Facile synthesis of 2-arylphenols via palladium-catalyzed cross-coupling of aryl iodides with 6-diazo-2-cyclohexenones

Article abstract of DOI:10.1021/ol303484f

2-Arylphenols were conveniently synthesized from aryl iodides and 6-diazo-2-cyclohexenones, in moderate to excellent yields, via tandem Pd-catalyzed cross-coupling/aromatization. The preliminary results for the corresponding enantioselective version showe

Full text of DOI:10.1021/ol303484f

ORGANIC
LETTERS
2013
Vol. 15, No. 4
808–811
Facile Synthesis of 2‑Arylphenols via
Palladium-Catalyzed Cross-Coupling
of Aryl Iodides with
6‑Diazo-2-cyclohexenones
Ke Yang,† Jun Zhang,† Yun Li,† Bin Cheng,† Liang Zhao,† and Hongbin Zhai*,†,‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, China, and CAS Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
zhaih@lzu.edu.cn
Received December 19, 2012
ABSTRACT
2-Arylphenols were conveniently synthesized from aryl iodides and 6-diazo-2-cyclohexenones, in moderate to excellent yields, via tandem
Pd-catalyzed cross-coupling/aromatization. The preliminary results for the corresponding enantioselective version showed that the coupling
products could be generated in up to 72% ee.
Owing to the ubiquity of biaryl scaffolds in ligands,
natural products, and pharmaceuticalagents, great endeav-
ors have been devoted to the synthesis of these molecules.1
Generally, biaryl compounds are prepared either by cross-
coupling reactions of two aryl synthons (Scheme 1, eq 1) or
by oxidative aromatization of an aryl substituted cyclo-
hexadiene or its equivalent (Scheme 1, eq 2). Furthermore,
currently available protocols2 for obtaining optically ac-
tive biaryls are limited to resolution of the corresponding
racemates, ligand-catalyzed reactions, and auxiliary-
controlled asymmetric synthesis. However, these methods
each have their respective drawbacks. For instance, in the
case of resolution, a maximum yield of 50% can only be
expected for each enantiomer. Substrate dependence or
troublesome removal of the chiral auxiliaries can be pro-
blematical in the remaining methods mentioned above.
Therefore, there remains an urgent need to develop alter-
native efficient syntheses of biaryl compounds, especially
asymmetric syntheses.
Pd-catalyzed cross-coupling reactions of diazo com-
pounds have attracted considerable attention over the past
decade.3,4 Although many results have been reported,
especially the enlightening synthesis of R,β-unsaturated
ketones from R-diazoketones by Wang and co-workers,3g to
the best of our knowledge, the synthesis of biaryls from diazo
compounds has not been reported yet. Herein, we wish to
present a new Pd-catalyzed cross-coupling/aromatization
† Lanzhou University.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schultz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359. (b) Cepanec, I., Ed. Synthesis of Biaryls;
Elsevier Ltd.: Oxford, 2004. (c) Metal-Catalyzed Cross-Coupling Reac-
tions; de Meijere, A., Diederich, F., Eds., Wiley-VCH: New York, 2004. (d)
Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844. (e) Taylor,
W. I.; Battersby, A. R. Oxidative Coupling of Phenols; Marcel Dekker:
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Gevorgyan, V. Org. Lett. 2010, 12, 2442. (h) Lockner, J. W.; Dixon,
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Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209.
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G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111, 563.
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r
10.1021/ol303484f
Published on Web 01/30/2013
2013 American Chemical Society

toluene or THF (entries 14 and 15) compared with the one
in dioxane. Lower yields (21À50%) were obtained when
the reaction was conducted in CH3CN or DCE (entries 16
and 17). Lower catalyst loading led to decreased product
yield (entry 18). In addition, when Pd2(dba)3 was used as
the precatalyst, only a complex mixture was generated.
Scheme 1. Previous Syntheses of Biaryls and a New Approach to
2-Arylphenols
Table 1. Optimization of the Reaction Conditionsa
entry
1a:2a
base
Et3N
solvent
yieldb (%)
1
1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
2.1:1
2.1:1
1.5:1
2.1:1
2.1:1
2.1:1
2.1:1
2.1:1
2.1:1
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
33
50
50
52
54
47
22
11
66
70
92
82
73
76
80
21
50
85
2
Et3N
approach for the synthesis of 2-arylphenols from aryl iodides
and 6-diazo-2-cyclohexenones (Scheme 1, eq 3). In addition,
some optically active arylphenols were synthesized from
5-substituted 6-diazo-2-cyclohexenones through a point-to-
axial chirality transfer strategy.
3
K2CO3
Li2CO3
KOAc
CsF
4
5
6
7
Cs2CO3
t-BuOK
8
We started our investigations by examining the coupling
reaction between diazo compound 1a and aryl iodide 2a, in
thepresenceof Et3N (3 equiv) and Pd(PPh3)4 (10mol %) in
1,4-dioxane at 50 °C for 5 h, and the reaction afforded
biaryl 3a in 33% yield (Table 1, entry 1). We subsequently
screened the reaction conditions, such as the bases, molar
ratios of 1a to 2a, and solvents. Various bases were care-
fully tested. Comparable product yields (47À54%) were
obtained when Et3N, K2CO3, Li2CO3, KOAc, or CsF was
used as the base (entries 2À6), while using stronger bases
such as Cs2CO3 and t-BuOK resulted in lower yields of
9
K3PO4 3H2O
3
10
11
12
13c
14
15
16
17
18d
K3PO4 3H2O
3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
CH3CN
DCE
1,4-dioxane
a Reaction conditions: 2a (0.25 mmol), Pd(PPh3)4 (10 mol %), base
(3 equiv), solvent (4 mL). b Isolated yield. c K3PO4 (1.1 equiv). d Pd(PPh3)4
(5 mol %).
the product (entries 7 and 8). In the case of K3PO4 3H2O
3
chosen as the base, the yield of 3a was further enhanced to
66À70% (entries 9 and 10). An excellent yield (92%) was
achieved when anhydrous K3PO4 was employed as the
With the optimized reaction conditions in hand, we
next examined the scope of the current Pd-catalyzed
cross-coupling/aromatization protocol. An array of aryl
iodide/6-diazo-2-cyclohexenone combinations were sub-
jected to the optimized conditions, and the results are
summarized in Table 2.5 In general, different 6-diazo-2-
cyclohexenones were found to couple smoothly with 2a or
2btogivethe corresponding biarylsindecent yields (entries
1À6). The substituents on the 6-diazo-2-cyclohexenones
did not dramatically affect the reaction yield, although
5-substituted 6-diazo-2-cyclohexenones required much
longer reaction times (entries 3 and 4). When ester 2b
was used as a substrate, lactonized biaryls 3f and 3g were
obtained in excellent yields (entries 5 and 6). When 1a was
used as the diazo substrate, iodobenzenes bearing with
either electron-donating or electron-withdrawing groups
base instead of K3PO4 3H2O, while the molar ratio of
3
1a/2a was maintained at 2.1:1 (entry 11), demonstrating
that the presence of even a trace amount of water could
be detrimental to the reaction. Solvent-screening experi-
mentsshowed thatthe reaction proceededlesseffectively in
(3) (a) Peng, C.; Cheng, J.; Wang, J. J. Am. Chem. Soc. 2007, 129,
8708. (b) Greenman, K. L.; Van Vranken, D. L. Tetrahedron 2005, 61,
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J. Am. Chem. Soc. 2008, 130, 1566. (g) Peng, C.; Yan, G.; Wang, Y.;
Jiang, Y.; Wang, J. Synthesis 2010, 4154. (h) Shu, Z.; Zhang, J.; Zhang,
Y.; Wang, J. Chem. Lett. 2011, 40, 1009. (i) Zhou, L.; Liu, Y.; Zhang, Y.;
Wang, J. Chem. Commun. 2011, 3622. (j) Zhang, Z.; Liu, Y.; Ling, L.; Li,
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(5) (a) While 1bÀg could be stored at À20 °C for two months without
appreciable decomposition, 1a was relatively less stable. Even when 1a
was stored at À20 °C for two days, an unidentified new compound could
be detected. (b) In all cases, Pd(PPh3)4 was used as freshly prepared. It
was found that even a trace amount of Pd(II) could lead to a decrease of
the yields of the desired coupling products. For Pd(II)-mediated poly-
merization of diazoacetates, see: Ihara, E.; Haida, N.; Iio, M.; Inoue, K.
Macromolecules 2003, 36, 36.
(4) For recent reviews, see: (a) Zhang, Y.; Wang, J. Eur. J. Org. Chem.
2011, 1015. (b) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013 DOI:
10.1021/ar300101k.
Org. Lett., Vol. 15, No. 4, 2013
809

Table 2. Palladium-Catalyzed Cross-Coupling/Aromatization Reactions of Aryl Iodides with 6-Diazo-2-cyclohexenonesa
a Reaction conditions: 1 (0.52 mmol), 2 (0.25 mmol), K3PO4 (0.75 mmol), Pd(PPh3)4 (10 mol %), 1,4-dioxane (3.5 mL), 50 °C. b Isolated yield.
c Pd(PPh3)4 (30 mol %), 70 °C.
at the ortho-, meta-, or para-position could deliver the
biaryls in moderate to good yield (entries 6À17, except 12).
It seems that the reaction time might be dependent upon
the rate of oxidative addition of the palladium catalyst to
the iodides. When iodobenzene 2f (with a relative bulky
isopropyl group at the ortho-position) was tested for the
reaction, higher catalyst loading and higher temperatures
were needed to ensure a good yield (entry 10). For the
reaction of 1a with 2g, the TBS group was deprotected and
diphenol 3l was formed in 64% yield (entry 11). Note that
light-sensitive 4-iodopyridine could also serve as an aryl
iodide substrate (entry 12).
The importance of the 2-arylphenol motif in natural
products is noteworthy, and the phenols can be further
converted into phosphine ligands,6a,b phosphoric acids,6c
and phosphoramidite ligands.6d We envisioned that this
cross-coupling/aromatization approach might be used to
synthesize optically active biaryl compounds from chiral
5-substituted 6-diazo-2-cyclohexenones7 via point-to-axial
chirality transfer.8 Indeed, the coupling of 1e (derived from
L-(À)-carvone) with 2n and 2f delivered 3s (63% ee) and 3t
(37% ee), respectively (Scheme 2). Use of sterically more
bulky isopropyl-substitutedsubstrate1gresultedin further
(7) For the synthesis of enantiomerically pure 5-substituted 2-cyclo-
hexenones, see: Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 811.
(8) For an example of point-to-axial chirality transfer in synthesis of
axially chiral allenes, see: Ohmiya, H.; Yokobori, U.; Makida, Y.;
Sawamura, M. Org. Lett. 2011, 13, 6312.
(6) (a) Uozumi, Y.; Kawatsura, M.; Hayashi, T. Org. Synth. 2004, 10,
363. (b) Liu, L.; Wu, H.; Yu, J. Chem.;Eur. J. 2011, 17, 10828. (c)
Jacques, J.; Fouquey1, C. Org. Synth. 1993, 8, 50. (d) Smith, C. R.;
Mans, D.; RajanBabu, T. V. Org. Synth. 2008, 85, 238.
810
Org. Lett., Vol. 15, No. 4, 2013

Scheme 2. Chirality Transfer Experiments
Scheme 3. Proposed Mechanism
moderate to excellent yields. Preliminary results on an
asymmetric version of the reaction indicated the possibility
of point-to-axial chirality transfer, which provides a new
promising approach to preparing chiral biaryl ligands from
the corresponding ketones. Further improvement and ap-
plications in chiral biaryl ligands synthesis are in progress.
improvement in the ee value of 2-arylphenol products
(72% ee for 3u; 49% ee for 3v).
A plausible mechanism for the coupling/aromatization
reaction is proposed in Scheme 3, which is similar to that
reported by Wang.3g The process presumably starts with
oxidativeaddition ofaryliodide 2 toPd(0) catalyst I togive
complexII, whichreactswithdiazo compound1 andforms
palladiumÀcarbene complex III. Migratory insertion of
the aryl group produces intermediate IV, β-elimination
of which provides V and the eventually regenerated Pd(0)
catalyst I. Intermediate V rapidly isomerizes to afford
2-arylphenol 3 via aromatization.
In summary, we have developed a new synthesis of
2-arylphenols from aryl iodides and 6-diazo-2-cyclohexe-
nones through tandem Pd-catalyzed cross-coupling/
aromatization. A wide range of aryl iodides have been
tested in this reaction, which gave the biaryl products in
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program: 2010CB833200),
NSFC (21172100; 21272105, 21290183), Program for
Changjiang Scholars and Innovative Research Team in
University (PCSIRT: IRT1138), and “111” Program of
MOE for financial support. We are grateful to Professors
Yongmin Liang and Xueyuan Liu of Lanzhou University
for enlightening discussions.
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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