatographic purification. The unsymmetrically substituted diaryl ester (17) used to synthesize 1k (Ar = Ph, Ar' = 3-methoxyphenyl) was prepared by literature procedures (refs 6a,b).
6. (a) T. Kametani, K. Kigasawa, M. Hiiragi, T. Aoyama and O. Kusama, J. Org. Chem., 1971, 36, 327; (b) T. Kametani, K. Kigasawa, M. Hiiragi and T. Aoyama, J. Med. Chem., 1971, 14, 1235; (c) G. Hilt and F. Galbiati, Synthesis, 2006, 3589.
7. C. P. Owens, A. Varela-Álvarez, V. Boyarskikh, D. G. Musaev, H. M. L. Davies and S. B. Blakey, Chem. Sci., 2013, 4, 2590.
8. SMART; Bruker AXS: Madison, WI, USA, 2007. 9. APEX2, Version 2.0; Bruker AXS: Madison, WI, USA, 2007. 10. SAINT; Bruker AXS: Madison, WI, USA, 2007. 11. Sheldrick, G. M. SADABS, Version 2.10; Bruker AXS Inc.: Madison, WI, USA, 2000. 12. Sheldrick, G. M. SHELXTL; Bruker AXS Inc.: Madison, WI, USA, 2008. 13. Sheldrick, G. M. CELL_NOW; Bruker AXS: Madison, WI, USA, 2004. 14. Sheldrick, G. M. TWINABS, Version 2008/2; Bruker AXS: Madison, WI, USA, 2008.
S17
KINETIC PLOTS
Pseudo first-order rate constant for 3a formation (incorporates catalyst concentration):
kobs = 2(2) x 10-4 min-1
S18
Pseudo first-order rate constant for 3a formation (incorporates catalyst concentration):
kobs = 2.3(2) x 10-3 min-1
S19
Pseudo zero-order rate constant for 2a formation (incorporates concentrations of catalyst and
1a): kobs = 11.4(7) mM min-1
Pseudo first-order rate constant for 3a formation (incorporates catalyst concentration):
kobs = 1.18(5) x 10-3 min-1
S20
Pseudo zero-order rate constant for 2a formation (incorporates concentrations of catalyst and
1a): kobs = 17.5(2) mM min-1
S21
Pseudo first-order rate constant for 3a formation (incorporates catalyst concentration):
kobs = 2.7(2) x 10-3 min-1
S22
Pseudo zero-order rate constant for 2a formation (incorporates concentrations of catalyst and
1a): kobs = 6.6(2) mM min-1
S23
Pseudo first-order rate constant for 3a formation (incorporates catalyst concentration):
kobs = 3.63(8) x 10-3 min-1
S24
Pseudo first-order rate constant for 3a formation (incorporates catalyst concentration):
kobs = 1.34(6) x 10-3 min-1
S25
Pseudo first-order rate constant for 3a formation (incorporates catalyst concentration):
kobs = 1.0(8) x 10-5 min-1
S26
(note: the left plot suggests a change in the catalyst after 50 min)
Pseudo first-order rate constant for 3a formation (incorporates catalyst concentration):
kobs = 1.37(6) x 10-3 min-1
S27
1H AND 13C NMR SPECTRA
6.10
4.00
1.00
1.00
0.950.94
9.67
1.481.501.511.531.541.552.062.082.092.112.122.142.152.162.172.652.682.682.713.003.013.033.045.045.055.065.075.085.085.095.105.195.217.217.227.227.237.237.247.287.287.297.307.307.317.317.327.347.357.367.367.367.377.387.387.397.407.40
1H NMR (400 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S28
8.00
3.97
1.00
1.01
0.97
0.94
9.67
1.491.511.521.531.551.571.581.592.242.252.252.272.292.642.662.672.703.033.043.063.075.025.035.045.055.055.065.075.255.255.255.275.275.277.227.237.247.287.297.307.307.317.317.327.327.347.357.367.367.367.377.377.387.387.397.397.417.41
27.32
28.70
29.09
29.67
30.56
37.88
44.49
58.35
73.84
76.83
77.15
77.35
77.46
122.33
127.25
127.53
127.81
127.85
128.46
129.08
139.88
142.42
150.34
177.37
127.25
127.53
127.81
127.85
128.46
129.08
13C NMR (101 MHz, CDCl3)
1H NMR
(400 MHz, CDCl3)
S29
1H NMR (400 MHz, CDCl3)
26.55
27.92
28.36
29.77
37.13
44.46
57.56
73.43
76.84
77.16
77.48
118.46
128.76
128.84
129.18
129.43
138.21
140.32
149.31
176.62
13C NMR (101 MHz, CDCl3)
6.28
4.00
1.00
1.02
0.970.96
7.91
1.481.521.531.541.541.561.592.092.112.12
2.602.622.632.662.922.932.962.97
5.025.035.045.045.055.055.065.085.165.187.207.217.227.227.237.247.257.257.267.277.297.297.307.327.337.337.347.35
S30
4.26
4.18
1.10
1.11
1.04
1.00
8.14
2.142.172.172.192.272.282.282.302.302.312.332.332.592.622.622.652.952.972.993.004.874.884.894.894.904.914.924.935.325.335.335.345.345.355.357.207.217.227.227.237.247.247.257.257.267.267.277.277.287.297.297.307.327.327.337.347.357.35
1.04
1.00
4.874.884.894.894.904.914.924.93
5.325.335.335.345.345.355.35
25.99
26.33
29.40
34.16
43.95
57.47
75.78
76.84
77.16
77.48
117.00
128.77
128.84
129.17
129.41
134.17
138.21
140.39
153.22
176.55
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S32
4.02
4.13
1.01
1.02
4.12
4.04
1.00
0.86
0.900.890.971.880.99
26.02
26.37
29.37
29.89
29.92
34.13
44.91
57.54
71.56
71.66
75.69
76.84
77.16
77.48
108.84
109.34
117.64
124.53
124.78
126.91
127.35
128.10
131.99
135.10
152.36
159.22
159.70
178.17
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S33
6.28
3.052.05
1.00
0.94
0.98
8.17
1.531.541.551.571.581.591.601.611.612.132.142.152.162.182.222.252.262.282.692.712.722.747.127.137.147.147.147.157.167.167.167.177.187.187.187.187.197.207.217.227.227.247.247.257.267.267.277.287.297.307.307.307.317.327.337.337.347.35
26.58
27.96
28.39
29.81
37.15
50.32
50.80
73.82
76.84
77.16
77.48
116.73
117.64
119.04
122.86
123.69
124.11
124.33
125.87
127.45
129.00
129.28
148.82
151.01
151.70
177.33
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S34
26.02
26.37
29.44
34.16
50.25
76.18
76.84
77.16
77.37
77.48
116.74
117.57
117.63
122.86
123.71
124.09
124.32
125.89
127.44
129.00
129.28
151.00
151.70
152.87
177.28
4.00
5.20
1.03
0.990.93
6.261.91
1.521.621.641.651.661.671.691.712.212.242.242.272.692.712.722.745.397.107.117.117.117.127.127.127.137.137.147.147.157.157.167.167.167.167.187.197.197.217.217.217.227.237.247.257.267.277.277.287.287.297.297.307.317.317.317.317.337.33
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S35
6.75
4.11
1.00
1.00
0.890.97
2.67
0.874.51
1.551.561.572.102.112.122.142.152.172.182.632.652.662.672.672.682.692.713.013.013.023.033.043.053.053.063.753.785.095.105.205.226.876.876.886.886.906.946.956.967.027.027.207.227.247.267.287.307.307.317.327.337.357.377.397.407.407.42
1H NMR (400 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S36
4.00
4.181.041.061.07
1.08
1.00
0.96
10.04
1.521.531.531.541.551.561.561.571.581.591.591.601.611.621.921.931.981.991.992.232.252.272.282.442.462.482.492.562.592.602.622.993.003.023.034.434.444.454.464.485.517.217.237.247.257.277.287.297.307.317.337.337.347.357.367.377.377.38
14.27
26.61
27.93
27.94
28.39
29.74
29.76
37.14
44.84
55.38
55.45
58.44
73.36
73.47
76.84
77.16
77.37
77.48
113.02
119.00
119.76
127.28
127.49
127.81
127.84
128.48
129.09
130.02
141.35
142.26
143.94
148.65
148.68
159.62
160.13
177.20
177.31
13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S37
22.28
22.90
25.36
29.02
43.60
43.69
58.18
76.16
76.84
77.16
77.48
125.18
127.25
127.48
127.77
127.83
128.46
129.02
129.06
132.71
139.95
142.38
177.29
13C NMR (101 MHz, CDCl3)
S39
2.20
4.321.112.15
1.11
1.00
0.91
10.37
1.841.861.871.881.901.922.272.292.312.312.332.342.352.352.442.452.472.492.602.622.632.642.652.662.673.043.063.083.094.504.514.534.545.507.247.247.257.257.267.267.277.297.307.317.317.327.337.347.347.357.367.377.387.397.407.417.417.50
23.49
32.59
35.67
36.76
43.71
58.19
76.03
76.84
77.16
77.48
127.25
127.44
127.62
127.76
127.80
128.45
129.00
138.78
140.01
142.33
177.14
13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S40
4.08
2.05
3.89
1.17
2.01
1.00
0.95
0.91
10.10
1.421.431.431.441.451.461.461.471.541.701.711.732.052.072.082.102.112.112.122.132.252.272.282.302.572.592.602.622.982.993.013.024.424.435.657.227.227.247.247.247.277.277.287.287.297.297.297.297.307.307.327.347.357.357.367.367.377.38
26.73
27.15
28.52
32.50
33.24
43.66
45.57
58.21
76.21
76.84
77.16
77.48
127.27
127.52
127.79
127.87
128.49
129.04
130.59
139.11
139.98
142.51
177.29
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S41
4.37
3.96
0.96
2.01
1.07
1.00
0.90
7.88
1.531.541.551.551.561.571.581.591.591.601.611.621.621.631.641.921.942.002.002.242.252.272.292.452.472.492.502.532.552.562.582.932.942.962.974.424.434.454.465.527.227.227.237.247.257.267.277.277.287.287.297.307.327.337.337.357.357.36
0.96
2.01
1.07
2.242.252.272.292.452.472.492.502.532.552.562.58
2.932.942.962.97
22.26
22.89
25.37
29.04
43.40
43.49
57.28
76.23
76.84
77.16
77.48
125.46
128.76
128.80
129.16
129.35
132.47
133.59
134.12
138.23
140.40
176.51
125.46
128.76
128.80
129.16
129.35
132.47
133.59
134.12
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S42
2.04
4.250.852.02
1.06
1.00
0.91
2.175.90
1.811.831.851.871.892.232.242.282.302.512.542.552.572.932.942.962.98
4.424.444.454.464.474.49
5.46
7.197.207.217.227.227.247.247.257.267.267.277.277.287.307.317.327.337.337.34
2.232.242.262.272.282.282.302.312.402.412.442.452.512.542.552.572.582.602.62
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S43
4.11
4.39
0.92
2.12
1.07
4.00
1.024.18
1.00
1.96
1.09
3.01
1.531.551.561.571.571.581.591.601.601.611.631.941.992.222.242.262.272.442.452.482.492.502.512.542.902.912.932.953.133.163.183.204.414.434.444.514.544.554.564.574.595.526.686.706.746.766.966.966.986.987.087.097.107.117.137.167.187.19
22.34
22.97
25.41
29.11
29.88
29.92
43.66
44.47
57.40
71.56
71.66
76.15
76.84
77.15
77.36
77.47
124.49
124.76
125.13
126.93
127.36
128.05
132.11
132.87
135.14
159.24
159.69
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S44
1.84
3.970.920.911.01
1.00
4.18
1.044.18
0.83
1.830.992.84
1.851.871.881.902.172.262.272.292.312.332.442.462.492.522.532.552.592.612.932.952.972.983.143.163.183.204.454.474.484.494.524.544.554.564.574.584.605.486.686.716.746.766.966.976.986.997.097.097.117.117.147.147.197.197.257.267.277.27
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S45
4.05
4.05
2.09
0.89
1.00
0.99
0.96
8.28
1.471.481.491.511.541.561.571.952.272.292.302.332.342.362.382.392.462.472.492.502.522.742.762.782.79
4.974.985.01
5.557.147.157.167.167.187.187.207.247.267.297.317.317.317.337.337.347.357.357.37
21.78
22.37
24.73
28.30
38.89
39.10
39.31
39.52
39.73
39.94
40.15
43.22
47.97
48.60
76.47
116.26
116.86
122.38
123.00
124.08
124.31
124.40
126.43
127.82
129.17
129.40
132.76
149.41
150.34
176.82
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S46
1.92
4.951.062.00
0.98
0.82
7.80
1.821.841.861.871.881.902.182.202.212.242.282.292.312.452.472.492.502.662.682.692.702.702.712.722.744.784.804.814.824.824.834.844.865.497.097.117.117.127.137.137.137.157.167.177.187.187.197.207.207.247.267.267.287.297.297.307.327.32
23.51
32.63
35.80
37.28
49.85
49.96
76.49
76.82
77.14
77.46
116.75
117.58
122.81
123.58
124.07
124.27
125.80
127.38
128.20
129.02
129.27
138.36
150.78
151.62
177.15
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S48
1H NMR (400 MHz, CDCl3)
26.55
26.78
26.85
26.96
27.55
28.79
53.19
76.84
77.16
77.36
77.48
85.41
122.25
124.44
126.88
127.97
128.10
128.27
129.71
135.69
138.70
141.88
174.36
13C NMR (101 MHz, CDCl3)
S49
0.903.073.021.060.891.13
2.00
1.00
0.90
0.950.995.78
1.541.711.711.721.741.741.751.771.771.811.831.841.861.881.882.002.022.162.182.192.452.462.482.492.512.512.532.542.542.892.916.636.657.167.167.187.187.207.207.267.277.277.297.297.317.317.407.417.427.437.437.447.457.477.477.487.497.50
1.541.711.721.741.741.751.771.831.841.861.882.182.192.492.512.512.532.542.91
26.27
26.59
27.28
27.89
27.90
30.54
42.19
53.52
76.84
77.16
77.48
85.74
122.28
124.20
127.01
127.97
128.19
128.26
129.70
135.73
139.61
141.51
174.54
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S50
12.05
4.93
1.00
1.02
7.27
1.551.681.892.042.172.192.202.222.512.532.58
6.646.657.177.187.207.267.297.317.427.437.437.447.457.467.477.487.487.497.49
27.19
27.72
28.14
29.17
40.71
53.19
76.83
77.15
77.47
122.12
124.43
126.86
127.95
128.06
128.24
129.70
135.71
141.89
174.45
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S53
3.033.032.121.131.111.062.071.071.08
3.05
1.001.032.382.77
0.66
1.281.311.341.361.371.431.451.461.491.491.511.521.631.641.661.881.891.901.911.932.022.032.042.262.572.602.602.612.622.792.802.882.893.826.816.817.117.117.227.237.237.247.247.257.267.267.277.277.287.287.297.297.307.307.317.317.327.32
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S54
-4.90
18.44
23.54
25.98
42.40
51.95
74.63
76.84
77.16
77.48
81.95
88.60
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S56
5.99
9.21
4.747.191.941.05
1.14
1.17
2.14
1.00
0.12
0.91
3.473.483.503.513.533.903.903.91
4.35
5.035.035.045.05
7.26
-4.90
18.40
20.53
22.98
23.46
25.58
25.95
32.11
40.00
41.39
51.98
63.64
76.84
77.16
77.48
81.00
83.35
86.64
96.70
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S57
6.01
9.93
8.105.152.483.37
1.20
1.28
2.18
1.00
-4.94
18.35
20.74
22.02
22.20
25.55
25.89
28.79
32.37
40.82
42.16
51.92
63.67
76.83
77.15
77.47
78.39
83.78
87.43
96.04
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S58
4.363.334.272.101.170.96
1.14
1.11
2.10
1.00
1.501.511.521.541.551.551.561.671.681.681.691.701.701.711.711.721.721.721.731.741.741.751.761.771.771.781.791.791.801.801.811.811.821.831.831.841.851.911.921.931.951.961.971.972.162.182.193.503.523.533.924.284.295.045.055.055.067.26
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S59
10.63
3.152.140.872.260.87
1.11
1.10
2.09
1.00
1.481.491.501.511.521.531.531.541.551.561.571.601.611.621.631.641.651.651.661.671.671.681.691.691.711.821.841.851.861.871.871.901.951.971.981.981.992.002.012.022.032.113.493.503.513.533.923.933.943.953.973.984.305.075.085.085.097.26
20.41
22.06
22.25
22.28
25.60
28.25
28.71
32.35
41.19
41.96
43.16
51.29
63.33
76.84
77.16
77.48
78.11
83.52
88.55
95.66
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S60
8.16
8.32
3.65
1.000.99
1.661.661.671.671.671.681.681.691.692.352.352.362.362.362.372.372.372.372.382.382.382.382.392.39
4.034.04
5.245.255.255.255.255.265.265.265.275.275.285.285.285.325.325.32
27.42
31.68
53.48
53.66
53.84
54.02
54.20
61.34
92.70
107.06
196.34
13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S61
28.59
29.44
32.59
61.24
76.84
77.16
77.48
89.71
107.99
200.69
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S62
4.03
4.11
2.08
0.83
1.901.00
1.80
1.621.631.631.641.651.651.661.672.362.372.372.382.392.40
4.784.805.295.305.305.315.325.335.34
7.267.427.447.467.547.557.578.058.058.068.07
27.15
31.31
63.86
76.84
77.16
77.48
87.39
106.14
128.42
129.74
130.59
132.96
166.49
198.78
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S63
8.33
4.01
1.95
0.80
2.111.00
1.97
1.491.501.511.521.521.531.541.541.581.581.591.591.601.601.611.611.621.621.632.242.252.252.252.262.272.272.282.282.284.774.785.205.215.215.225.237.417.427.427.437.447.457.457.467.537.537.547.557.557.567.578.068.068.068.078.088.088.08
28.45
29.43
32.29
63.89
76.84
77.16
77.48
84.67
106.90
128.40
129.76
132.93
166.48
203.34
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S64
8.15
3.91
2.00
3.05
0.88
10.58
1.48
1.992.002.012.01
3.093.11
3.70
4.694.704.704.714.724.724.734.744.74
7.237.237.237.247.247.257.257.257.267.267.277.277.287.297.307.31
1H NMR (400 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S65
28.55
29.46
32.17
39.59
52.48
60.72
76.84
77.16
77.48
84.28
103.85
126.85
127.90
129.11
129.25
142.63
174.75
203.92
6.51
4.01
2.00
2.93
8.05
1.421.431.451.471.481.491.541.851.861.86
3.003.02
3.67
4.624.634.634.644.644.654.664.66
7.167.177.187.187.197.237.247.257.26
13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S66
26.14
27.37
31.17
39.49
52.70
59.87
76.82
77.14
77.46
83.82
102.34
128.15
128.57
128.64
130.55
133.06
133.95
140.78
173.94
200.79
13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S67
27.05
30.94
39.20
52.73
59.83
76.83
77.14
77.46
86.50
103.68
128.16
130.54
133.06
173.94
199.62
13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S68
26.26
27.51
30.00
31.33
40.21
52.41
59.70
71.49
76.83
77.15
77.47
84.87
101.77
108.44
125.81
126.49
128.95
135.11
158.90
175.42
200.50
13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S69
27.07
29.98
30.95
39.84
52.40
59.65
71.46
76.81
77.13
77.45
87.52
103.06
108.43
125.79
126.45
128.87
135.09
158.86
175.37
199.30
6.32
4.03
2.00
2.80
0.85
8.17
13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S71
26.92
30.73
41.01
52.94
76.82
77.14
77.46
85.28
103.76
116.68
121.47
123.25
127.22
128.57
128.62
128.82
133.76
133.95
150.82
174.41
199.68
13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
S74
8.25
3.94
2.00
0.94
10.78
1.43
1.951.97
3.053.07
4.674.674.684.694.694.704.714.714.72
7.237.237.247.247.257.257.267.277.277.287.297.297.307.317.327.32
28.51
29.45
32.10
39.39
60.56
76.83
77.15
77.46
84.04
104.02
127.07
127.97
129.23
129.34
142.08
179.28
204.03
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S76
4.12
4.11
2.00
1.02
9.65
1.531.531.541.551.562.052.072.082.092.092.10
3.003.01
4.744.754.764.774.78
7.197.207.227.247.247.267.27
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S77
6.40
4.00
1.984.05
4.110.88
1.87
3.80
26.26
27.49
29.98
31.27
40.09
59.53
71.54
76.83
77.15
77.47
84.63
101.95
108.53
125.93
126.62
129.08
134.50
159.10
200.66
215.63
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S79
6.28
3.99
2.01
1.00
3.894.34
1.241.311.321.54
2.912.93
4.38
7.007.017.047.067.207.227.247.247.24
26.13
27.26
31.02
40.77
50.26
76.84
77.16
77.48
82.53
102.11
116.81
120.72
123.30
127.58
128.89
150.88
178.96
201.18
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S80
3.922.042.00
1.95
0.92
3.75
4.18
1401.411.421.431.431.571.581.601.611.621.621.631.821.831.841.861.861.871.87
2.993.00
4.554.564.574.584.594.594.60
7.037.037.057.077.217.227.237.247.247.257.267.27
26.91
30.71
39.55
49.88
76.84
77.16
77.37
77.48
85.17
104.14
116.81
120.69
123.34
127.41
128.95
150.89
178.46
199.75
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)
S81
5.99
4.03
2.00
2.98
0.93
0.91
1.90
6.27
1.401.421.43
1.87
3.023.043.063.073.083.093.103.123.72
4.704.714.724.724.734.734.744.754.756.876.886.886.927.177.197.217.237.247.257.277.287.317.317.317.337.33
26.23
27.41
31.16
31.19
39.47
55.34
60.56
76.83
77.15
77.47
84.30
102.08
112.01
115.89
121.77
127.07
127.93
128.86
129.33
141.93
143.68
159.27
179.28
200.73
1H NMR (400 MHz, CDCl3)
13C NMR (101 MHz, CDCl3)