Iridium-Catalyzed C4-Alkylation of 2,6-Di-tert-butylphenol by Using Hydrogen-Borrowing Catalysis

Article abstract of DOI:10.1055/s-0035-1561439

An iridium-catalyzed hydrogen-borrowing process has been developed whereby 2,6-di-tert-butylphenol can be alkylated at the C4-position by using a range of primary alcohols (11 examples, 40-93% yield). Following this, a selection of the products obtained underwent retro-Friedel-Crafts reactions to provide para-substituted phenols, which could potentially undergo further synthetic manipulations.

Full text of DOI:10.1055/s-0035-1561439

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
J. R. Frost et al.
Paper
Synthesis
Iridium-Catalyzed C4-Alkylation of 2,6-Di-tert-butylphenol by
Using Hydrogen-Borrowing Catalysis
James R. Frost
[Cp*IrCl2]2 (5 mol%)
KOH (4.0 equiv)
ROH
OH
OH
OH
AlCl3 (6.0 equiv)
PhMe/MeNO2
Choon Boon Cheong
Timothy J. Donohoe*
t-Bu
t-Bu
t-Bu
t-Bu
60 °C
65–125 °C
Ar, 24 h
Department of Chemistry, University of Oxford, Chemical
Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK
timothy.donohoe@chem.ox.ac.uk
retro-Friedel–Crafts
alkylation
hydrogen borrowing
R
R
11 examples
40–93%
Received: 24.03.2016
Accepted: 02.04.2016
R
OH
R
Nu
Published online: 12.05.2016
DOI: 10.1055/s-0035-1561439; Art ID: ss-2016-z0210-op
[M]
[M]
H
Abstract An iridium-catalyzed hydrogen-borrowing process has been
developed whereby 2,6-di-tert-butylphenol can be alkylated at the C4-
position by using a range of primary alcohols (11 examples, 40–93%
yield). Following this, a selection of the products obtained underwent
retro-Friedel–Crafts reactions to provide para-substituted phenols,
which could potentially undergo further synthetic manipulations.
oxidation
reduction
[M]
or [M]
H
H
R
O
R
Nu
H2O
Scheme 1 General scheme for hydrogen-borrowing catalysis
Nu
Key words iridium, catalysis, hydrogen borrowing, phenols, alkyla-
tion
The efficiency of many synthetic organic procedures is
limited by the need to perform separate sequential oxida-
tion and reduction (redox) steps to generate further molec-
ular 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 reduc-
tion steps in a one-pot process, with bond formation be-
tween 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 manipula-
tions and toxic reagents.1
In a recent research program, we have started to devel-
op new reactions relating to hydrogen-borrowing chemis-
try, with particular focus on the alkylation of methylene ke-
tones 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 pro-
cesses leading to a variety of consumer products.3 However,
one of the main issues concerning phenol alkylation chem-
istry is that the reaction can occur on either an oxygen or a
carbon atom. Studies by Kornblum and Seltzer4 have shown
that the alkylation of 2,6-di-tert-butylphenol can be
achieved at either the oxygen or the C4-position, the prod-
uct distribution being affected by changes in the steric na-
ture of the alkyl halide electrophile. Conversely, hy-
droxymethylation 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 in-
volves the generation of an aldehyde in situ from the corre-
sponding 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 won-
dered whether it would be possible to use higher primary
alcohols (i.e., those more complex than MeOH) in this pro-
cess. A subsequent search of the literature revealed that hy-
drogen-borrowing chemistry involving phenols was rela-
tively underexplored. Recent research by Yi and co-work-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
J. R. Frost et al.
Paper
Synthesis
ers6a and by Walton and Williams6b has shown that phenols
can be alkylated at the C2-position by a dehydrative cou-
pling process, whereas Li’s group has reported7 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.
phenol (1) as substrate. Initial application of these condi-
tions pleasingly gave a small quantity of the desired C4-al-
kylated product 2a (6%) as well as 32% of unreacted 1 (Table
1
1, entry 1). Although not isolated, it was clear from its H
NMR spectrum that the remaining crude material consisted
of bisphenol 3 and bi(cyclohexadienylidene)dione 4.8 Prod-
uct 3 presumably resulted from addition of 1 to an interme-
diate p-quinone methide generated in situ,9,10 which subse-
quently rearomatized, whereas 4 arose by oxidative di-
merization 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) in-
creased the amount of 2a to 29% in both cases. With the
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 excel-
lent yield.2b These conditions were therefore chosen as a
starting point for the present study with 2,6-di-tert-butyl-
Table 1 Optimization of Conditions for the C4-Alkylation of 2,6-Di-tert-butylphenol
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
conditions
MeOH (c = 0.2 M)
Ar, 24 h
1
2a
Additional products observed (not isolated):
t-Bu
t-Bu
t-Bu
t-Bu
O
O
HO
OH
t-Bu
t-Bu
t-Bu
t-Bu
3
4
Entry
Precatalyst and ligand
KOH (equiv)
Temp (°C)
Yielda (%)
1
2a
1
2
[Ir(cod)Cl]2 (1 mol%), PPh3 (4 mol%)
[Ir(cod)Cl]2 (1 mol%), PPh3 (4 mol%)
[Ir(cod)Cl]2 (1 mol%), PPh3 (4 mol%)
2
4
6
4
4
4
4
4
4
4
4
4
4
–
4
65
65
65
65
65
65
65
65
25
45
65
65
65
65
65
32
15
6
6
29
29
22
40
45
82
2
3
4
[Ir(cod)Cl]2 (5 mol%), PPh3 (20 mol%)
[Cp*IrCl2]2 (1 mol%)
[Cp*IrCl2]2 (2 mol%)
[Cp*IrCl2]2 (5 mol%)
[Cp*RhCl2]2 (5 mol%)
[Cp*IrCl2]2 (5 mol%)
[Cp*IrCl2]2 (5 mol%)
[Cp*IrCl2]2 (5 mol%)
[Cp*IrCl2]2 (5 mol%)
[Cp*IrCl2]2 (5 mol%)
[Cp*IrCl2]2 (5 mol%)
–
12
9
5
6
0
7
0
8
8
9
53
55
46
0
0
10
11b
12c
13d,e
14
15f
11
40
75
0
0
99
0
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.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
J. R. Frost et al.
Paper
Synthesis
amount of KOH fixed at 4.0 equivalents, the catalyst/ligand
loading was increased five-fold (entry 4); this did not, how-
ever, 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-pentamethylcyclopentadien-
yl). 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 (en-
try 7). Surprisingly, despite previous success,2a switching to
Rh(III) resulted in extremely poor conversion into the de-
sired 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 en-
sure complete reaction and excellent yield.
[Cp*IrCl2]2 (5 mol%)
KOH (4.0 equiv)
ROH (c = 0.2 M)
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
Temp
Ar, 24 h
R
1
2a, 5a–14a
OH
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
2a: 82%a
5a: 71%c
6a: 42%c
OH
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
With the optimal conditions in hand (entry 7), we also
attempted to run the reaction under an atmosphere of oxy-
gen. Previous research by our group2a and by others11 had
shown oxygen to have a beneficial effect in hydrogen-bor-
rowing 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 ma-
terial to provide the dimerized product 4 (entry 15).
O
7a: 64%d
8a: 64%c
9a: 40%b
OH
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
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 uniden-
tified byproducts were obtained when the reaction was
performed at 65 °C (not shown). We speculate that the ad-
ditional steric bulk of these alcohols hinders the addition of
the metal hydride, thereby making the reduction step diffi-
cult and preventing efficient formation of the desired al-
kylated product.
O
O
10a: 72%d
11a: 84%d
12a: 80%d
t-Bu
OH
OH
t-Bu
t-Bu
t-Bu
S
N
13a: 66%d
14a: 93%c
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 con-
ventional Friedel–Crafts-type alkylation processes, which
instead involve rearrangement of the putative unstable pri-
mary cation to a more favorable secondary cation to yield
the corresponding branched alkylated product.12 Cyclopro-
pylmethanol could also be employed under the reaction
conditions to provide phenol 9a, but temperatures exceed-
ing 85 °C resulted in competitive ring opening to give phe-
nol 5a in appreciable amounts. Several benzylic and hetero-
Reaction performed at: a65 °C; b85 °C; c105 °C; d125 °C
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.
cyclic 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
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
J. R. Frost et al.
Paper
Synthesis
para-substituted phenols 2b, 7b, 10b, and 14b in good to
excellent yields, thereby permitting subsequent synthetic
manipulation at the ortho-positions.
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 condi-
tions 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 pur-
chased in the highest available purity. TLC was performed on precoat-
ed aluminum-backed Merck TLC Silica Gel 60 F254 plates that were vi-
sualized by UV irradiation (λ = 254 nm) and/or by staining with
KMnO4 or vanillin solutions. Flash column chromatography was per-
formed 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 evapo-
rated 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 spec-
trometer 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 inter-
nal deuterium lock. 1H NMR spectra were recorded at 400 MHz, and
13C NMR spectra were recorded at 101 MHz with broadband decou-
pling. 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-d6: 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 Ex-
active orbitrap spectrometer equipped with a Waters Equity LC sys-
OH
OH
AlCl3 (6.0 or 9.0 equiv)
PhMe/MeNO2
t-Bu
t-Bu
60 °C, 5 mins
R
R
2a: R = CH3
2b: R = CH3, 84%
7a: R = CH2CH2CH(CH3)2
10a: R = CH2(2-THF)
14a: R = CH2(3-Pyr)
7b: R = CH2CH2CH(CH3)2, 89%
10b: R = CH2(2-THF), 99%
14b: R = CH2(3-Pyr), 58%
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 ox-
idation of the primary alcohol to the corresponding alde-
hyde in situ to generate an iridium hydride15 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 pro-
duces p-quinone methide 16 as a fleeting intermediate,
which might be subsequently reduced by the iridium hy-
dride to give the desired alkylated product (Scheme 4).
tem with
a flow rate of 0.2 mL/min for H2O–MeOH–HCO2H
OH
OH
(10:89.9:0.1) as eluent. The system uses a heated electrospray ioniza-
tion (HESI-II) probe for ESI– and has a resolution of 50 000 FWHM un-
der conditions for maximum sensitivity, with an accuracy of better
than 5 ppm for 24 h following external calibration on the day of anal-
ysis. The reported mass is that containing the most abundant iso-
topes, 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.
t-Bu
t-Bu
t-Bu
t-Bu
R
1
17
KOH
H2O
[Ir]
H
[Ir]
H
O–
O
4-Alkyl-2,6-di-tert-butylphenols 2a, 5a–14a; General Procedure A
t-Bu
t-Bu
t-Bu
t-Bu
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 elu-
tion by the appropriate eluent system to remove inorganics and ex-
cess alcohol), and concentrated in vacuo. The product was purified by
column chromatography.
H2O
R
O
R
15
16
A
H
H
+
+
[Ir]
+
KOH
[Ir]
+
H2O
R
OH
R
O
A
Scheme 4 Proposed mechanism for the C4-alkylation reaction; the
iridium dihydride is shown for clarity15
In conclusion, we have shown that 2,6-di-tert-butylphe-
nol can be straightforwardly alkylated at the C4-position by
using a variety of alcohols. The tert-butyl groups can subse-
quently be removed under retro-Friedel–Crafts conditions
to provide additional phenol products. Examinations of fur-
ther applications of hydrogen-borrowing chemistry and its
relevance to phenols are currently underway in our labora-
tory.
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 tempera-
ture for 5 min. The mixture was subsequently cooled and poured into
a separatory funnel containing ice and Et2O (1:1). The layers were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
J. R. Frost et al.
Paper
Synthesis
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.
the mixture was cooled and filtered through a plug of silica gel (elut-
ing 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].
2,6-Di-tert-butyl-4-methylphenol (2a)
IR (film): 3649, 3003, 2954, 2912, 2870, 1484, 1468, 1434, 1388,
1363, 1314, 1269, 1250, 1231, 1212, 1197, 1157, 1121, 1095, 1025,
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, pen-
tane) afforded the title compound 2a (54.1 mg, 82%) as a colorless sol-
id; 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,
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.
21.3.
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 [elut-
ing with pentane–Et2O (98:2)]. Purification by column chromatogra-
phy [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].
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 pen-
tane). Purification by column chromatography (silica gel, eluent load,
pentane) afforded a colorless oil; yield: 56.0 mg (71%); Rf = 0.29 (pen-
tane) [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
.
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 = 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.
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 C18H29O2: 277.2173; found:
277.2172.
HRMS (ESI): m/z [M – H]– calcd for C18H29O1: 261.2224; found:
261.2224.
2,6-Di-tert-butyl-4-(cyclopropylmethyl)phenol (9a)
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 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 (elut-
ing 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].
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 (elut-
ing 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): 3646, 3076, 3002, 2954, 2913, 2872, 1484, 1468, 1434,
1392, 1361, 1317, 1305, 1250, 1231, 1211, 1196, 1157, 1120, 1044,
IR (film): 3649, 3003, 2952, 2911, 2868, 2844, 1484, 1467, 1434,
1394, 1385, 1362, 1315, 1271, 1250, 1233, 1214, 1196, 1157, 1120,
1015, 981 cm–1
.
1089, 1024, 932 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.
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 C18H27O1: 259.2067; found:
259.2066.
HRMS (ESI): m/z [M – H]– calcd for C18H29O1: 261.2224; found:
261.2223.
2,6-Di-tert-butyl-4-(tetrahydrofuran-2-ylmethyl)phenol (10a)
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 tetrahydrofurfuryl al-
cohol (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
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,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
J. R. Frost et al.
Paper
Synthesis
[eluting with pentane–Et2O (98:2)]. Purification by column chroma-
tography [silica gel, eluent load, pentane–Et2O (98:2)] afforded a col-
orless solid; yield: 62.5 mg (72%); mp 74–76 °C; Rf = 0.26 (pentane–
Et2O, 95:5) [UV, KMnO4].
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 [elut-
ing with pentane–Et2O (100:0 to 98:2 to 95:5)]. Purification by col-
umn chromatography [silica gel, eluent load, pentane–Et2O (99:1)] af-
forded a yellow solid; yield: 60.0 mg (66%); mp 39–41 °C; Rf = 0.50
(pentane–Et2O, 98:2) [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
.
IR (film): 3628, 3000, 2967, 2953, 2912, 2870, 1484, 1430, 1391,
1360, 1314, 1271, 1249, 1229, 1211, 1195, 1183, 1146, 1121, 1104,
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.
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 C19H29O2: 289.2173; found:
289.2172.
HRMS (ESI): m/z [M – H]– calcd for C19H25O1S1: 301.1632; found:
301.1631.
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 pen-
tane). 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].
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 [elut-
ing with pentane–Et2O (50:50)]. Purification by column chromatogra-
phy [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 (pen-
tane–Et2O, 50:50) [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
.
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%)].
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).
IR (film): 3297, 2993, 2961, 2948, 2916, 2868, 1576, 1481, 1455,
1435, 1423, 1390, 1359, 1288, 1266, 1234, 1212, 1198, 1172, 1136,
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.
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.
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 [elut-
ing with pentane–Et2O (99:1)]. Purification by column chromatogra-
phy [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].
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 Gener-
al 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).
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 = 153.3, 130.2, 130.1, 115.2, 20.6.
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:
4-Isopentylphenol (7b)
285.1859.
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
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
J. R. Frost et al.
Paper
Synthesis
Procedure B. Purification by column chromatography [silica gel, elu-
ent load, pentane–Et2O (90:10)] afforded a colorless oil; yield:
26.4 mg (89%); Rf = 0.26 (pentane–Et2O, 85:15) [UV, KMnO4].
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561439.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
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
.
References
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.
(1) For recent reviews, see: (a) Dobereiner, G. E.; Crabtree, R. H.
Chem. Rev. 2010, 110, 681. (b) Bähn, S.; Imm, S.; Neubert, L.;
Zhang, M.; Neumann, H.; Beller, M. ChemCatChem 2011, 3, 1853.
(c) Pan, S.; Shibata, T. ACS Catal. 2013, 3, 704. (d) Gunanathan,
C.; Milstein, D. Science 2013, 341, 1229712. (e) Ketcham, J. M.;
Shin, I.; Montgomery, T. P.; Krische, M. J. Angew. Chem. Int. Ed.
2014, 53, 9142. (f) Obora, Y. ACS Catal. 2014, 4, 3972. (g) Yang,
Q.; Wang, Q.; Yu, Z. Chem. Soc. Rev. 2015, 44, 2305.
(h) Nandakumar, A.; Midya, S. P.; Landge, V. G.; Balaraman, E.
Angew. Chem. Int. Ed. 2015, 54, 11022.
(2) (a) Chan, L. M. K.; Poole, D. L.; Shen, D.; Healy, M. P.; Donohoe, T.
J. Angew. Chem. Int. Ed. 2014, 53, 761. (b) Shen, D.; Poole, D. L.;
Shotton, C. C.; Kornahrens, A. F.; Healy, M. P.; Donohoe, T. J.
Angew. Chem. Int. Ed. 2015, 54, 1642. (c) Frost, J. R.; Cheong, C.
B.; Akhtar, W. M.; Caputo, D. F. J.; Stevenson, N. G.; Donohoe, T.
J. J. Am. Chem. Soc. 2015, 137, 15664.
HRMS (ESI): m/z [M – H]– calcd for C11H15O1: 163.1128; found:
163.1128.
4-(Tetrahydrofuran-2-ylmethyl)phenol (10b)
To a solution of 2,6-di-tert-butyl-4-(tetrahydrofuran-2-ylmethyl)phe-
nol (10a; 87.1 mg, 0.30 mmol) in toluene (15 mL) was added a solu-
tion of AlCl3 (240.0 mg, 1.80 mmol) in MeNO2 (0.80 mL) in one por-
tion according to General Procedure B. Purification by column chro-
matography [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].
(3) Weissemel, K.; Arpe, H.-J. In Industrial Organic Chemistry, 3rd
ed.; Wiley-VCH: Weinheim, 1997, 358.
(4) Kornblum, N.; Seltzer, R. J. Am. Chem. Soc. 1961, 83, 3668.
(5) (a) Lederer, L. J. Prakt. Chem. 1894, 50, 223. (b) Manasse, O. Ber.
Dtsch. Chem. Ges. 1894, 27, 2409.
(6) (a) Lee, D.-H.; Kwon, K.-H.; Yi, C. S. J. Am. Chem. Soc. 2012, 134,
7325. (b) Walton, J. W.; Williams, J. M. J. Angew. Chem. Int. Ed.
2012, 51, 12166.
(7) Chen, Z.; Zeng, H.; Girard, S. A.; Wang, F.; Chen, N.; Li, C.-J.
Angew. Chem. Int. Ed. 2015, 54, 14487.
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,
(8) (a) For 1H NMR data for 3, see: Baik, W.; Lee, H. J.; Yoo, C. H.;
Jung, J. W.; Kim, B. H. J. Chem. Soc., Perkin Trans. 1 1997, 587.
(b) For 1H NMR data for 4, see: Barton, B.; Logie, C. G.;
Schoonees, B. M.; Zeelie, B. Org. Process Res. Dev. 2005, 9, 62.
(9) Bi(cyclohexadienylidene)dione 4 is not isolable, but has been
previously characterized in solution by 1H NMR spectroscopy;
see: (a) Winstein, S.; Filar, L. J. Tetrahedron Lett. 1960, 9.
(b) Dyall, L. K.; Winstein, S. J. Am. Chem. Soc. 1972, 94, 2196.
(10) Although not observed in the 1H NMR spectrum of the crude
product, it is likely that addition of MeOH to the benzoquinone
methide is also a competitive process; as a result, elimination of
methoxide may also be required prior to reduction. See: Omura,
K. J. Org. Chem. 1991, 56, 921.
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)
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 (sili-
ca 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,
(11) (a) Gabrielsson, A. A.; van Leeuwen, P. P.; Kaim, W. W. Chem.
Commun. 2006, 4926. (b) Jiang, B.; Feng, Y.; Ison, E. A. J. Am.
Chem. Soc. 2008, 130, 14462.
1187, 1175, 1124, 1101, 1047, 1032, 1009, 956 cm–1
.
1H NMR (500 MHz, DMSO-d6): 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-d6): δ = 155.7, 149.5, 147.1, 137.4, 135.9,
130.5, 129.5, 123.5, 115.3, 37.2.
(12) (a) Friedel, C.; Crafts, J. M. J. Chem. Soc. 1877, 32, 725. (b) Friedel,
C.; Crafts, J. M. Bull. Soc. Chim. Fr. 1877, 530.
(13) Application of this methodology to other phenols has so far
proven limited.
(14) (a) Matsuura, B. S.; Keylor, M. H.; Li, B.; Lin, Y.; Allison, S.; Pratt,
D. A.; Stephenson, C. R. J. Angew. Chem. Int. Ed. 2015, 54, 3754.
(b) Saleh, S. A.; Tashtoush, H. I. Tetrahedron 1998, 54, 14157.
(15) At this stage we cannot comment with any certainty whether
an iridium mono- or dihydride species is formed.
(16) Phillips, J. P.; Gillmore, J. G.; Schwartz, P.; Brammer, L. E. Jr.;
Berger, D. J.; Tanko, J. M. J. Am. Chem. Soc. 1998, 120, 195.
(17) Nishinaga, A.; Nakamura, K.; Matsuura, T.; Rieker, A.; Koch, D.;
Griesshammer, R. Tetrahedron 1979, 35, 2493.
HRMS (ESI): m/z [M + H]+ calcd for C12H12N1O1: 186.0913; found:
186.0914.
Acknowledgment
We are grateful to the EPSRC [J.R.F., T.J.D., Established Career Fellow-
ship (EP/L023121/1)] and A*STAR, Singapore (C.B.C.) for financial sup-
port.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G