Direct transition-metal-free intramolecular arylation of phenols

Article abstract of DOI:10.1021/ol801897m

(Chemical Equation Presented) Direct transition-metal-free, base-mediated intramolecular arylation of phenols with aryl halides has been developed. In the presence of 2.5 equiv of t-BuOK in dioxane at 140 °C, the intramolecular cyclization of 3-(2-halobenzyloxy)phenols affords 6H-benzo[c]chromenes in high yields. This reaction proceeds by an initial formation of a benzyne intermediate followed by an aromatic sp² C-H functionalization (a formal C-H activation) to form the carbon-carbon bond.

Full text of DOI:10.1021/ol801897m

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4625-4628
Direct Transition-Metal-Free
Intramolecular Arylation of Phenols
Gan B. Bajracharya and Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5003
olafs@uh.edu
Received August 13, 2008
ABSTRACT
Direct transition-metal-free, base-mediated intramolecular arylation of phenols with aryl halides has been developed. In the presence of 2.5
equiv of t-BuOK in dioxane at 140 °C, the intramolecular cyclization of 3-(2-halobenzyloxy)phenols affords 6H-benzo[c]chromenes in high
yields. This reaction proceeds by an initial formation of a benzyne intermediate followed by an aromatic sp2 C-H functionalization (a formal
C-H activation) to form the carbon-carbon bond.
Arylation of aromatic C-H bonds has become a topic of
intense interest in recent years.1 The methodology has
potential advantages over the well-known cross-coupling
reactions because the arylmetal coupling partner can be
replaced by a simple arene.2 Recently, palladium catalysis
has appeared as a general tool for the synthesis of biaryls
by C-H bond functionalization methodology.3 We are
interested in developing simple and efficient protocols for
direct arylation of sp2 C-H bonds.4 We have previously
reported copper-catalyzed intermolecular arylation of C-H
bonds of heteroaromatics and polyfluorobenzenes with aryl
halides.5 Minor amounts of arylation products were detected
in the reaction mixtures even in the absence of copper
catalyst if t-BuOK base was used. By using deuterium
labeling, it was determined that these reactions proceed via
benzyne intermediates. We reasoned that generation of a
benzyne with a tethered aryl nucleophile should result in an
efficient aryl-aryl bond formation in the absence of a
transition-metal catalyst (Scheme 1). Several catalytic sys-
Scheme 1
.
Direct Transition-Metal-Free Intramolecular
Arylation of Phenols
(1) (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(b) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (c) Dick,
A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (d) Yu, J.-Q.; Giri, R.;
Chen, X. Org. Biomol. Chem. 2006, 4, 4041. (e) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174. (f) Ackermann, L. Synlett 2007,
507.
tems that accomplish such transformations by using either
transition-metal catalysis or radical chemistry have been
reported. In pioneering work, Rawal and co-workers have
developed a method for anion-accelerated palladium-
catalyzed intramolecular coupling of phenols with aryl
halides under mild conditions.6 Subsequently, Fagnou and
(2) (a) Metal-catalyzed cross-coupling reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998. (b) Hassan, J.; Se´vignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359.
(3) (a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (b) Campeau,
L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (c) Daugulis, O.; Zaitsev,
V. G.; Shabashov, D.; Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382. (d)
Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173.
(4) (a) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211. (b) Chiong,
H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. (c) Chiong, H. A.; Pham,
Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (d) Shabashov,
D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720.
(5) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128.
10.1021/ol801897m CCC: $40.75
Published on Web 09/18/2008
2008 American Chemical Society

co-workers developed related palladium-based catalytic
systems that are more general.7 Tributyltin hydride reagent
has also been utilized to effect oxidative radical cyclizations
of similar substrates.8 Herein, we report that direct intramo-
lecular arylation of 3-(2-halobenzyloxy)phenols can be
achieved in the presence of t-BuOK base at 140 °C without
a transition-metal catalyst (Scheme 1).
Table 1. Optimization of the Reaction Conditionsa
In the 1950s, Bunnett9 and Huisgen10 developed the
intramolecular addition reactions of aryne-tethered nucleo-
philes.11 This strategy was successfully employed in the
synthesis of benzo-fused heterocycles such as indolines,12
indoles,13 phenothiazines,13 benzoxazoles,13,14 xanthenes,15
and benzothiazoles13,16 by using tethered nitrogen, oxygen
or sulfur nucleophiles. However, tethered carbanions have
rarely been used in the benzyne cyclization reactions. For
this purpose, either a stabilized carbanion17 or an atom
capable of supporting a negative charge must be employed.18
Benzyne coupling with a tethered aryllithium followed by
quenching with an external electrophile has been described.19
The initial experiments were carried out in the presence
of a copper(I) catalyst. Upon treatment of 3-(2-bromoben-
zyloxy)phenol (1) with 10 mol % of CuI and 3 equiv of
t-BuOK in DMF at 140 °C, 1-hydroxy-6H-benzo[c]chromene
(2) and 3-hydroxy-6H-benzo[c]chromene (3) were isolated
in 25% and 28% yields, respectively. Interestingly, the
reaction performed without addition of CuI proceeds with
an improved regioselectivity (Table 1, entry 1). Other alkali
metal bases such as t-BuONa and t-BuOLi are less effective
(entries 2 and 3). Weaker bases such as K2CO3 and Cs2CO3
are ineffective, and starting material was recovered quanti-
tatively (entries 4 and 5). These results rule out the
involvement of a nucleophilic substitution-type mechanism.
Reaction proceeds in a range of solvents and dioxane was
the solvent of choice affording 2 and 3 in a 78% combined
yield (entries 6-12). Decreasing the amount of t-BuOK to
2.5 equivalents improves the yield (entry 13). Employing 2
entry
base (equiv)
solvent
2, yield (%) 3, yield (%)
1
2
3
4
5
6
7
8
t-BuOK (3)
t-BuONa (3)
t-BuOLi (3)
K2CO3 (3)
DMF
DMF
DMF
DMF
DMF
DMA
DMPU
NMP
toluene
DMSO
m-xylene
dioxane
dioxane
dioxane
44b
26
20 b
30
trace
0
trace
0
Cs2CO3 (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (3)
t-BuOK (2.5)
t-BuOK (2)
trace
30
trace
36
38
36
28
35
9
20
22
10
11
12
13
14
15c
16
41
12
22
60
18
68
20
60
22
t-BuOK (2.5) dioxane
t-BuOK (2.5) dioxane
73b
62
23b
17
c d
,
16
a Substrate (1 equiv, 0.5 mmol), base (2-3 equiv), solvent (1 mL), 16 h
1
at 140 °C. Yields are calculated by H NMR integration of crude reaction
mixtures employing CH3NO2 internal standard. b Isolated yield. c Concentration
0.3 M. d Reaction run at 100 °C for 3 days.
equiv of t-BuOK is almost as effective (entry 14). The best
results for the cyclization of 1 were obtained by using 2.5
equiv of t-BuOK in dioxane at 0.3 M concentration at 140
°C (entry 15). The reaction proceeds at lower temperature
of 100 °C; however, several days are required for achieving
complete conversion (entry 16).
The scope of the intramolecular arylation is presented in
Table 2. Under optimized reaction conditions, bromide 1,
iodide 4, and chloride 5 underwent smooth cyclization
(entries 1-3). Bromine-substituted reactant displayed supe-
rior reactivity compared to iodine- and chlorine-containing
compounds. Methoxy and methyl substituents in the 5-posi-
tion are well tolerated yielding corresponding chromenes in
excellent yields (entries 4 and 5). Substrate 12 bearing methyl
group at 2-position produced only 13 in a 64% yield (entry
6). Compound 14, in which the 4-position is blocked with a
tert-butyl group, was cyclized producing 15 in excellent yield
(entry 7). Substrates possessing an electron-withdrawing
trifluromethyl group or an electron-donating methoxy sub-
stituent at the aryl halide moiety smoothly underwent
cyclization to afford corresponding products in high yields
(entries 8 and 9). Proof for the intermediacy of benzyne was
obtained by employing substrate 22 that produced 23 in 56%
yield (entry 10). The cyclization of 3-((2-bromopheny-
loxy)methyl)phenol (24) regioselectively produced 25 in a
good yield (entry 11). In all cases, arylation ortho to the
phenolate is the major reaction pathway.
(6) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 62,
2.
(7) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 581.
(8) (a) Rosa, A. M.; Lobo, A. M.; Branco, P. S.; Prabhakar, S.
Tetrahedron 1997, 53, 285. (b) Bowman, W. R.; Mann, E.; Parr, J. J. Chem.
Soc., Perkin Trans. 1 2000, 2991.
(9) (a) Hrutford, B. F.; Bunnett, J. F. J. Am. Chem. Soc. 1958, 80, 2021.
(b) Bunnett, J. F.; Skorcz, J. A. J. Org. Chem. 1962, 27, 3836.
(10) (a) Huisgen, R.; König, H. Angew. Chem. 1957, 69, 268. (b)
Huisgen, R.; Sauer, J. Angew. Chem. 1960, 72, 91. (c) Huisgen, R.; König,
H.; Lepley, A. R. Chem. Ber. 1960, 93, 1496.
(11) For general reviews: (a) Kessar, S. V. Acc. Chem. Res. 1978, 11,
283. (b) Biehl, E. R.; Khanapure, S. P. Acc. Chem. Res. 1989, 22, 275. (c)
Pellissier, H.; Santelli, M. Tetrahedron, 2003, 59, 701. Benzyne reactions
with Pd species: (d) Liu, Z.; Larock, R. C. J. Org. Chem. 2007, 72, 223.
(12) Sielecki, T. M.; Meyers, A. I. J. Org. Chem. 1992, 57, 3673.
(13) Bunnett, J. F.; Hrutfiord, B. F. J. Am. Chem. Soc. 1961, 83, 1691.
(14) Clark, R. D.; Caroon, J. M. J. Org. Chem. 1982, 47, 2804
(15) Knight, D. W.; Little, P. B. Synlett 1998, 1141.
.
(16) (a) Stanetty, P.; Krumpak, B. J. Org. Chem. 1996, 61, 5130. (b)
Fairhurst, R. A.; Janus, D.; Lawrence, A. Org. Lett. 2005, 7, 4697
(17) Iwao, M. J. Org. Chem. 1990, 55, 3622.
.
(18) (a) Kessar, S. V.; Gupta, Y. P.; Balakrishnan, P.; Sawal, K. K.;
Mohammad, T.; Dutt, M. J. Org. Chem. 1988, 53, 1708. (b) Kametani, T.;
Shibuya, S.; Kigasawa, K.; Hiiragi, M.; Kusama, O. J. Chem. Soc. C 1971,
2712. (c) Kessar, S. V.; Randhawa, R.; Gandhi, S. S. Tetrahedron Lett.
1973, 14, 2923.
Under the standard conditions used for the cyclization of
1, methyl ether analogue 26 produced substitution products
27 (70%) and 28 (19%) (eq 1). This result clearly indicates
(19) Sanz, R.; Ferna´ndez, Y.; Castroviejo, M. P.; Pe´rez, A.; Fan˘ana´s,
F. J. Eur. J. Org. Chem. 2007, 62.
4626
Org. Lett., Vol. 10, No. 20, 2008

Table 2. Scope of Base-Mediated Direct Intramolecular Arylation of Phenolsa
a Substrate (1 equiv, 0.5 mmol), t-BuOK (2.5 equiv), dioxane (1.5 mL), 16 h at 140 °C. b Isolated yields. See the Supporting Information for details.
c Reaction time 48 h.
that if tethered arene is less nucleophilic, benzyne intermedi-
ate is trapped by an external nucleophile.
in dioxane with 2.5 equiv of t-BuOD (Scheme 2A). After
completion, the reaction mixture was quenched with 2 N
HCl followed by usual workup and purification. Products
2-d and 3-d were obtained with deuterium incorporated both
at C-10 and the methylene group. A similar level of
deuterium incorporation was observed when the reaction was
performed employing t-BuOK and t-BuOD in dioxane-d8
followed by quenching with 2 N DCl in D2O (Scheme 2B).
Furthermore, heating potassium 3-(2-bromobenzyloxy)phe-
nolate (29) in the presence of t-BuOK (1.5 equiv) and
t-BuOD (2.5 equiv) in dioxane afforded 2-d and 3-d with
increased deuterium incorporation (Scheme 2C). These
observations point to tert-butyl alcohol being a source of
protonation at C-10.
The reaction mechanism was investigated (Scheme 2). The
cyclization of 1 was carried out in the presence of t-BuOK
Org. Lett., Vol. 10, No. 20, 2008
4627

Scheme 2
.
Deuteration Experiments
Scheme 3. Mechanistic Considerations
In conclusion, we have developed a method for direct
transition-metal-free, base-mediated intramolecular arylation
of phenols with aryl halides. The sp2 C-H bond function-
alization occurs via a benzyne intermediate. At this point, a
phenolate activating group is essential for the arylation.
Further scope elaboration is under progress in our labora-
tories.
We speculate that this reaction proceeds by an initial
formation of a benzyne intermediate followed by an aromatic
sp2 C-H functionalization. The benzyne intermediate generated
in the presence of a strong base, undergoes cyclization via ortho
(and/or para)-arylation (Scheme 3). Subsequent protonation by
tert-butyl alcohol and aromatization leads to the final products.
Catalysis by trace amounts of palladium is unlikely since aryl
cloride 5 affords the cyclized products in a good yield.20
Acknowledgment. G.B.B. is the recipient of the
2008-2009 Eby Nell McElrath Postdoctoral Fellowship.
We thank the Welch Foundation (Grant No. E-1571),
NIGMS (Grant No. R01GM077635), A. P. Sloan Founda-
tion, and Camille and Henry Dreyfus Foundation for
supporting this research.
(20) It has been shown that ppb to ppm level palladium contaminants
in commercial bases allows cross-coupling reactions to proceed without
adding transition-metal catalysts. However, (1) aryl chlorides should not
be reactive under such conditions (Table 2, entry 3), (2) deuterium
incorporation in 10-position of the product would not be observed if the
reactions proceed by conventional cross-coupling pathways (Scheme 2),
and (3) the cyclization is less regioselective compared with Rawal’s Pd-
catalyzed method (ref 6). Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.;
Williams, V. A.; Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161.
Supporting Information Available: Experimental details,
data, and spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL801897M
4628
Org. Lett., Vol. 10, No. 20, 2008