Divergent reaction pathways for phenol arylation by arynes: Synthesis of helicenes and 2-arylphenols

Article abstract of DOI:10.1039/c2sc21288a

Two reactions of phenols with arynes have been developed. If LiTMP base is employed, arynes generated from aryl chlorides react with phenols to form helicenes. o-Arylation of phenols can be achieved by employing tBuONa base in the presence of AgOAc. Direc

Full text of DOI:10.1039/c2sc21288a

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Divergent reaction pathways for phenol arylation by
arynes: synthesis of helicenes and 2-arylphenols†
Cite this: Chem. Sci., 2013, 4, 531
*
Thanh Truong and Olafs Daugulis
Received 16th August 2012
Accepted 2nd October 2012
Two reactions of phenols with arynes have been developed. If LiTMP base is employed, arynes generated
from aryl chlorides react with phenols to form helicenes. o-Arylation of phenols can be achieved by
employing tBuONa base in the presence of AgOAc. Direct arylation of binol was achieved leading to the
shortest pathway to o,o0-diarylbinols.
DOI: 10.1039/c2sc21288a
www.rsc.org/chemicalscience
2-Arylphenol functionality can be found in organocatalysts, are commercially available. Consequently, we used readily
sensors, phosphite ligands, and biologically active substances.1 accessible and cheap aryl chlorides as aryne sources. Two
The most common methods for synthesis of these structures different reaction conditions were investigated for phenol ary-
involve cross-coupling of an organometallic reagent with an lation. The rst set of conditions employs lithium 2,2,6,6-tet-
aryl halide or pseudohalide.1a,2 In addition to several step ramethylpiperidide (LiTMP) base. These conditions are based
synthesis of both coupling components, the phenol moiety on our earlier report for heterocycle arylation by aryl halides.5a
usually has to be protected. Shorter synthetic pathways to 2- The second set of conditions involves an alkali metal alkoxide
arylphenols can be achieved by employing transition-metal base in dioxane and is based on intramolecular arylation of
catalyzed C–H bond functionalization methodology.3 First phenol derivatives.5c Very different reaction outcomes were
palladium-catalyzed phenol ortho-arylations were reported by observed depending on the conditions used.
Miura et al.3a However, in many cases polyarylation was
If a solution of phenol and chlorobenzene in THF was
observed. Subsequently, Bedford et al. published a method for treated by TMPLi, diphenyl ether was formed together with a
rhodium-catalyzed arylation of 2-substituted phenols.3b More hydrocarbon in 4/1 ratio (Table 1, entry 1). Spectroscopic anal-
recently, Bedford et al., Dong et al., and Liu et al. have shown ysis showed that hydrocarbon product is benzo[c]phenanthrene
that phenols possessing ester and carbamate directing groups (tetrahelicene). Helicenes have been used in asymmetric catal-
can be arylated under palladium catalysis by aryl halides or ysis, as molecular machines, and as organic electronic mate-
simple arenes.3c–e Gevorgyan has shown that selective phenol rials.7 Their syntheses are typically lengthy,8 and one-step access
derivative ortho-arylation is possible by employing a silicon- to helicenes from simple, commercially available starting
based tether that can be subsequently removed.3f Gaunt has materials would make these interesting structures more
reported para-arylation of phenol ethers by diaryliodonium
salts.3g Direct intermolecular ortho-arylation of unprotected
Table 1 Optimization of reaction conditionsa
phenols by aryl chlorides has not yet been disclosed. We report
here a method for base- and silver-promoted phenol direct
ortho-arylation by aryl chlorides that proceeds via benzyne
mechanism. A one-step transition-metal-free synthesis of hel-
icenes is also disclosed.
Phenol O-arylation can be accomplished by benzynes.4
Minor amounts of C-arylation products may accompany diaryl
ethers.4 Since the ratio of C- vs. heteroatom arylation can be
tuned by changing reaction solvent,5a,b we decided to explore
phenol o-arylation. Arynes can be generated from silyl aryl tri-
ates under nearly neutral conditions at room temperature.6
These starting materials are expensive and only a few of them
Entry
PhOH/PhCl/LiTMP
Solvent
1/2/conv
1
1/2/3.6
1/2/3.6
1/2/3.6
1/2/3.6
1/2/3.6
1/4/6
THF
Et2O
C5H12
C5H12–THF 20 : 1
C5H12–THF 50 : 1
C5H12–THF 50 : 1
4/1/32%
3/1/21%
1/7/35%
1/40/52%
1/50/65%
1/50/80%
2
3b
4
Department of Chemistry, University of Houston, Houston, TX 77204-5003, USA.
E-mail: olafs@uh.edu
5
6
† Electronic supplementary information (ESI) available. CCDC 897191. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2sc21288a
a
Volume of solvent 1 mL, 0.25 mmol scale, 24 h, 25 ꢀC. Conversion by
GC analysis. See ESI† for details. b At 40 ꢀC.
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Table 2 Helicene synthesisa
Entry
1
Phenol
PhOH
Helicene
Yield, %
67
Scheme 1 Hexahelicene synthesis.
2
3
4
2-tBu-phenol
2,3-Di-Me-phenol
2-Ph-phenol
48
58
65
Scheme 2 Reaction intermediates.
5
2,6-Di-iPr-phenol
40
6
7
3-CF3-phenol
40
51
Scheme 3 Reaction mechanism.
3-tBu-phenol
Table 3 Optimization of phenol arylationa
8
3-TBSO-phenol
52
Entry
PhCl/PhOH/base
Solvent, T
1/20/conv
a
Scale: 0.5 mmol. Yields are isolated yields. See ESI† for details.
1
2
2/1/3.9/LiTMP
2/1/3.9/tBuOK
2/1/3.9/tBuONa
2/1/3.9/tBuONa
2/1/3.9/tBuONa
Et2O, 25 ꢀ
C
50/<1/32%
9/1/91%
7/1/87%
1/30/87%
1/15/65%
Dioxane, 110 ꢀC
Dioxane, 155 ꢀC
Dioxane, 155 ꢀC
Dioxane, 155 ꢀC
3
4b
5c
available. For example, parent hexahelicene has been prepared
in six steps by employing ring-closing metathesis.8c Conse-
quently, we decided to optimize the helicene formation and
investigate the reaction mechanism. Optimization of the
a
Solvent (1 mL), 0.25 mmol scale, 24 h. Conversion by GC analysis.
Additive: 1 equiv. AgOAc. c Additive: 0.1 equiv. AgOAc.
b
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reaction conditions showed that increase of phenol–chloro-
benzene ratio to 1/4 and use of mixed pentane–THF solvent
resulted in 80% conversion to tetrahelicene (entry 6).
Table 4 Phenol arylationa
Examples of the helicene synthesis are presented in Table 2.
Reaction of phenol with chlorobenzene affords a 67% isolated
yield of tetrahelicene (entry 1). If 2-tert-butylphenol is reacted
with chlorobenzene, 5-tert-butyltetrahelicene is obtained in
48% yield (entry 2). 5,6-Dimethyltetrahelicene is produced from
2,3-dimethylphenol in 58% yield (entry 3). 2-Phenylphenol is
converted to 5-phenyltetrahelicene in 65% yield (entry 4).
Hindered 2,6-diisopropylphenol is reactive and 5,8-diisopro-
pyltetrahelicene was formed in 40% yield (entry 5). 6-Tri-
uoromethyltetrahelicene can be synthesized in 40% yield
(entry 6). 3-tert-Butylphenol can be converted to 6-tert-butyl-
tetrahelicene in 51% yield (entry 7).
A TBS-protected resorcinol afforded the product in a good
yield (entry 8). The reaction of 2,6-dimethylphenol with 1-
chloronaphthalene resulted in formation of two isomeric
hydrocarbons in 2.1/1 ratio and 60% yield. The major product
was hexahelicene 11 that could be isolated in 26% yield by
fractional crystallization of the isomer mixture (Scheme 1).
Analysis of the reaction products shows that helicenes are
formed by the reaction of two molecules of aryl chloride with
one molecule of phenol. Informative results were obtained in
the reaction of 3-tert-butylphenol with 1.6 equiv. chlorobenzene
(Scheme 2). Benzocyclooctadienone 12 was obtained in 61%
yield. If 3 equiv. of chlorobenzene and 4.2 equiv. of LiTMP were
employed, structure 13 was isolated in 64% yield. Compound 12
could be converted to 13 by reaction with 2 equiv. of PhCl in the
presence of 3.2 equiv. LiTMP. Both 12 and 13 can be trans-
formed to tert-butyltetrahelicene 8 as shown in Scheme 2. Direct
reaction of 4 equiv. chlorobenzene with 3-tert-butylphenol in
the presence of 6 equiv. LiTMP affords 8 (entry 7, Table 2). These
experiments show that 12 and 13 are competent intermediates
en route to 8. In addition, the reaction of 4-hydroxybiphenyl with
chlorobenzene afforded 14 which cannot easily aromatize by
elimination. X-Ray crystallographic analysis of O-methyl deriv-
ative of 14 showed that hydroxyl and phenyl groups are in cis
arrangement.
Entry Phenol
ArCl
Product
Yield, %
78
1
2
Phenol
Phenol
PhCl
PhCl
60
72
64
3
4
Phenol
Phenol
1-Cl-3-FC6H4
2-Cl-1-MeOC6H4
5b
6
3-Me-phenol PhCl
80
58
4-OH-benzo-
PhCl
phenone
7
1-Naphthol
2-Naphthol
PhCl
PhCl
82
8c
80, 77d
9c
2-Naphthol
2-Naphthol
3-Cl-1-CF3C6H4
74
66
The following reaction mechanism is proposed (Scheme 3).
Reaction of phenol with benzyne generated from chlorobenzene
forms a benzocyclobutene 15. Ring-opening affords 16 which
undergoes another reaction with benzyne to form 17. Subse-
quent opening of the strained four-membered ring in 17 gives a
ten-membered ring ketone 18. Intramolecular nucleophilic
attack followed by dehydration affords tetrahelicene 2. Inter-
mediates related to 16 and 19 have been isolated and charac-
terized (12, 13, and 14, Scheme 1). Benzene cycloaddition with
benzyne producing a benzocyclobutane derivative that subse-
quently ring-opens to give benzocyclooctatetraene in low yield
has been reported showing the viability of intermediates such
as 15 and 17.9
3-Br-1-
tBuO2CC6H4
10c
11c
2-Naphthol
3-Cl-1-CNC6H4
65
As described above, use of LiTMP base afforded no detectable
phenol C-arylation. The application of tBuONa in dioxane gave
minor amounts of C-arylation (Table 3). In enolate chemistry, the
C- vs. O-functionalization ratios are inuenced by the coun-
terion,10 and C-functionalization of hexauoroacetylacetone can
a
Scale: 0.5 mmol, 48–96 h, 0.5–2 equiv. AgOAc, 1.6–5/1/3.6–8 ratio of
b
ArCl/phenol/base. Yields are isolated yields. Crude: 9/1 isomer
mixture. Yield of pure major isomer. No AgOAc. Reaction scale: 10
mmol.
c
d
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in 50% yield and 95 % ee, showing the applicability of the
method to synthesis of enantioenriched organocatalysts.
In conclusion, we have described two reactions of phenols
with arynes. If LiTMP base is employed, arynes generated from
aryl chlorides react with phenols to form helicene derivatives. If
tBuONa base is used in dioxane at elevated temperature in the
presence of AgOAc, selective o-arylation of phenols can be
achieved. Diarylation of binol was demonstrated resulting in
the shortest pathway to o,o0-diarylbinols. Enantiopure binol was
o-arylated by 3-chloroanisole affording 3-(3-methoxyphenyl)
binol in 95% ee.
Acknowledgements
We thank the Welch Foundation (grant no. E-1571), NIGMS
(grant no.R01GM077635), and Camille and Henry Dreyfus
Foundation for supporting this research. We also thank Dr
James Korp for collecting and solving the X-ray structure of
methyl ether of 14.
Scheme 4 Binaphthol arylation.
Notes and references
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resulted in a good selectivity for C-arylation. The optimized
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The arylation scope is presented in Table 4. Phenol can be
either mono- or diarylated in good yield depending on phenol–
chlorobenzene ratio (entries 1 and 2). Introduction of 3-uo-
rophenyl substituent is possible (entry 3). Reaction of phenol
with 2-chloroanisole affords the 3-methoxyphenylated deriva-
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(entry 5), 4-hydroxybenzophenone (entry 6), 1-naphthol
(entry 7), and 2-naphthol (entry 8) can be phenylated in good to
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The reaction is surprisingly functional group tolerant despite
the use of strong tert-butoxide base. Thus, uoride (entry 3),
ether (entry 4), ketone (entry 6), triuoromethyl (entry 9), ester
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in 77% yield (entry 8).
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possible route to such compounds. This pathway should also
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moiety, thus allowing access to structurally diverse organo-
catalysts. Diarylation of binol with excess chlorobenzene affor-
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unsymmetrical diarylbinol was also achieved. Thus, binol was
phenylated to afford 3-phenylbinol 22 in 67% yield. Subse-
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3,30-diarylbinol 23 in 60% yield. Additionally, arylation of
enantiopure (R)-binol with 3-chloroanisole afforded product 24
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