Iridium-catalyzed C-H activation/borylation/oxidation for the preparation of bis-protected phloroglucinol derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.03.049

The preparation of bis-protected phloroglucinol derivatives from a range of protected resorcinol substrates is presented. Functionalization was achieved via a two-step, one-pot iridium-catalyzed C-H activation/borylation/oxidation protocol. Our system gave high conversions to the arylboronic esters and good yields of the desired phenols following subsequent oxidation. A range of common protecting group categories was studied including alkyl, silyl, ether and ester.

Full text of DOI:10.1016/j.tetlet.2010.03.049

Tetrahedron Letters 51 (2010) 2690–2692
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Tetrahedron Letters
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Iridium-catalyzed C–H activation/borylation/oxidation for the preparation
of bis-protected phloroglucinol derivatives
Laura J. Marshall a, Karl M. Cable b, Nigel P. Botting a,
*
a School of Chemistry, University of St. Andrews, St. Andrews, Fife, KY16 9ST, UK
b GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of bis-protected phloroglucinol derivatives from a range of protected resorcinol sub-
strates is presented. Functionalization was achieved via a two-step, one-pot iridium-catalyzed C–H acti-
vation/borylation/oxidation protocol. Our system gave high conversions to the arylboronic esters and
good yields of the desired phenols following subsequent oxidation. A range of common protecting group
categories was studied including alkyl, silyl, ether and ester.
Received 8 February 2010
Revised 4 March 2010
Accepted 12 March 2010
Available online 17 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Resorcinol
Phloroglucinol
C–H activation
Oxidation
New routes for the preparation of phenols are important in nat-
ural product synthesis as many naturally occurring compounds
such as the flavonoids and the anthocyanins, contain mono-pheno-
lic or polyphenolic moieties.1 In 1993, Marder and co-workers2 re-
ported the borylation of toluene in the presence of catecholborane
and an iridium catalyst—this was the beginning of iridium-cata-
lyzed C–H activation/borylation as we know it now.3 Maleczka
et al.4 reported the preparation of phenols from electron-poor sub-
strates using an iridium-catalyzed C–H activation/borylation/oxi-
dation procedure. Miyaura and co-workers5 also utilized a similar
system, and in both papers the majority of substrates studied were
restricted to those containing halide substituents. This route to
phenols is of great importance as it allows the introduction of a
meta-arylboronic ester in arenes bearing ortho/para directing
groups, followed by conversion into the meta-substituted phenol
via oxidation. The regioselectivity observed is largely due to steric
factors in both the substrate and the catalyst/ligand system.
According to the conditions reported by Maleczka,4 transforma-
tion of the 1,3-disubstituted benzene into the arylboronic ester
was achieved through treatment of the arene with pinacolborane
(HBPin), an iridium catalyst (Ind)Ir(COD) and either 1,2-bis(dim-
ethylphosphanyl)ethane (dmpe) or 1,2-bis(diphenylphospha-
nyl)ethane (dppe) as a ligand, at temperatures ranging from
room temperature to 150 °C. Conversion of the arylboronic ester
into the phenol was accomplished by treatment with a 50:50
mixture of acetone and aqueous OxoneÒ at room temperature
(Scheme 1).
Due to the importance of polyphenolic compounds and also the
desire for the use of a range of protecting groups in organic synthe-
sis, we chose to expand the scope of the existing methodology to
include the use of electron-rich diprotected resorcinol substrates
to yield phloroglucinol derivatives 3a–g (Scheme 1). Protecting
groups bearing aromatic or unsaturated hydrocarbon units were
not suitable for this protocol, as these moieties would also be func-
tionalized during the borylation step. Scheme 1 outlines the sub-
strates utilized in our studies (1a–g) which incorporate a range
of common protecting groups.
Studieswere undertakenin order to determinethe optimumcon-
ditions required for the C–H activation/borylation of our substrates.
We found that the reagents and conditions reported by Maleczka
et al.4 for relatively electron-poor substrates were not suitable. Un-
der these conditions no conversion was achieved to the desired aryl-
boronic ester intermediates 2a–g even after prolonged heating. Due
to the fact that our protected resorcinol substrates 1a–g were com-
paratively electron-rich, it was concluded that an alternative system
would be required. Indeed, it was found that the use of bis(pinacola-
to)diboron (B2Pin2) in iso-hexane, catalyzed by the iridium dimer
[Ir(OMe)(COD)]2 with 4,40-di-tert-butyl-2,20-bipyridine (dtbpy) as
ligand4,5 was successful for the majority of our substrates (Table 1).6
We found that a decrease in catalyst/ligand loading was benefi-
cial (1.0 mol % catalyst, 2.0 mol % ligand, cf. 1.5 mol % and
3.0 mol %, respectively4). An increase in the quantity of B2Pin2
(0.6–1.0 equiv) was also required to reach conversions above 60%.
As expected, due to the electron-rich nature of our substrates,
* Corresponding author. Tel.: +44 1334 463856; fax: +44 1334 3080.
E-mail address: npb@st-andrews.ac.uk (N.P. Botting).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.049

L. J. Marshall et al. / Tetrahedron Letters 51 (2010) 2690–2692
2691
RO
OR
Ir-catalysed
OR
RO
OR
RO
C-H activation/borylation
oxidation
B
O
O
OH
3a: R = Me
1a: R = Me
1b
: R = MOM
3b
1c
: R = MOM
: R = MEM
2a
: R = Me
3c: R = MEM
3d: R = TMS
1d: R = TMS
1e: R = Boc
2b: R = MOM
2c: R = MEM
2d: R = TMS
3e
1f
: R = Boc
: R = Ac
: R = Ac
3f
1g: R = H
2e
: R = Boc
3g: R = H
2f: R = Ac
2g: R = H
Scheme 1. Synthesis of 1,3,5-trisubstituted arenes from protected resorcinol derivatives.
Table 1
Reaction conditions and results for the C–H activation/borylation/oxidation6
Entry
Substrate
Product
B2Pin2 (equiv)
[Ir(OMe)(COD)]2 (mol %)
dtbpy (mol %)
Conversion to intermediate 2a–fa (%)
Yield of 3 (%)
1
2
3
4
1a
1b
1c
1d
1e
1f
3a
3b
3c
3g
3e
3f
1.0
1.0
1.0
1.0
1.6
1.0
1.0
1.0
1.0
1.0
1.3
2.0
2.0
2.0
2.0
2.0
2.1
2.0
97
95
59
61
71
62
92b
99
87c
51
5
6d
45
44
a
b
c
Conversion calculated from the integration of the 1H NMR signals of the starting material and intermediate.
Desired intermediate 2d isolated.
Unprotected phloroglucinol (3g) obtained as the only product.
d
HBPin (1.0 equiv) was also added to reaction mixture; dppe was used as the ligand in place of dtbpy.
we observed that the use of a higher reaction temperature (110 °C cf.
25 °C)4,5 significantly increased the conversions. Oxidation of the
arylboronic esters 2a–g to the desired phenols 3a–c,e–g also took
longer than reported (30 min cf. 7 min).
it should be noted that HBPin alone was not the best reagent for
the borylation. We found that use of a combination of both
B2Pin2 (1 equiv) and HBPin (1 equiv) was optimal for the reaction.
A higher catalyst/ligand loading was also required, as was the use
of dppe as ligand in place of dtbpy. Under these conditions, conver-
sion into 2f was achieved, giving 3,5-diacetoxyphenol (3f) in 44%
yield after oxidation and purification.14 Although this substrate
proved to be the most troublesome, with significantly lower con-
versions being observed, the yield of the 3f was only slightly lower
than those achieved for substrates 1a–1e.
We conclude that the scope of the iridium-catalyzed C–H acti-
vation/borylation/oxidation procedure2–4 has been extended to in-
clude the use of bis-protected resorcinols. The use of such
substrates gives potential for the methodology to be applied to
the synthesis of polyphenols. We report the successful regioselec-
tive functionalization of six substrates utilizing a range of protect-
ing group classes which are common in natural product synthesis.
Use of our optimized conditions resulted in high conversions into
the arylboronic ester intermediates and good to excellent yields
of the desired arenes bearing 1,3,5-substitution. A noteworthy re-
sult was the preparation of phloroglucinol (3g) from 1,3-di(tri-
methylsilyl)resorcinol (1d) with cleavage of the silyl-protecting
groups being observed during the oxidation step.
Initially, we investigated the reaction of 1,3-dimethoxybenzene
(1a). Efficient conversion into the arylboronic ester 2a was achieved
after heating at 110 °C for 18 h (Table 1, entry 1).6 Subsequent oxida-
tion of this intermediate followed by purification yielded 3,5-dime-
thoxyphenol (3a) in 59% yield.7,8 We then undertook studies using
the other five protecting groups previously outlined (Scheme 1) in
order to expand the scope of the reaction. Similar results were ob-
tained using MOM- and MEM-protected substrates 1b and 1c, giving
95% and 71% conversion to arylboronic esters 2b and 2c, respec-
tively. Isolated yields of 61% of 3b9 and 62% of 3c10 were recorded
(Table 1, entries 2 and 3).
An interesting result was obtained with the TMS-protected sub-
strate 1d (Table 1, entry 4). Analysis of the crude intermediate
showed 92% conversion to arylboronic ester 2d. However, during
the oxidation step, deprotection of the TMS groups was observed,
with phloroglucinol (3g) being isolated in 87% yield as the sole
product.11,12 This result is of particular importance when consider-
ing the preparation of phloroglucinol via this route, as a deprotec-
tion step would not be required. Under all conditions attempted,
the reaction was not successful with resorcinol (1g) as a substrate.
Application of the optimized conditions to the borylation of
Boc-protected resorcinol 1e resulted in lower conversions than
those observed for all other substrates studied so far. It was found
that increasing the quantity of B2Pin2 and increasing the catalyst/
ligand loading were beneficial, with 99% conversion to arylboronic
ester 2e being achieved (Table 1, entry 5). Subsequent oxidation
and purification gave 3e in 51% yield.13
Acknowledgements
Financial support from the BBSRC and GlaxoSmithKline is grate-
fully acknowledged.
References and notes
Conversion of the acetoxy-protected resorcinol 1f into arylbo-
ronate 2f was poor (<10%) using our conditions (Table 1, entry
6). Use of HBPin and dppe, as previously reported for electron-poor
substrates was more successful.4 The highest conversion achieved
using the conditions described in the literature4 was 11%. However,
1. Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier: New York, 1996.
2. Nguyen, P.; Bloom, H. P.; Westcott, S. A.; Taylor, N. J.; Marder, T. B. J. Am. Chem.
Soc. 1993, 115, 9329–9330.
3. Marder, T. B. Organomet. Chem. 2008, 34, 46–57.
4. Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III J. Am. Chem. Soc. 2003,
125, 7792–7793.

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L. J. Marshall et al. / Tetrahedron Letters 51 (2010) 2690–2692
5. Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem., Int. Ed. 2002,
41, 3056–3058.
OH); dC (100 MHz, CDCl3) 56.0 (CH3), 94.3 (CH2), 97.2 (CH-2), 97.6 (CH-4,6),
157.8 (C-OH), 159.0 (C-OMOM); HRMS (CI): MH+, C10H15O5 requires 215.0919,
found 215.0919.
6. General procedure for the preparation of 3a–g via 2a–g: A degassed solution of
substrate (1 equiv) in iso-hexane (5 mL/mmol) was transferred into an air-free
flask containing B2Pin2, HBPin (if required), [Ir(OMe)(COD)]2 and either dtbpy
or dppe. The flask was sealed and the reaction mixture was stirred at 110 °C for
18 h. Iso-hexane was removed under reduced pressure to give the intermediate
borolane 2a–g. Acetone (3.2 mL/mmol) was added to the crude aryl boronate
and aqueous OxoneÒ (1.2 equiv in 3.2 mL/mmol H2O) added dropwise over 2–
4 min. The reaction mixture was stirred vigorously for 30 min and then the
reaction was quenched by the addition of saturated Na2SO3 solution. The
aqueous phase was extracted with EtOAc. The organic solvents were removed
under reduced pressure and the crude material was dissolved in CH2Cl2 and
passed through a plug of silica gel. The solvents were then removed under
reduced pressure to give the crude product 3a–g. Purification was by column
chromatography.
10. 3,5-Bis(2-methoxyethoxymethoxy)phenol (3c):
m
max/cmꢀ1 3381, 2952, 2899,
1598, 1495, 1469, 1213, 1149, 1029, 918, 830; dH (400 MHz, CDCl3) 3.31 (6H,
s, CH3O), 3.48–3.52 (4H, m, CH2OCH3), 3.71–3.76 (4H, m, CH2O), 5.12 (4H, s,
OCH2O), 6.19 (2H, d, J = 2.1 Hz, H-2,6), 6.22 (1H, t, J = 2.1 Hz, H-4); dc (100 MHz,
CDCl3) 59.0 (CH3O), 67.6 (CH2O), 71.6 (CH2OCH3), 93.5 (OCH2O), 97.4 (CH-4),
97.6 (CH-2,6), 157.7 (C-1), 159.0 (C-3,5); HRMS (ES): M+Na+, C14H22O7Na
requires 325.1263, found 325.1262.
11. Phloroglucinol (3g): mp 213–214 °C (lit.12 216 °C); dH (300 MHz, CDCl3-DMSO-
d6) 5.82 (3H, s, H-2,4,6); dC (100 MHz, CDCl3-DMSO-d6) 94.8 (CH-2,4,6), 158.8
(C-1,3,5).
12. Ismaili, L. J. Pharm. Biomed. Anal. 2009, 32, 549–553.
13. Di-tert-butyl 5-hydroxy-1,3-phenylene biscarbonate (3e): m
max/cmꢀ1 3373, 2950,
2871, 1597, 1481, 1210, 1124, 915; dH (400 MHz, CDCl3) 1.48 (18H, s, CH3),
6.45 (2H, d, J = 2.1 Hz, H-4,6), 6.57 (1H, t, J = 2.1 Hz, H-2); dc (100 MHz, CDCl3)
27.7 (CH3), 84.0 (C(CH3)3), 106.5 (CH-2), 106.9 (CH-4,6), 151.4 (C = O), 151.9 (C-
1,3), 157.0 (C-5); HRMS (ES): M+Na+, C16H22O7Na requires 349.1263, found
349.1263.
7. 3,5-Dimethoxyphenol (3a): mp 41–42 °C (lit.8 40 °C); dH (400 MHz, CDCl3) 3.76
(6H, s, CH3), 6.04 (2H, d, J = 2.2 Hz, H-2,6), 6.08 (1H, t, J = 2.2 Hz, H-4); dC
(100 MHz, CDCl3) 55.3 (CH3), 93.1 (CH-4), 94.3 (CH-2,6), 157.4 (C-OH), 161.6 (C-
3,5).
8. Loubinoux, B.; Coudert, G.; Guillaumet, G. Synthesis 1980, 638–640.
14. 3,5-Diacetoxyphenol (3f): mp 165 °C (lit.15 168 °C); dH (400 MHz, CDCl3) 2.18
(6H, s, CH3), 6.32 (1H, t, J = 2.0 Hz, H-4), 6.40 (2H, d, J = 2.0 Hz, H-2,6), 8.40 (1H,
br s, OH).
9. 3,5-Bis(methoxymethyl)phloroglucinol (3b): m
max/cmꢀ1 3365, 2958, 1601, 1498,
1467, 1214, 1149, 1031, 922, 828; dH (400 MHz, CDCl3) 3.39 (6H, s, CH3), 5.03
(4H, s, CH2), 6.14–6.17 (2H, m, H-4,6), 6.20–6.23 (1H, m, H-2), 6.62 (1H, br s,
15. Campbell, T. W. J. Am. Chem. Soc. 1951, 73, 2708–2712.