Key words
iridium - catalysis - hydrogen borrowing - phenols - alkylation
The efficiency of many synthetic organic procedures is limited by the need to perform
separate sequential oxidation and reduction (redox) steps to generate further molecular
complexity. As a result, hydrogen-borrowing catalysis has emerged as a useful alternative
to achieve C–C bond formation. This concept relies on the use of an appropriate transition-metal
catalyst to carry out oxidation and reduction steps in a one-pot process, with bond
formation between the reactive intermediates generated in situ (Scheme [1]). The entire process involves no net change in oxidation state and therefore constitutes
a powerful method for rapid C–C bond assembly, avoiding laborious chemical manipulations
and toxic reagents.[1]
Scheme 1 General scheme for hydrogen-borrowing catalysis
In a recent research program, we have started to develop new reactions relating to
hydrogen-borrowing chemistry, with particular focus on the alkylation of methylene
ketones to form branched products.[2] In doing so, we were able to complement this methodology with the synthesis of a
host of carboxylic acid derivatives.[2c] Our search for new substrates with which to perform hydrogen-borrowing chemistry
led us to consider phenols, because this class of molecules contributes widely to
numerous industrial processes leading to a variety of consumer products.[3] However, one of the main issues concerning phenol alkylation chemistry is that the
reaction can occur on either an oxygen or a carbon atom. Studies by Kornblum and Seltzer[4] have shown that the alkylation of 2,6-di-tert-butylphenol can be achieved at either the oxygen or the C4-position, the product
distribution being affected by changes in the steric nature of the alkyl halide electrophile.
Conversely, hydroxymethylation by using formaldehyde and hydroxide base proceeds exclusively
at the phenolic carbon positions. This so-called Lederer–Manasse reaction is an effective
means of producing C2- and/or C4-hydroxymethylated phenols, depending on the starting
phenol used.[5]
Given that hydrogen-borrowing chemistry typically involves the generation of an aldehyde
in situ from the corresponding primary alcohol and that it requires a base, we considered
that the Lederer–Manasse reaction might be adapted to this chemistry and thereby provide
a means to generate various alkylated products instead. We also wondered whether it
would be possible to use higher primary alcohols (i.e., those more complex than MeOH)
in this process. A subsequent search of the literature revealed that hydrogen-borrowing
chemistry involving phenols was relatively underexplored. Recent research by Yi and
co-workers[6a] and by Walton and Williams[6b] has shown that phenols can be alkylated at the C2-position by a dehydrative coupling
process, whereas Li’s group has reported[7] cleavage of the C–O bond to allow cross-coupling with amines. Here we report our
preliminary investigations that have led to the development of a hydrogen-borrowing
process that permits C4-alkylation of 2,6-di-tert-butylphenol.
Table 1 Optimization of Conditions for the C4-Alkylation of 2,6-Di-tert-butylphenol
|
|
Entry
|
Precatalyst and ligand
|
KOH (equiv)
|
Temp (°C)
|
Yielda (%)
|
|
|
|
|
1
|
2a
|
|
1
|
[Ir(cod)Cl]2 (1 mol%), PPh3 (4 mol%)
|
2
|
65
|
32
|
6
|
|
2
|
[Ir(cod)Cl]2 (1 mol%), PPh3 (4 mol%)
|
4
|
65
|
15
|
29
|
|
3
|
[Ir(cod)Cl]2 (1 mol%), PPh3 (4 mol%)
|
6
|
65
|
6
|
29
|
|
4
|
[Ir(cod)Cl]2 (5 mol%), PPh3 (20 mol%)
|
4
|
65
|
12
|
22
|
|
5
|
[Cp*IrCl2]2 (1 mol%)
|
4
|
65
|
9
|
40
|
|
6
|
[Cp*IrCl2]2 (2 mol%)
|
4
|
65
|
0
|
45
|
|
7
|
[Cp*IrCl2]2 (5 mol%)
|
4
|
65
|
0
|
82
|
|
8
|
[Cp*RhCl2]2 (5 mol%)
|
4
|
65
|
8
|
2
|
|
9
|
[Cp*IrCl2]2 (5 mol%)
|
4
|
25
|
53
|
0
|
|
10
|
[Cp*IrCl2]2 (5 mol%)
|
4
|
45
|
55
|
11
|
|
11b
|
[Cp*IrCl2]2 (5 mol%)
|
4
|
65
|
46
|
40
|
|
12c
|
[Cp*IrCl2]2 (5 mol%)
|
4
|
65
|
0
|
75
|
|
13d,e
|
[Cp*IrCl2]2 (5 mol%)
|
4
|
65
|
0
|
0
|
|
14
|
[Cp*IrCl2]2 (5 mol%)
|
–
|
65
|
99
|
0
|
|
15f
|
–
|
4
|
65
|
0
|
0
|
a Isolated combined yields of 1 and 2a. These products were inseparable by column chromatography and so the ratio 1/2a was determined by 1H NMR analysis of the purified mixture.
b Concentration = 0.1 M.
c Concentration = 0.4 M.
d O2 atmosphere.
e Only compounds 3 and 4 were observed by 1H NMR spectroscopy.
f Compound 4 was the major product; no 1, 2a, or 3 was observed by 1H NMR spectroscopy.
Previous research in our group has shown that [Ir(cod)Cl]2 (cod = cyclooctadiene; 1 mol%) and PPh3 (4 mol%) in combination with KOH and MeOH can be used to α-methylate various methylene
ketones in good to excellent yield.[2b] These conditions were therefore chosen as a starting point for the present study
with 2,6-di-tert-butylphenol (1) as substrate. Initial application of these conditions pleasingly gave a small quantity
of the desired C4-alkylated product 2a (6%) as well as 32% of unreacted 1 (Table [1], entry 1). Although not isolated, it was clear from its 1H NMR spectrum that the remaining crude material consisted of bisphenol 3 and bi(cyclohexadienylidene)dione 4.[8] Product 3 presumably resulted from addition of 1 to an intermediate p-quinone methide generated in situ,[9]
[10] which subsequently rearomatized, whereas 4 arose by oxidative dimerization of 1. To improve the product distribution in favor of 2a, we first chose to vary the amount of KOH. The addition of more base (4.0 or 6.0
equiv; entries 2 and 3) increased the amount of 2a to 29% in both cases. With the amount of KOH fixed at 4.0 equivalents, the catalyst/ligand
loading was increased five-fold (entry 4); this did not, however, result in a larger
quantity of 2a being formed. We then changed the precatalyst from Ir(I) to Ir(III), by employing
[Cp*IrCl2]2 (entry 5; Cp* = η5-pentamethylcyclopentadienyl). The addition of more [Cp*IrCl2]2 at the beginning of the reaction improved the yield of 2a considerably, with 5 mol% [Cp*IrCl2]2 providing clean formation of 2a in 82% yield (entry 7). Surprisingly, despite previous success,[2a] switching to Rh(III) resulted in extremely poor conversion into the desired C4-methylated
phenol (entry 8). Further investigation with [Cp*IrCl2]2 revealed that a temperature of 65 °C was crucial for the desired reaction pathway
to occur, with little 2a being formed at 25 °C and none being formed at 45 °C (entries 9 and 10). Concentration
was also shown to have an effect (entries 11 and 12), with 0.2 M appropriate to ensure
complete reaction and excellent yield.
With the optimal conditions in hand (entry 7), we also attempted to run the reaction
under an atmosphere of oxygen. Previous research by our group[2a] and by others[11] had shown oxygen to have a beneficial effect in hydrogen-borrowing chemistry when
MeOH was used as the alkylating agent. However, in this instance a complex mixture
was formed that contained neither unreacted 1 nor the desired product 2a (entry 13). Control experiments in which either KOH or [Cp*IrCl2]2 was omitted resulted in only unreacted 1 (entry 14) or in complete consumption of the starting material to provide the dimerized
product 4 (entry 15).
With the optimization studies complete, we next chose to investigate the scope of
the alcohols that could be used in this process (Scheme [2]). During this investigation, it quickly became apparent that higher temperatures
were required to obtain the desired alkylated products, as unreacted 2,6-di-tert-butylphenol (1), dimer 4, and several other unidentified byproducts were obtained when the reaction was performed
at 65 °C (not shown). We speculate that the additional steric bulk of these alcohols
hinders the addition of the metal hydride, thereby making the reduction step difficult
and preventing efficient formation of the desired alkylated product.
Scheme 2 Alcohol scope of the iridium-catalyzed C4-alkylation of 2,6-di-tert-butylphenol. The reactions were performed by using 0.30 mmol of 2,6-di-tert-butylphenol.
Pleasingly, adjustment of the reaction temperature (as shown in Scheme [2] for each alcohol) provided a wide range of C4-alkylated products. Both linear and
branched primary alcohols were readily processed by using this method, forming the
desired compounds in good yields (Scheme [2]; 5a–8a). Such materials would be difficult to make by conventional Friedel–Crafts-type alkylation
processes, which instead involve rearrangement of the putative unstable primary cation
to a more favorable secondary cation to yield the corresponding branched alkylated
product.[12] Cyclopropylmethanol could also be employed under the reaction conditions to provide
phenol 9a, but temperatures exceeding 85 °C resulted in competitive ring opening to give phenol
5a in appreciable amounts. Several benzylic and heterocyclic alcohols were also shown
to be viable alkylating agents, giving rise to products 10a–14a in good to excellent isolated yields (66–93%).[13]
Next, we attempted to remove the tert-butyl groups by means of a retro-Friedel–Crafts reaction. A selection of C4-alkylated
products were treated with AlCl3 in the presence of toluene as a tert-butyl acceptor (Scheme [3]).[14] Pleasingly, this process proceeded rapidly to deliver the corresponding para-substituted phenols 2b, 7b, 10b, and 14b in good to excellent yields, thereby permitting subsequent synthetic manipulation
at the ortho-positions.
Scheme 3 Removal of the tert-butyl groups under retro-Friedel–Crafts conditions
With respect to the mechanism of the C4-alkylation process, we assume that the reaction
proceeds by initial oxidation of the primary alcohol to the corresponding aldehyde
in situ to generate an iridium hydride[15] species. Deprotonation of the phenol then provides anion 15, which reacts through the π-system to form the corresponding C4-hydroxymethylated
species. Elimination of hydroxide produces p-quinone methide 16 as a fleeting intermediate, which might be subsequently reduced by the iridium hydride
to give the desired alkylated product (Scheme [4]).
Scheme 4 Proposed mechanism for the C4-alkylation reaction; the iridium dihydride is shown
for clarity[15]
In conclusion, we have shown that 2,6-di-tert-butylphenol can be straightforwardly alkylated at the C4-position by using a variety
of alcohols. The tert-butyl groups can subsequently be removed under retro-Friedel–Crafts conditions to
provide additional phenol products. Examinations of further applications of hydrogen-borrowing
chemistry and its relevance to phenols are currently underway in our laboratory.
Reactions performed according to General Procedure A were run in glassware that was
not flame-dried. Reactions performed according to General Procedure B were run under
argon in anhydrous conditions in flame-dried glassware. Benzyl alcohol was purchased
from Avocado, and used as supplied. All other reagents were commercially sourced from
Sigma-Aldrich, Alfa Aesar, or Fluorochem and were purchased in the highest available
purity. TLC was performed on precoated aluminum-backed Merck TLC Silica Gel 60 F254 plates that were visualized by UV irradiation (λ = 254 nm) and/or by staining with
KMnO4 or vanillin solutions. Flash column chromatography was performed with Merck Geduran® Si 60 (0.040–0.063 mm) silica gel with the indicated solvent systems. All solvents
used for chromatographic purification were of HPLC grade or equivalent and were supplied
by Sigma-Aldrich. Fourier-transform IR spectra were recorded on evaporated films on
a Bruker Tensor 27 spectrometer equipped with a Pike Miracle attenuated total reflectance
(ATR) sampling accessory. All NMR spectra were recorded on either a Bruker AVIII HD
400 spectrometer equipped with a 5 mm z-gradient BBFO probe or an AVIII HD 500 spectrometer equipped with a 5 mm double-resonance
BBF/H SMART probe, with the deuterated solvent acting as an internal deuterium lock.
1H NMR spectra were recorded at 400 MHz, and 13C NMR spectra were recorded at 101 MHz with broadband decoupling. Residual protic
solvent signal acted as an internal reference for 1H NMR, and the deuterated solvent carbon signal acted as an internal reference for
13C NMR (CDCl3: 1H NMR, δ = 7.26 ppm; 13C NMR, δ = 77.16 ppm; DMSO-d
6: 1H NMR, δ = 2.50 ppm; 13C NMR, δ = 39.50 ppm). Chemical shifts are quoted to the nearest 0.01 ppm for 1H NMR or 0.1 ppm for 13C NMR. Coupling constants are quoted to the nearest 0.1 Hz. High-resolution mass spectra
were recorded on a Thermo Exactive orbitrap spectrometer equipped with a Waters Equity
LC system with a flow rate of 0.2 mL/min for H2O–MeOH–HCO2H (10:89.9:0.1) as eluent. The system uses a heated electrospray ionization (HESI-II)
probe for ESI– and has a resolution of 50 000 FWHM under conditions for maximum sensitivity, with
an accuracy of better than 5 ppm for 24 h following external calibration on the day
of analysis. The reported mass is that containing the most abundant isotopes, with
each value given to four decimal places; all were within 5 ppm of the calculated mass.
Melting points were obtained by using a Leica VMTG heated-stage microscope equipped
with a Testo 720 thermometer and are uncorrected.
4-Alkyl-2,6-di-tert-butylphenols 2a, 5a–14a; General Procedure A
4-Alkyl-2,6-di-tert-butylphenols 2a, 5a–14a; General Procedure A
A 2–5 mL Biotage® microwave vial equipped with a stirrer bar was successively charged with 2,6-di-tert-butylphenol (1; 1.0 equiv), the appropriate alcohol (0.2 M), [Cp*IrCl2]2 (5 mol%), and KOH (4.0 equiv) in the open atmosphere. The vessel was sealed with
a microwave vial cap equipped with a Reseal septum and then purged with argon for
5 mins by using a balloon. The vial, complete with argon balloon, was heated to the
required temperature in a preheated oil bath for 24 h. The mixture was cooled to r.t.,
filtered through a silica plug (with elution by the appropriate eluent system to remove
inorganics and excess alcohol), and concentrated in vacuo. The product was purified
by column chromatography.
4-Alkylphenols 2b, 7b, 10b, and 14b; General Procedure B
4-Alkylphenols 2b, 7b, 10b, and 14b; General Procedure B
To a solution of the appropriate phenol (1.0 equiv) in toluene (0.02 M) at r.t. was
added a solution of AlCl3 (6.0 or 9.0 equiv) in MeNO2 (2.25 M) in one portion. The mixture was immediately heated to 60 °C by using a preheated
oil bath and maintained at this temperature for 5 min. The mixture was subsequently
cooled and poured into a separatory funnel containing ice and Et2O (1:1). The layers were separated and the aqueous layer was extracted with Et2O (×3). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. The product was purified by column chromatography.
2,6-Di-tert-butyl-4-methylphenol (2a)
2,6-Di-tert-butyl-4-methylphenol (2a)
2,6-Di-tert-butylphenol (1; 62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and MeOH (1.5 mL) were subjected
to General Procedure A at 65 °C. After 24 h, the mixture was cooled and filtered through
a plug of silica gel (eluting with pentane). Purification by column chromatography
(silica gel, eluent load, pentane) afforded the title compound 2a (54.1 mg, 82%) as a colorless solid; Rf
= 0.63 (pentane–Et2O, 98:2) [UV, KMnO4].
1H NMR (400 MHz, CDCl3): δ = 6.99 (s, 2 H), 5.02 (s, 1 H), 2.28 (s, 3 H), 1.44 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 151.7, 135.9, 128.4, 125.7, 34.4, 30.5, 21.3.
4-Butyl-2,6-di-tert-butylphenol (5a)
4-Butyl-2,6-di-tert-butylphenol (5a)
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and BuOH (1.5 mL) were subjected
to General Procedure A at 105 °C. After 24 h, the mixture was cooled and filtered
through a plug of silica gel (eluting with pentane). Purification by column chromatography
(silica gel, eluent load, pentane) afforded a colorless oil; yield: 56.0 mg (71%);
Rf
= 0.29 (pentane) [UV, KMnO4].
IR (film): 3649, 2955, 2928, 2914, 2873, 2856, 1484, 1467, 1433, 1392, 1361, 1315,
1249, 1231, 1212, 1196, 1157, 1121, 1024, 933 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.98 (s, 2 H), 5.02 (s, 1 H), 2.52 (dd, J = 8.0, 7.9 Hz, 2 H), 1.62–1.52 (m, 2 H), 1.44 (s, 18 H), 1.39 (app. sext, J = 7.2 Hz, 2 H), 0.94 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 151.8, 135.7, 133.7, 125.0, 35.9, 34.4, 34.4, 30.5, 22.9, 14.2.
HRMS (ESI): m/z [M – H]– calcd for C18H29O1: 261.2224; found: 261.2224.
4-Isobutyl-2,6-di-tert-butylphenol (6a)[16]
4-Isobutyl-2,6-di-tert-butylphenol (6a)[16]
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and 2-methylpropan-1-ol (1.5 mL)
were subjected to General Procedure A at 105 °C. After 24 h, the mixture was cooled
and filtered through a plug of silica gel (eluting with pentane). Purification by
column chromatography (silica gel, eluent load, pentane) afforded a colorless oil;
yield: 32.8 mg (42%); Rf
= 0.29 (pentane) [UV, KMnO4].
IR (film): 3649, 3003, 2952, 2911, 2868, 2844, 1484, 1467, 1434, 1394, 1385, 1362,
1315, 1271, 1250, 1233, 1214, 1196, 1157, 1120, 1089, 1024, 932 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.94 (s, 2 H), 5.02 (s, 1 H), 2.39 (d, J = 7.1 Hz, 2 H), 1.80 (app. nonet, J = 6.7 Hz, 1 H), 1.45 (s, 18 H), 0.92 (d, J = 6.7 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 151.8, 135.5, 132.4, 125.7, 45.6, 34.4, 30.6, 30.6, 22.7.
HRMS (ESI): m/z [M – H]– calcd for C18H29O1: 261.2224; found: 261.2223.
2,6-Di-tert-butyl-4-isopentylphenol (7a)
2,6-Di-tert-butyl-4-isopentylphenol (7a)
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and 3-methylbutan-1-ol (1.5 mL)
were subjected to General Procedure A at 125 °C. After 24 h, the mixture was cooled
and filtered through a plug of silica gel (eluting with pentane). Purification by
column chromatography (silica gel, eluent load, pentane) afforded a colorless oil;
yield: 53.4 mg (64%); Rf
= 0.38 (pentane) [UV, KMnO4].
IR (film): 3649, 3003, 2954, 2912, 2870, 1484, 1468, 1434, 1388, 1363, 1314, 1269,
1250, 1231, 1212, 1197, 1157, 1121, 1095, 1025, 932 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.00 (s, 2 H), 5.04 (s, 1 H), 2.57–2.51 (m, 2 H), 1.63 (app. nonet, J = 6.5 Hz, 1 H), 1.54–1.46 (m, 2 H), 1.46 (s, 18 H), 0.97 (d, J = 6.6 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 151.7, 138.8, 133.8, 124.9, 41.5, 34.5, 34.0, 30.5, 28.2, 22.8.
HRMS (ESI): m/z [M – H]– calcd for C19H31O1: 275.2380; found: 275.2380.
2,6-Di-tert-butyl-4-(2-ethoxyethyl)phenol (8a)
2,6-Di-tert-butyl-4-(2-ethoxyethyl)phenol (8a)
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and 2-ethoxyethanol (1.5 mL) were
subjected to General Procedure A at 105 °C. After 24 h, the mixture was cooled and
filtered through a plug of silica gel [eluting with pentane–Et2O (98:2)]. Purification by column chromatography [silica gel, eluent load, pentane–Et2O (98:2)] afforded a colorless oil; yield: 53.7 mg (64%); Rf
= 0.40 (pentane–Et2O, 95:5) [UV, KMnO4].
IR (film): 3646, 3003, 2972, 2954, 2913, 2865, 1485, 1434, 1392, 1375, 1359, 1316,
1272, 1250, 1233, 1212, 1197, 1157, 1131, 1107, 1048, 1025, 994 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.03 (s, 2 H), 5.07 (s, 1 H), 3.61 (t, J = 7.5 Hz, 2 H), 3.53 (q, J = 7.0 Hz, 2 H), 2.82 (t, J = 7.5 Hz, 2 H), 1.44 (s, 18 H), 1.23 (t, J = 7.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 152.3, 135.8, 129.5, 125.6, 72.3, 66.3, 36.4, 34.4, 30.5, 15.4.
HRMS (ESI): m/z [M – H]– calcd for C18H29O2: 277.2173; found: 277.2172.
2,6-Di-tert-butyl-4-(cyclopropylmethyl)phenol (9a)
2,6-Di-tert-butyl-4-(cyclopropylmethyl)phenol (9a)
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and cyclopropylmethanol (1.5 mL)
were subjected to General Procedure A at 85 °C. After 24 h, the mixture was cooled
and filtered through a plug of silica gel (eluting with pentane). Purification by
column chromatography (silica gel, eluent load, pentane) afforded a colorless solid;
yield: 31.0 mg (40%); mp 40–42 °C; Rf
= 0.29 (pentane) [UV, KMnO4].
IR (film): 3646, 3076, 3002, 2954, 2913, 2872, 1484, 1468, 1434, 1392, 1361, 1317,
1305, 1250, 1231, 1211, 1196, 1157, 1120, 1044, 1015, 981 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.08 (s, 2 H), 5.05 (s, 1 H), 2.47 (d, J = 6.8 Hz, 2 H), 1.44 (s, 18 H), 0.97 (ttt, J = 8.0, 6.9, 5.0 Hz, 1 H), 0.55–0.49 (m, 2 H), 0.20–0.17 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 152.0, 135.7, 132.8, 125.0, 40.4, 34.4, 30.5, 12.2, 4.8.
HRMS (ESI): m/z [M – H]– calcd for C18H27O1: 259.2067; found: 259.2066.
2,6-Di-tert-butyl-4-(tetrahydrofuran-2-ylmethyl)phenol (10a)
2,6-Di-tert-butyl-4-(tetrahydrofuran-2-ylmethyl)phenol (10a)
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and tetrahydrofurfuryl alcohol (1.5 mL)
were subjected to General Procedure A at 125 °C. After 24 h, the mixture was cooled
and filtered through a plug of silica gel [eluting with pentane–Et2O (98:2)]. Purification by column chromatography [silica gel, eluent load, pentane–Et2O (98:2)] afforded a colorless solid; yield: 62.5 mg (72%); mp 74–76 °C; Rf
= 0.26 (pentane–Et2O, 95:5) [UV, KMnO4].
This procedure was also scaled up five-fold (1.50 mmol of 2,6-di-tert-butylphenol) to give 10a in comparable yield [321 mg (74%)].
IR (film): 3637, 2975, 2955, 2917, 2873, 2855, 1484, 1432, 1399, 1390, 1367, 1359,
1305, 1271, 1235, 1213, 1197, 1164, 1139, 1120, 1060, 1027, 968 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.01 (s, 2 H), 5.05 (s, 1 H), 4.03 (app. quint, J = 6.7 Hz, 1 H), 3.90 (ddd, J = 8.3, 7.2, 6.1 Hz, 1 H), 3.74 (td, J = 7.9, 6.2 Hz, 1 H), 2.85 (dd, J = 13.6, 6.1 Hz, 1 H), 2.65 (dd, J = 13.6, 6.8 Hz, 1 H), 1.99–1.78 (m, 3 H), 1.62–1.51 (m, 1 H), 1.43 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 152.3, 135.7, 129.6, 125.8, 80.6, 68.0, 42.1, 34.4, 31.2, 30.5, 25.7.
HRMS (ESI): m/z [M – H]– calcd for C19H29O2: 289.2173; found: 289.2172.
4-Benzyl-2,6-di-tert-butylphenol (11a)[17]
4-Benzyl-2,6-di-tert-butylphenol (11a)[17]
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and BnOH (1.5 mL) were subjected
to General Procedure A at 125 °C. After 24 h, the mixture was cooled and filtered
through a plug of silica gel (eluting with pentane). Purification by column chromatography
(silica gel, eluent load, pentane) afforded a colorless solid; yield: 75.1 mg (84%);
mp 47–49 °C; Rf
= 0.29 (pentane) [UV, KMnO4].
IR (film): 3623, 2960, 2954, 2912, 2872, 1495, 1482, 1454, 1431, 1392, 1363, 1308,
1246, 1232, 1212, 1197, 1176, 1143, 1120, 1076, 1027, 935 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.30 (m, 2 H), 7.27–7.20 (m, 3 H), 7.04 (s, 2 H), 5.11 (s, 1 H), 3.95
(s, 2 H), 1.46 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 152.2, 141.9, 135.9, 131.7, 129.0, 128.5, 125.9, 125.6, 42.0, 34.4, 30.5.
HRMS (ESI): m/z [M – H]– calcd for C21H27O1: 295.2067; found: 295.2067.
2,6-Di-tert-butyl-4-(2-furylmethyl)phenol (12a)
2,6-Di-tert-butyl-4-(2-furylmethyl)phenol (12a)
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and furfuryl alcohol (1.5 mL) were
subjected to General Procedure A at 125 °C. After 24 h, the mixture was cooled and
filtered through a plug of silica gel [eluting with pentane–Et2O (99:1)]. Purification by column chromatography [silica gel, eluent load, pentane–Et2O (100:0 to 99:1)] afforded a colorless solid; yield: 68.5 mg (80%); mp 72–74 °C;
Rf
= 0.44 (pentane) [UV, KMnO4].
IR (film): 3639, 2976, 2952, 2915, 2876, 2862, 1509, 1471, 1432, 1401, 1390, 1360,
1307, 1272, 1236, 1213, 1197, 1169, 1138, 1120, 1068, 1028, 1004, 938 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.34 (dd, J = 1.8, 0.8 Hz, 1 H), 7.04 (s, 2 H), 6.30 (dd, J = 3.1, 1.9 Hz, 1 H), 6.00 (dd, J = 3.1, 0.8 Hz, 1 H), 5.10 (s, 1 H), 3.90 (s, 2 H), 1.43 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 155.5, 152.5, 141.4, 136.0, 128.8, 125.4, 110.3, 106.1, 34.4, 34.4, 30.4.
HRMS (ESI): m/z [M – H]– calcd for C19H25O2: 285.1860; found: 285.1859.
2,6-Di-tert-butyl-4-(2-thienylmethyl)phenol (13a)
2,6-Di-tert-butyl-4-(2-thienylmethyl)phenol (13a)
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and 2-thienylmethanol (1.5 mL) were
subjected to General Procedure A at 125 °C. After 24 h, the mixture was cooled and
filtered through a plug of silica gel [eluting with pentane–Et2O (100:0 to 98:2 to 95:5)]. Purification by column chromatography [silica gel, eluent
load, pentane–Et2O (99:1)] afforded a yellow solid; yield: 60.0 mg (66%); mp 39–41 °C; Rf
= 0.50 (pentane–Et2O, 98:2) [UV, KMnO4].
IR (film): 3628, 3000, 2967, 2953, 2912, 2870, 1484, 1430, 1391, 1360, 1314, 1271,
1249, 1229, 1211, 1195, 1183, 1146, 1121, 1104, 1073, 1036, 1023, 932 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.15 (dd, J = 5.1, 1.2 Hz, 1 H), 7.08 (s, 2 H), 6.94 (dd, J = 5.1, 3.4 Hz, 1 H), 6.81 (dd, J = 3.4, 1.1 Hz, 1 H), 5.12 (s, 1 H), 4.10 (s, 2 H), 1.45 (s, 18 H).
13C NMR (101 MHz, CDCl3): δ = 152.4, 145.2, 136.0, 131.0, 126.9, 125.3, 124.9, 123.7, 36.0, 34.5, 30.4.
HRMS (ESI): m/z [M – H]– calcd for C19H25O1S1: 301.1632; found: 301.1631.
2,6-Di-tert-butyl-4-(pyridin-3-ylmethyl)phenol (14a)
2,6-Di-tert-butyl-4-(pyridin-3-ylmethyl)phenol (14a)
2,6-Di-tert-butylphenol (62.0 mg, 0.30 mmol), [Cp*IrCl2]2 (12.0 mg, 0.015 mmol), KOH (67.3 mg, 1.20 mmol), and pyridin-3-ylmethanol (1.5 mL)
were subjected to General Procedure A at 105 °C. After 24 h, the mixture was cooled
and filtered through a plug of silica gel [eluting with pentane–Et2O (50:50)]. Purification by column chromatography [silica gel, eluent/CH2Cl2 load, pentane–Et2O (50:50)] afforded a colorless solid; yield: 83.0 mg (93%); mp 139–141 °C; Rf
= 0.22 (pentane–Et2O, 50:50) [UV, KMnO4].
This procedure was also scaled up five-fold (1.50 mmol of 2,6-di-tert-butylphenol), and afforded 14a in a comparable yield [384 mg (86%)].
IR (film): 3297, 2993, 2961, 2948, 2916, 2868, 1576, 1481, 1455, 1435, 1423, 1390,
1359, 1288, 1266, 1234, 1212, 1198, 1172, 1136, 1116, 1097, 1042, 1021, 985 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.50 (d, J = 1.9 Hz, 1 H), 8.45 (dd, J = 4.8, 1.6 Hz, 1 H), 7.49 (dt, J = 7.7, 1.9 Hz, 1 H), 7.20 (dd, J = 7.7, 4.8 Hz, 1 H), 6.96 (s, 2 H), 5.12 (s, 1 H), 3.89 (s, 2 H), 1.41 (s, 18 H).
13C NMR (126 MHz, CDCl3): δ = 152.5, 150.3, 147.6, 137.3, 136.4, 136.2, 130.5, 125.5, 123.5, 39.1, 34.5,
30.4.
HRMS (ESI): m/z [M – H]– calcd for C20H26N1O1: 296.2020; found: 296.2018.
p-Cresol (2b)
To a solution of 2,6-di-tert-butyl-4-methylphenol (2a; 66.1 mg, 0.30 mmol) in toluene (15 mL) was added a solution of AlCl3 (240.0 mg, 1.8 mmol) in MeNO2 (0.80 mL) in one portion according to General Procedure B. Purification by column
chromatography [silica gel, eluent load, pentane–Et2O (85:15)] afforded a colorless solid; yield: 27.1 mg (84%); Rf
= 0.20 (pentane–Et2O, 90:10) [UV, KMnO4].
1H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 8.4 Hz, 2 H), 6.74 (d, J = 8.4 Hz, 2 H), 4.88 (br s, 1 H), 2.28 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 153.3, 130.2, 130.1, 115.2, 20.6.
4-Isopentylphenol (7b)
To a solution of 2,6-di-tert-butyl-4-isobutylphenol (7a; 48.7 mg, 0.18 mmol) in toluene (9 mL) was added a solution of AlCl3 (144.0 mg, 1.08 mmol) in MeNO2 (0.48 mL) in one portion according to General Procedure B. Purification by column
chromatography [silica gel, eluent load, pentane–Et2O (90:10)] afforded a colorless oil; yield: 26.4 mg (89%); Rf
= 0.26 (pentane–Et2O, 85:15) [UV, KMnO4].
IR (film): 3333, 2955, 2930, 2901, 2869, 2849, 1614, 1597, 1513, 1468, 1453, 1441,
1384, 1366, 1336, 1265, 1237, 1219, 1171, 1115, 1097, 1082, 1016, 855 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.06 (d, J = 8.5 Hz, 2 H), 6.76 (d, J = 8.5 Hz, 2 H), 4.81 (s, 1 H), 2.57–2.52 (m, 2 H), 1.58 (app. nonet, J = 6.6 Hz, 1 H), 1.51–1.43 (m, 2 H), 0.93 (d, J = 6.6 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 153.4, 135.5, 129.5, 115.2, 41.2, 33.0, 27.7, 22.7.
HRMS (ESI): m/z [M – H]– calcd for C11H15O1: 163.1128; found: 163.1128.
4-(Tetrahydrofuran-2-ylmethyl)phenol (10b)
4-(Tetrahydrofuran-2-ylmethyl)phenol (10b)
To a solution of 2,6-di-tert-butyl-4-(tetrahydrofuran-2-ylmethyl)phenol (10a; 87.1 mg, 0.30 mmol) in toluene (15 mL) was added a solution of AlCl3 (240.0 mg, 1.80 mmol) in MeNO2 (0.80 mL) in one portion according to General Procedure B. Purification by column
chromatography [silica gel, eluent load, pentane–Et2O (80:20 to 70:30)] afforded a colorless oil; yield: 53.0 mg (99%); Rf
= 0.21 (pentane–Et2O, 70:30) [UV, KMnO4].
IR (film): 3261, 3019, 2976, 2950, 2922, 2874, 2858, 1614, 1595, 1514, 1444, 1373,
1359, 1309, 1267, 1227, 1202, 1171, 1111, 1041, 1012, 954.
1H NMR (400 MHz, CDCl3): δ = 7.04 (d, J = 8.4 Hz, 2 H), 6.68 (d, J = 8.4 Hz, 2 H), 4.94 (s, 1 H), 4.08 (quint, J = 6.6 Hz, 1 H), 3.91 (ddd, J = 8.3, 7.1, 6.5 Hz, 1 H), 3.78 (ddd, J = 8.2, 7.6, 6.1 Hz, 1 H), 2.82 (dd, J = 13.7, 6.7 Hz, 1 H), 2.69 (dd, J = 13.7, 6.2 Hz, 1 H), 1.99–1.80 (m, 3 H), 1.63–1.52 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 154.5, 130.6, 130.3, 115.4, 80.6, 68.0, 41.1, 31.0, 25.7.
HRMS (ESI): m/z [M + H]+ calcd for C11H15O2: 179.1067; found: 179.1068
4-(Pyridin-3-ylmethyl)phenol (14b)
4-(Pyridin-3-ylmethyl)phenol (14b)
To a solution of 2,6-di-tert-butyl-4-(pyridin-3-ylmethyl)phenol (14a; 89.2 mg, 0.30 mmol) in toluene (15 mL) was added a solution of AlCl3 (240.0 mg, 1.80 mmol) in MeNO2 (0.80 mL) in one portion according to General Procedure B. Purification by column
chromatography (silica gel, solid load, Et2O) afforded a colorless solid; yield: 32.0 mg (58%); mp 185–187 °C; Rf
= 0.25 (Et2O) [UV, KMnO4].
IR (film): 3063, 3041, 2956, 2921, 2852, 2791, 2723, 2674, 2607, 2360, 2341, 2324,
2189, 2166, 1990, 1610, 1593, 1579, 1512, 1481, 1454, 1433, 1420, 1379, 1348, 1319,
1294, 1278, 1267, 1246, 1204, 1187, 1175, 1124, 1101, 1047, 1032, 1009, 956 cm–1.
1H NMR (500 MHz, DMSO-d
6): δ = 9.22 (s, 1 H), 8.46 (br s, 1 H), 8.39 (br s, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.29 (br s, 1 H), 7.02 (d, J = 8.2 Hz, 2 H), 6.68 (d, J = 8.4 Hz, 2 H), 3.83 (s, 2 H).
13C NMR (126 MHz, DMSO-d
6): δ = 155.7, 149.5, 147.1, 137.4, 135.9, 130.5, 129.5, 123.5, 115.3, 37.2.
HRMS (ESI): m/z [M + H]+ calcd for C12H12N1O1: 186.0913; found: 186.0914.
