The Journal of Organic Chemistry
Note
129.7, 116.3, 112.5, 62.1, 53.4, 46.1, 18.4, 12.9, 12.5; HRESIMS m/z
[M + H]+ 322.2582 (calcd for C19H36NOSi, 322.2561).
1H), 5.29 (dd, J = 8.0, 3.0 Hz, 1H), 4.5 (s, 2H), 4.23 (s, 1H), 4.66 (d, J
= 5.0, 1H), 3.67−3.47 (m, 6H), 3.37 (d, J = 7.3 Hz, 2H), 2.58 (s, 2H),
2.31 (s, 3H), 1.81−1.68 (m, 6H), 1.30 (s, 3H), 1.12 (s, 2H); 13C NMR
(C4D8O, 125 MHz): δ = 168.3, 161.3, 160.7, 158.4, 157.0, 150.9,
133.4, 130.5, 129.6, 128.1, 123.6, 122.9, 122.7, 115.4, 114.4, 111.2,
104.0, 100.1, 82.2, 79.3, 72.6, 70.5, 68.2, 61.5, 29.1, 28.9, 26.3, 23.2,
17.9, 8.7; HRESIMS m/z [M + H]+ 613.2367 (calcd for C31H37N2O11,
613.2392).
Deprotection of TIPS-1 to Give 4-(4-Hydroxyphenyl)-2-butanone
(5). Yield = 75%, 19 mg; 1H NMR (C4D8O, 400 MHz): δ = 7.96 (bs,
1H), 6.95 (d, J = 7.4 Hz, 2H), 6.61 (d, J = 7.4 Hz, 2H), 2.76−2.60 (m,
4H), 2.01 (s, 3H); 13C NMR (C4D8O, 100 MHz): δ = 206.5, 156.9,
132.8, 129.9, 116.0, 46.0, 29.9, 29.7; HRESIMS m/z [M + NH4]+
182.1182 (calcd for C10H16NO2, 182.1176).
TBDMS-4-Z-Amino-cyclohexanol (S6). 1H NMR (C4D8O, 500
MHz): δ = 7.35−7.24 (m, 4H), 7.23 (t, J = 6.9 Hz, 1H), 6.26 (bs, 1H),
5.01 (s, 2H), 3.67−3.56 (m, 2H), 3.45−3.34 (m, 2H), 1.99−1.67 (m,
4H), 1.44−1.16 (m, 4H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR
(C4D8O, 125 MHz): δ = 156.2, 138.7, 128.9, 128.3, 126.6, 71.3, 66.3,
50.0, 35.1, 31.4, 26.3, 26.2, 18.6, −4.4; HRESIMS m/z [M + H]+
364.2297 (calcd for C20H34NO3Si, 364.2302).
1
TIPS4-Z-Amino-cyclohexanol (S7). H NMR (C4D8O, 500 MHz):
δ = 7.36−7.23 (m, 4H), 7.23 (t, J = 6.9, 1H), 6.25 (bs, 1H), 3.79 (s,
2H), 3.46−3.35 (m, 2H), 2.01−1.87 (m, 4H), 1.49−1.18 (m, 4H),
1.18−1.01 (m, 21H); 13C NMR (C4D8O, 125 MHz): δ = 155.2, 138.8,
128.9, 128.7, 128.3, 71.5, 66.3, 50.1, 35.3, 31.5, 18.6, 13.3; HRESIMS
m/z [M + H]+ 406.2776 (calcd for C23H40NO3Si, 406.2772).
TBDMS-4-(Z-Amino)-1-butanol (S8). 1H NMR (C4D8O, 500
MHz): δ = 7.34−7.26 (m, 4H), 7.23 (t, J = 7.1 Hz, 1H), 6.34 (bs,
1H), 5.02 (s, 2H), 3.67−3.61 (m, 2H), 3.16−3.10 (m, 2H), 1.57−1.49
(m, 4H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (C4D8O, 125 MHz): δ
= 157.0, 138.8, 128.9, 128.6, 128.3, 66.3, 63.4, 41.4, 30.9, 27.4, 26.3,
18.8, −5.2; HRESIMS m/z [M + H]+ 338.2177 (calcd for
C18H32NO3Si, 338.2146).
Deprotection of TIPS-2 to Give Acetovanillone (6). Yield = 75%,
1
20 mg; H NMR (C4D8O, 400 MHz): δ = (bs, 1H), 7.59−7.51 (m,
2H), 6.85 (d, J = 7.1 Hz, 1H), 3.94 (s, 3H), 2.50 (s, 3H); 13C NMR
(C4D8O, 100 MHz): δ = 195.3, 152.6, 148.4, 130.6, 124.2, 115.3,
111.1, 56.1, 25.9; HRESIMS m/z [M + H]+ 167.0702 (calcd for
C9H11O3, 167.0703).
Deprotection of TIPS-3 to Give Acetaminophen (7). Reaction of
1
171 mg, Yield = 79%, 64 mg; H NMR ((CD3)2SO, 500 MHz): δ =
TIPS-4-(Z-Amino)-1-butanol (S9). 1H NMR (C4D8O, 400 MHz): δ
= 7.36−7.26 (m, 4H), 7.24 (t, J = 7.1 Hz, 1H), 6.37 (bs, 1H), 5.03 (s,
2H), 3.74 (t, J = 6.1 Hz, 2H), 3.15 (t, J = 6.0 Hz, 2H), 1.62−1.54 (m,
4H), 1.16−1.02 (m, 21H); 13C NMR (C4D8O, 100 MHz): δ = 157.0,
138.7, 128.9, 128.5, 128.3, 66.3, 63.9, 41.5, 31.1, 27.4, 18.5, 18.4, 12.9;
HRESIMS m/z [M + H]+ 380.2626 (calcd for C21H38NO3Si,
380.2615).
9.63 (s, 1H), 9.13 (s, 1H), 7.33 (d, J = 6.8 Hz, 2H), 6.67 (d, J = 6.9
Hz, 2H), 1.97 (s, 3H); 13C NMR ((CD3)2SO, 500 MHz): δ = 167.6,
153.2, 131.0, 120.9, 115.0, 23.7; HRESIMS m/z [M + H]+ 152.0706
(calcd for C8H10NO2, 152.0706).
Activation of Resin for Hydroxyl Group Capture. To a 20 mL
scintillation vial equipped with a septum was added 200 mg of
hydroxymethyl polystyrene resin (loading capacity of 1.1 mmol/g).
The vessel was purged with Ar. The resin was swollen in 3 mL of
anhydrous dichloromethane (DCM). To this was added 14 equiv of
freshly distilled triethylamine (3.1 mmol, 450 μL) followed by 10
equiv of the desired dichlorodialkylsilane (2.2 mmol). Next, the resin
was removed from Ar atmosphere, 1.2 equiv of 4-dimethylaminopyr-
idine (DMAP, 0.26 mmol, 32 mg) was added, and the vessel was
quickly capped. The resin was agitated for 4 h at room temperature.
Next, the resin was filtered through a 10 mL biospin vessel under
positive Ar pressure and rinsed 3 × 8 mL with anhydrous DCM. This
resin was reswollen in 2.5 mL of anhydrous DCM and aliquoted into 5
oven-dried 2 mL vials. Three of the five vials were capped with a
septum and placed under Ar. The fourth vial was transferred to a 2 mL
biospin vessel and rinsed with 1:1 THF:MeOH. This hydrolyzes the
Si−Cl bond to yield inactivated resin that will not capture hydroxyl-
containing molecules to provide a control. The loading capacity for
resin 9 was 0.2 mmol/g and was determined as previously described.6
Coupling with activated resin 9 and washing of the resin prior to
cleavage were performed as previously described.6
TBDMS-erthryo-1,2-Diphenyl-ethanol (S10). 1H NMR (C4D8O,
500 MHz): δ = 7.28−7.11 (m, 10H), 6.93−6.87 (m, 2H), 6.45 (dd, J =
8.2, 7.5 Hz, 3H), 4.96 (d, J = 5.9 Hz, 1H), 4.79 (bd, J = 6.9 Hz, 1H),
4.50 (dd (apparent triplet, J = 6.4 Hz), 1H), 0.83 (d, J = 2.6 Hz, 9H),
−0.13 (s, 3H), −0.27 (s, 3H); 13C NMR (C4D8O, 125 MHz): δ =
148.3, 143.0, 141.5, 129.3, 128.5, 128.3, 128.2, 127.9, 127.6, 117.5,
114.2, 79.3, 65.5, 26.2, 18.7, −4.6, −5.1; HRESIMS m/z [M + H]+
404.2411 (calcd for C26H34NOSi, 404.2404).
TMG Deprotection of Aryl Hydroxyl Groups in Solution. To a
one dram vial equipped with a stir bar was added 50 mg (1 equiv) of a
TBDMS- or TIPS-protected aryl hydroxyl, which was then dissolved in
500 μL of THF. In a separate vial was mixed 500 μL of ACN, 10 equiv
TMG, 11.5 equiv glacial acetic acid, and 10 μL H2O. This cleavage
cocktail was added to the protected hydroxyl and allowed to stir
overnight at room temperature. The reaction was quenched with water
(5 mL) and extracted three times with ethyl acetate (3 × 10 mL). The
organic extracts were combined, dried with sodium sulfate, filtered,
and concentrated to dryness. Purification was performed by silica gel
chromatography with mixtures of ethyl acetate and hexanes or
preparatory HPLC as described in General Methods section.
Deprotection of 1 to Give 4-(4-Hydroxyphenyl)-2-butanone (5).
Chlorodimethyl Benzylsiloxane Resin (9). FT-IR (on-bead KBr
pellet) νmax: 2922, 1068, 698 cm−1; gel-phase 13C NMR (125 MHz,
CD2Cl2) δ: 40.8, 2.4.
1
Yield = 95%, 16 mg; H NMR (C4D8O, 400 MHz): δ = 6.94 (d, J =
Chlorodiethyl Benzylsiloxane Resin (10).5 Chloroethylmethyl
Benzylsiloxane Resin (11). FT-IR (on-bead KBr pellet) νmax: 3025,
2921, 1071, 757, 698 cm−1; gel-phase 13C NMR (125 MHz, CD2Cl2)
δ: 40.8, 10.5, 6.5, 0.2.
7.4 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H), 2.75−2.60 (m, 4H), 2.01 (s,
3H); 13C NMR (C4D8O, 100 MHz): δ = 206.3, 156.9, 132.7, 129.8,
115.9, 46.0, 29.8, 29.6; HRESIMS m/z [M + NH4]+ 182.1190 (calcd
for C10H16NO2, 182.1176).
Deprotection of 2 to Give Acetovanillone (6). Yield = 63%, 10 mg;
1H NMR (C4D8O, 400 MHz): δ = 8.46 (bs, 1H), 7.40−7.37 (m, J =
2H), 6.68 (d, J = 7.1 Hz, 1H), 3.77 (s, 3H), 2.33 (s, 3H); 13C NMR
(C4D8O, 100 MHz): δ = 195.3, 152.6, 148.4, 130.7, 124.2, 115.3,
111.1, 56.1, 25.9; HRESIMS m/z [M + H]+ 167.0721 (calcd for
C9H11O3, 167.0703).
Chloroisopropylmethyl Benzylsiloxane Resin (12). FT-IR (on-
bead KBr pellet) νmax: 3025, 2923, 1064, 757, 696 cm−1; gel-phase 13
NMR (125 MHz, CD2Cl2) δ: 40.9, 20.8, 17.7, 16.6, 0.9.
C
Chloro-t-butylmethyl Benzylsiloxane Resin (13). FT-IR (on-bead
KBr pellet) νmax: 3025, 2924, 1076, 760, 698 cm−1; gel-phase 13C
NMR (125 MHz, CD2Cl2) δ: 40.9, 25.5, 20.8, −2.5.
Chloromethylphenyl Benzylsiloxane Resin (S11). FT-IR (on-bead
Deprotection of 3 to Give Acetaminophen (7). Yield = 63%, 10
KBr pellet) νmax: 3025, 2921, 2361, 1069, 758, 698 cm−1; gel-phase 13
NMR (125 MHz, CD2Cl2) δ: 133.9, 41.0, 1.4.
C
1
mg; H NMR (C4D8O, 500 MHz): δ = 8.74 (bs, 1H), 7.96 (bs, 1H),
7.36 (d, J = 7.8 Hz, 2H), 6.61 (d, J = 7.8 Hz, 2H), 1.96 (s, 3H); 13C
NMR (C4D8O, 125 MHz): δ = 167.6, 153.1, 131.1, 120.9, 115.0, 23.8;
HRESIMS m/z [M + H]+ 152.0711 (calcd for C8H10NO2, 152.0706).
Deprotection of 4 to Give Novobiocin (8). Yield = 58%, 14 mg; 1H
NMR (C4D8O, 500 MHz): δ = 9.22 (bs, 1H), 9.08 (bs, 1H), 7.81−
7.75 (m, 2H), 7.72 (d, J = 7.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.84
(d, J = 7.4 Hz, 1H), 5.93 (bs, 2H), 5.55 (s, 1H), 5.39 (t, J = 7.4 Hz,
Chloroisobutylmethyl Benzylsiloxane Resin (S12). FT-IR (on-
bead KBr pellet) νmax: 3025, 2922, 1070, 757, 698 cm−1; gel-phase 13
NMR (125 MHz, CD2Cl2) δ: 40.9, 28.7, 26.1, 25.9, 24.4, 1.9.
C
Chloro-n-butylmethyl Benzylsiloxane Resin (S13). FT-IR (on-
bead KBr pellet) νmax: 3025, 2922, 1071, 758, 698 cm−1; gel-phase 13
NMR (125 MHz, CD2Cl2) δ: 40.8, 26.2, 25.1, 18.1, 13.9, 0.8.
C
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dx.doi.org/10.1021/jo4010298 | J. Org. Chem. 2013, 78, 7349−7355