Palladium-catalysed ortho-arylation of carbamate-protected phenols

Article abstract of DOI:10.1039/b916724m

The carbamate (-O₂CNR₂) function is an excellent directing group for palladium-catalysed direct arylation reactions giving both protected or free mono- or di-substituted phenols, as well as an example of a dibenzopyranone, depending on coupling partners (aryl iodides or diaryliodonium salts) and conditions. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b916724m

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Palladium-catalysed ortho-arylation of carbamate-protected phenols†
Robin B. Bedford,*a Ruth L. Webstera and Charlotte J. Mitchellb
Received 10th July 2009, Accepted 17th August 2009
First published as an Advance Article on the web 30th September 2009
DOI: 10.1039/b916724m
The carbamate (–O2CNR2) function is an excellent directing group for palladium-catalysed direct
arylation reactions giving both protected or free mono- or di-substituted phenols, as well as an example
of a dibenzopyranone, depending on coupling partners (aryl iodides or diaryliodonium salts) and
conditions.
Introduction
The construction of a biaryl subunit is a key transformation in
the synthesis of many important compounds including natural
products, polymers, liquid crystals and ligands for homogenous
catalysis. Cross-coupling reactions (Scheme 1(a)), particularly the
Suzuki reaction (E = B(OH)2, B(OR)2), are routinely employed in
biaryl synthesis,1 but recently much attention has focused on direct
arylation reactions where aromatic C–H activation circumvents
the synthesis and use of an organometallic nucleophilic coupling
partner (Scheme 1(b).2,3
Scheme 2 (a) Directed intermolecular C–H activation and (b) the
rhodium-catalysed ortho-arylation of phenols.
which can be used in catalytic quantities as a consequence of
in situ transesterification of the resultant 2-arylphosphinite (or
phosphoramidate) with the free phenol.
There are, however, significant drawbacks with the current
methodology. Firstly the reactions require the use of rhodium
which is considerably more expensive than palladium. Secondly,
optimum product yield is obtained from substrates with a bulky
substituent, typically a tert-butyl group, in the ortho¢ position. Un-
substituted or 4-substituted phenols give lower rates and only ever
yield the ortho, ortho¢-diarylated products. Fortunately the tert-
butyl group can be removed, which allows for the construction of
unsymmetrical terphenyls,6d but its introduction and subsequent
loss is far from atom or step economical. A final consideration is
that the reactions need to be performed under an inert atmosphere.
In order to address all of these shortcomings we decided to
examine the use of carbamates as protecting/directing groups in
the unprecedented palladium-catalysed ortho-arylation of phe-
nols. The choice of aryl carbamates was made as they are
readily prepared, easy to convert back to free phenols, show
interesting biological properties in their own right8 and the 2-
arylated products are useful precursors for dibenzopyranones via
Snieckus–Fries rearrangements.9
Scheme 1 Biaryl bond-formation by catalytic (a) cross-coupling or
(b) direct arylation.
One method frequently employed in intermolecular arylation
is to modify the substrate with a ‘directing group’ that not only
protects what may otherwise be areactive centre, butalso facilitates
and selectively directs C–H activation (Scheme 2(a)). A recent
elegant example of this is the use of ureas as surrogates for anilines
in ortho-functionalisation reactions under very mild conditions
employing palladium catalysis.4 In a similar manner anilides have
been used extensively in place of anilines.5
We have an ongoing interest in the ortho-arylation of phenols
and have described a variety of rhodium-catalysed reactions
wherein the directing group is a phosphinite or phosphoramidite
ligand: (ArO)PY2, Y = R, NR2 respectively (Scheme 2(b)).6,7 An
advantage here is that the (ArO)PY2 function is formed in situ
from a phosphinite, chlorophosphine or aminophosphine all of
Results and discussion
Table 1 outlines selected results from the optimisation of the
ortho-arylation of diethyl carbamate 1a with 4-iodotoluene.†10
As a starting point we used the catalyst and solvent system
employed by Daugulis and co-workers for the ortho-arylation of
anilides, although we found that less forcing reaction conditions
and/or shorter reaction times were typically required.11 In all cases
reactions were performed under air using solvents as received; a
significant operational advantage.
aSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8
1TS, UK. E-mail: r.bedford@bristol.ac.uk
bGlaxoSmithKline, Stevenage, SG1 2NY, UK
† Electronic supplementary information (ESI) available: Table of opti-
misation data, spectroscopic data, 1H and 13C NMR spectra. See DOI:
10.1039/b916724m
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Table 1 Reaction optimisation (selected results).a
Spec. yield (%) b
Entry
Mol% Pd
Temp./◦C
50
Time/h
48
2a
3a
Total
1
10
5
10
45
46
46.5
27.5
43.5
<5
39
44
41
14
0
17
0
45
31
0
99
87
60.5
27.5
60.5
<5
84
2
3c
4d
5
90
110
100
18
6
7e
8e
9d,e
5
2
1
51
22.5
82
22.5
a Conditions: 1a (0.241 mmol), 4-IC6H4Me (0.963 mmol), AgOAc (0.482 mmol) and TFA (1 ml). b Determined by 1H NMR (1,3,5-C6H3(OMe)3 internal
standard). c 1 equiv. AgOAc. d 1 equiv. ArI. e Microwave heating.
At 50 ◦C within 48 h good to excellent conversions to ortho-
arylated products were seen, but with no selectivity between the
mono- and di-arylated compounds 2a and 3a respectively (entries
1 and 2). Lowering either the silver acetate or aryl iodide loadings
gave significant improvements in selectivity for 2a at the expense
of overall yield (entries 3 and 4). Mono-selectivity could also be
increased by raising the temperature and lowering the reaction
time (entry 5) but at higher temperature catalyst decomposition
occurred (entry 6). Gratifyingly, good activity was observed under
microwave heating conditions within much shorter reaction times.
Using the microwave heating conditions, with a 1–2 h reaction
time, we next examined the scope of the reaction and these results
are summarised in Table 2.† Varying the carbamate function
proved deleterious to the overall yield compared with diethyl-
carbamate, although both dimethyl and diisopropyl carbamates
gave enhanced mono-arylation selectivity (entries 1 and 3). Both
electron-withdrawing and donating groups were tolerated in the
para-position of the aryl iodide (entries 5–9) including a bromide
which opens the possibility of further catalytic functionalisation.
meta-Substitution was also well tolerated (entries 10–12) but
poor activity was seen with ortho-substituted aryl iodides (entries
13 and 14). The introduction of meta-substitution on the phe-
noxide residue led to selective mono-arylation with no diarylated
products observed (entries 15–20).
In order to improve mono-selectivity with unsubstituted or
para-substituted phenols, we examined briefly the coupling of
carbamates with diaryliodonium salts (Scheme 3).12,13 We were
pleased to find that in these cases, the reactions proceeded with
complete mono-selectivity. Under these reaction conditions, loss
of the carbamate occurred yielding the free phenols 4a–d. By
contrast, when the synthesis of 4a was performed at 80 ◦C then 1H
NMR analysis of the crude product mixture indicated ~40% 4a
along with ~20% of the corresponding carbamate 2c and ~18% of
the diarylated carbamate 3c. This, combined with the observation
that free 4-tert-butylphenol does not react with diaryliodonium
salts under the reaction conditions, suggests that the observed
mono-selectivity at higher temperature results from the rate of
deprotection of the products 4 being competitive with secondary
arylation at elevated temperature.
The isolated mono-arylated carbamates 2 could be used as
substrates in further arylation reactions to generate symmetrical
or unsymmetrical terphenyls; thus subjecting 2c to the same con-
ditions as those used in Table 2 for 2 h with 4-iodo methylbenzoate,
4-iodobromobenzene and 4-iodotoluene yielded the diarylated
arylcarbamates 3c, l and m respectively.
Scheme 3 Conditions: 1a (0.06 g, 0.241 mmol), diaryliodonium triflate
(0.482 mmol), Pd(OAc)2 (10 mol%), AcOH (1 ml).
Reaction of 1a with a 2-methylbenzoate-containing iodonium
salt yielded the dibenzopyranone 5a via a novel tandem arylation–
deprotection–lactonisation pathway. Dibenzopyranones are an
important class of natural products that display a range of
biological properties and consequently such a compact synthesis
is desirable.
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Table 2 ortho-Arylation of carbamates under microwave heating.a
Entry
1
Carbamateb
Aryl iodide
Time/ h
2
Spec. Yield (%) c(isolated)
1b
2b, 37.5 (20)
3b, 4 (3)
2
3
1a
2c, 60 (59)
3c, 24 (22)
2d, 22 (14)d
1c
1d
3d, 0
0
4
5
1a
2a, 39 (30)
3a, 45 (41)
2e, 43 (32)
6
3e, 35 (34)
2f, 40 (37)
7
3f, 42.5 (36)
2g, 27 (23)
8
1
2
3g, 65 (64)
2h, 57.5 (53)
9
3h, 22.5 (14)
2i, 53 (30)
10
1
2
3i, 33
2i, 30
3i, 70 (70)
2j, 42 (40)
11
12
2
3j, 8f
2k, 20 (16)g
3k, 0
13
14
0e
1e
2l, 89 (77)
15
16
2m, 33 (27)
2n, 74 (67)
1f
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Table 2 (Contd.)
Entry
17
Carbamateb
Aryl iodide
Time/ h
Spec. Yield (%) c(isolated)
2o, 64 (62)
2p, 33 (32)
18
1g
19
2p, 20 (17)
a Conditions: 1 (0.241 mmol), ArI (0.963 mmol), AgOAc (0.482 mmol), Pd(OAc)2 (5 mol%) and TFA (1 ml), microwave heating, 100 ◦C. b Site of arylation
indicated where ambiguous. c Spectroscopic yield determined by 1H NMR (1,3,5-C6H3(OMe)3 internal standard). d Isolated after 1 h reaction. e GC-MS
reveals significant homocoupling of the aryl iodide. f Not isolated. g Not isolated pure.
General methodology for the preparation of meta-substituted
phenyl-N,N-dialkyl carbamates
Conclusions
In summary, we have developed two complementary palladium-
catalysed ortho-arylation reactions of carbamate-protected phe-
nols with either aryl iodides or diaryliodonium salts. The former
gives both mono- and di-arylated products, whilst the latter
method favours mono-arylation. These processes represent a
significant improvement on the previously reported rhodium-
catalysed reactions in that palladium is substantially cheaper,
the reactions can be performed under air and small phenolic
precursors without 2-substitution are well tolerated. The use of
diaryliodonium salts as the arylating reagent leads to deprotection
of the phenol which can in turn be exploited in the one-pot
synthesis of a dibenzopyranone via a novel sequential arylation–
deprotection–lactonisation process, an area that we are currently
investigating further.
To a solution of the appropriate phenol (0.81 mmol) in MeCN
(15 ml) was added K2CO3 (2.23 g, 16.11 mmol) followed by
carbamoyl chloride (1.10 ml, 0.87 mmol). The reaction mixture
was heated at 85 ◦C for 18 h. The reaction mixture was then
diluted with water (20 ml) and washed with Et2O (3 ¥ 30 ml). The
organic extracts were then washed with NaOH solution (50 ml,
1 M) followed by water (50 ml), then brine (50 ml). The organic
extracted were then dried over MgSO4 and concentrated in vacuo.
The crude mixture was subjected to column chromatography to
yield the carbamate.
Optimisation for the palladium-catalysed ortho-arylation of 1a
with 4-iodotoluene
To a Schlenk tube, sealed Young’s tube or microwave vial was
added the appropriate catalyst, ligand, additive, 1a (0.060 g,
0.241 mmol), 4-iodotoluene (0.210 g, 0.963 mmol) and solvent
(1 ml). The mixture was stirred at the appropriate temperature
for the designated time period and then allowed to cool to
room temperature. H2O was added (5 ml) followed by NaHCO3
(saturated solution, 10 ml) and the organic phase was extracted
into dichloromethane (3 ¥ 10 ml). The combined organic extracts
were dried over MgSO4, filtered and the solvent removed under
reduced pressure. 1,3,5-Trimethoxybenzene (0.040 g, 0.241 mmol)
was added and the mixture dissolved in ~1 ml CDCl3, an aliquot
Experimental
General experimental conditions
Chemical reagents were used as supplied from commercial sources
unless otherwise specified. Melting points were uncorrected.
Microwave reactions were carried out with an Emrys Optimiser
Microwave (0-20 bar pressure range, 15–300 W power range from a
magnetron operating at 2.45 GHz). The reactions were carried out
in a 5 mL sealed microwave vial equipped with magnetic stirrer,
◦
heating at a rate of 2 to 5 C s-1, then held for the stated time
period. The temperature was monitored by an internal IR sensor.
1
was removed and the spectroscopic yield was determined by H
NMR spectroscopy.
General methodology for the preparation of 4-tert-butylphenyl-
N,N-dialkyl carbamates & 4-tert-butylphenyl diphenylcarbamate
General methodology for the ortho-arylation of N,N-dialkyl
carbamates & 4-tert-butylphenyl diphenylcarbamate using
Pd(OAc)2
To a solution of 4-tert-butylphenol (3.00 g, 20 mmol) in MeCN
(40 ml) was added K2CO3 (5.53 g, 40 mmol) followed by carbamoyl
chloride (2.8 ml, 22 mmol). The reaction mixture was heated at
85 ◦C for 18 h. The reaction mixture was then diluted with water
(30 ml) and washed with Et2O (3 ¥ 50 ml). The organic extracts
were washed with NaOH solution (80 ml, 1 M) followed by water
(80 ml), then brine (80 ml). The organic extracted were then dried
over MgSO4 and concentrated in vacuo. The crude mixture was
subjected to column chromatography to yield the carbamate.
To a microwave vial was added the appropriate carbamate
(0.241 mmol), aryl iodide (0.963 mmol), silver acetate (0.080 g,
0.482 mmol), Pd(OAc)2 (0.003 g, 0.012 mmol) and trifluoroacetic
acid (1 ml), the vial was sealed and the vessel subjected to mi-
crowave heating at 100 ◦C for the appropriate time. H2O was added
(5 ml) followed by NaHCO3 (saturated solution, 10 ml) and the
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organic phase was extracted into dichloromethane (3 ¥ 10 ml). The
combined organic extracts were dried over MgSO4, filtered and the
solvent removed under reduced pressure. The crude mixture was
purified on silica gel to afford the product.
Notes and references
1 (a) Metal-Catalyzed Cross-Coupling Reactions, ed. F. Diederich, and
P. J. Stang, Wiley-VCH, Weinheim, Germany, 1998; (b) N. Miyaura,
Ed., Cross-Coupling Reactions (Topics in Current Chemistry), vol. 219,
Springer, New York, 2002.
2 For a recent review see: D. Alberico, M. E. Scott and M. Lautens,
Chem. Rev., 2007, 107, 174.
3 For recent overviews, see: (a) Catalytic Aromatic C–H Activation
(Symposium in Print) Tetrahedron, vol. 64, 2008, pp. 5963–6138;
(b) Handbook of C–H Transformations, ed. G. Dyker, Wiley-VCH,
Weinheim, 2005.
4 C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G. Tyler,
M. R. Gagne´, G. C. Lloyd-Jones and K. I. Booker-Milburn, Angew.
Chem., Int. Ed., 2009, 48, 1830.
5 For an overview see: O. Daugulis, H.-Q. Do and D. Shabashov, Acc.
Chem. Res., 2009, 42, 1074.
6 (a) R. B. Bedford, S. J. Coles, M. B. Hursthouse and M. E. Limmert,
Angew. Chemie, Int. Ed., 2003, 42, 11; (b) R. B. Bedford and M. E.
Limmert, J. Org. Chem., 2003, 68, 8669; (c) R. B. Bedford, M. Betham,
A. J. M. Caffyn, J. P. H. Charmant, L. C. Lewis-Alleyne, P. D. Long,
D. Polo-Ceron and S. Prashar, Chem. Commun., 2008, 990; (d) R. B.
Bedford, M. F. Haddow, R. L. Webster and C. J. Mitchell, Org. Biomol.
Chem., 2009, 7, 3119.
General methodology for the preparation of unsymmetrical diaryl
phenyl carbamates 3c, 3k and 3l
To a microwave vial was added Pd(OAc)2 (0.7 mg, 0.003 mmol) as a
standard solution in TFA (0.25 M), 2c (0.025 g, 0.065 mmol), aryl
iodide (0.26 mmol) and trifluoroacetic acid (0.5 ml).◦The mixture
was subjected to microwave heating for 2 h at 100 C. H2O was
added (5 ml) followed by NaHCO3 (saturated solution, 10 ml)
and the organic phase was extracted into dichloromethane (3 ¥
10 ml). The combined organic extracts were dried over MgSO4,
filtered and the solvent removed under reduced pressure. The crude
mixture was purified on silica gel to afford the product.
General methodology for synthesis of mono-aryl substituted
phenols, 4 and chromenone 5a
7 S. Oi, S. Watanabe, S. Fukita and Y. Inoue, Tetrahedron Lett., 2003, 44,
8665.
To a microwave vial was added 1a (0.06 g, 0.241 mmol), hyperva-
lent iodine reagent (0.482 mmol), Pd(OAc)2 (5.4 mg, 0.024 mmol)
and acetic acid (1 ml). The vial was sealed and the solution heated
at 100 ◦C for 4 h. H2O was added (15 ml) and the organic phase
was extracted into dichloromethane (3 ¥ 10 ml). The combined
organic extracts were dried over MgSO4, filtered and the solvent
removed under reduced pressure. The crude mixture was purified
on silica gel to afford the product.
8 For example physostigmine, neostigmine and rivastigmine are acetyl-
choline esterase inhibitors used variously in the treatment of myas-
thenia gravis, Alzheimer’s and Parkinson’s diseases, carbofuran and
carbaryl are insecticides used in crop protection.
9 For a recent example and leading references see: C. A. James and V.
Snieckus, J. Org. Chem., 2009, 74, 4080.
10 For full optimisation data see Table S1 in the ESI†.
11 O. Daugulis and V. G. Zaitsev, Angew. Chem., Int. Ed., 2005, 44,
4046.
12 For selected recent examples of the use of Ar2I+ in direct arylation
reactions see: (a) R. J. Phipps and M. J. Gaunt, Science, 2009, 323,
1593; (b) R. J. Phipps, N. P. Grimster and M. J. Gaunt, J. Am. Chem.
Soc., 2008, 130, 8172; (c) N. R. Deprez, D. Kalyani, A. Krause and
M. S. Sanford, J. Am. Chem. Soc., 2006, 128, 4972 and ref. 11 above.
13 For an overview of Pd-catalysed Ar2I+ coupling reactions, see: N. R.
Deprez and M. S. Sanford, Inorg. Chem., 2007, 46, 1924.
Acknowledgements
We thank EPSRC and GSK for funding and Johnson Matthey for
the loan of palladium acetate.
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