Preparation of 3-aryl-substituted salicylaldehydes via Suzuki coupling

Article abstract of DOI:10.1016/S0040-4039(01)01674-4

An efficient method for the preparation of 3-arylsalicylaldehydes by palladium-catalyzed cross-coupling reaction of arylboronic acids and 3-bromo-5-tert-butylsalicylaldehyde is described. Parallel catalyst screening allowed rapid optimization of the reaction conditions.

Full text of DOI:10.1016/S0040-4039(01)01674-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7925–7928
Preparation of 3-aryl-substituted salicylaldehydes via Suzuki
coupling
Michael A. Zhuravel and SonBinh T. Nguyen*
Department of Chemistry, Northwestern University, Evanston, IL 60208, USA
Received 3 August 2001; revised 31 August 2001; accepted 6 September 2001
Abstract—An efficient method for the preparation of 3-arylsalicylaldehydes by palladium-catalyzed cross-coupling reaction of
arylboronic acids and 3-bromo-5-tert-butylsalicylaldehyde is described. Parallel catalyst screening allowed rapid optimization of
the reaction conditions. © 2001 Published by Elsevier Science Ltd.
In the course of studying asymmetric catalysis with
metal salen complexes we became interested in the
preparation of 3-aryl-substituted salen ligands. The
steric properties of 3-substituents in salen ligands can
significantly influence the stereochemical outcome of
asymmetric reactions. For example, transition metal
cyclopropanation catalysts generally produce trans
products as the predominant isomer.1–3 However, it has
been shown that incorporation of bulky aryl groups in
the 3-positions of the salen aryl rings can lead to
reverse selectivity in Ru(salen)-catalyzed olefin cyclo-
propanation to give the cis-isomers.4–6 While seemingly
simple, salicylaldehydes that serve as precursors to 3-
aryl-substituted salen ligands are not common, espe-
cially those which also bear an alkyl moiety in the
5-positions. Bulky 5-alkyl substituents, especially 5-tert-
butyl, have been shown to be essential for high selectiv-
ity in asymmetric catalysis with metal salen complexes.7
With these criteria in mind we set out to search for a
general synthetic route to 3-aryl-5-tert-butyl aldehydes.
from protected 2-bromophenol) and aryl halide fol-
lowed by formylation.8 The overall yield of this
sequence of reactions can be improved if the protec-
tion/deprotection steps are avoided. A simple solution
would entail the direct coupling of salicylaldehydes with
aryl precursors using functional group-tolerant Pd-
mediated cross-coupling which has been shown to be a
powerful tool for the synthesis of biaryls.9 Since we
were interested in a general method to prepare 3-aryl-5-
tert-butyl-substituted aldehydes, we decided to investi-
gate this reaction as it would allow us to achieve several
different 3-aryl-substituted salicylaldehydes in one step
from the readily available 3-bromo-5-tert-butylsalicyl-
aldehyde.
Chan and co-workers have synthesized 3-(2-pyridyl)-5-
tert-butylsalicylaldehyde via Stille coupling.10 In our
hands, the reaction of either 3-bromo-5-tert-butylsalicyl-
aldehyde (1a) or 3,5-dibromosalicylaldehyde (1b) with
PhSnBu3 (Eq. (1)) gave the desired 3-phenyl-5-tert-
butylsalicylaldehyde (2a) and 3,5-diphenylsalicylalde-
hyde (3) in 67 and 48% yields, respectively. While
relatively successful, the Stille reaction required pro-
longed heating (72 h) at high temperatures (>100°C).
These drawbacks led us to consider Suzuki coupling as
an alternative.
There are few reports on the synthesis of 3-aryl-substi-
tuted salicylaldehydes. The approach most commonly
used involves the initial preparation of 3-arylphenols
followed by formylation. For example, Grubbs et al.
prepared 3-(9-anthracenyl)salicylaldehyde by Ni-cata-
lyzed coupling of an aryl Grignard reagent (formed
(1)
* Corresponding author. Tel.: 847.467.3347; fax: 847.491.5123; e-mail: stn@chem.northwestern.edu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01674-4

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M. A. Zhura6el, S. T. Nguyen / Tetrahedron Letters 42 (2001) 7925–7928
During the last decade, Pd-catalyzed coupling of aryl
halides and organoboron compounds has undergone
rapid development. New protocols have appeared that
allow effective and rapid reactions under very mild
conditions.11,12 Unlike organostannanes, organoboronic
acids are generally solid and nontoxic. Their wide com-
mercial availability is an added advantage. However, the
coupling conditions tend to vary widely depending on the
steric and electronic properties of the substrate and often
have to be individually optimized. To reduce the time
required to optimize the coupling conditions, we carried
out parallel reactions in a 12-well heating block (Ther-
molyne 17600). Reaction on a scale of up to 0.5 mM can
be conducted in this fashion using 8 mL vials (equipped
with magnetic stir bar and a Teflon-lined septum-screw
cap for ease of sampling). Analysis can be performed
quickly by either gas chromatography or 1H NMR
spectroscopy. The results of three such parallel runs for
thecouplingof1aandPhB(OH)2 aresummarizedinTable
1.
further investigation. Additional experiments showed
that the synthesis of 2a using these methods could be
achieved in less than 3 h.
Having established the synthetic protocol for preparation
of our target products, we turned our attention to other
substituted phenylboronic acids. A series of 3-substituted
salicylaldehydes was prepared using methods A–C and
characterized by 1H and 13C NMR spectroscopy (Eq. (2)).
The results of these experiments are reported in Table 2.
Salicylaldehydes 2a–f and 2i were obtained in excellent
yields by using method A. Methods B and C, however,
gave no product when applied to the synthesis of 2e. All
three methods failed to produce 2g and 2h. Instead,
dehydroxyborylationproductswereobservedinthesetwo
cases. We then tried to prepare 2a and 2e–h employing
a protocol outlined by Fu and co-workers, which allows
coupling of boronic acids and aryl halides under mild
conditions using Pd2(dba)3/P(tBu)3 as a catalyst and KF
as a base.11 This method converted 1a into 2a in good
yield at room temperature but did not give good results
with the other substituted substrates. Raising the reaction
temperature to 50°C improved the yields of 2e and 2f but
did not give 2g or 2h. Suspecting that the formyl group
may be the cause behind the coupling difficulties, we
decided to employ a post-coupling formylation strategy
Of the catalysts used, Pd(dppf)Cl2 and Pd(PPh3)4 exhib-
ited the highest activity in the presence of K2CO3 as a
base, and mixture of DME/water (3:1) as a solvent. We
selected conditions reported in entries 5 (method A), 6
(method B) and 9 (method C) as primary candidates for
Table 1. Effect of reaction conditions on the Pd-catalyzed coupling of 3-bromo-5-tert-butyl salicylaldehyde and phenyl-
boronic acid
Entry
Catalyst
Base
Solventa
Temperature (°C)
Time (h)
Conversion (%)c
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dppf)Cl2
Pd(dppf)Cl2
Na2CO3
K2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KF
Toluene
Toluene
DME/water
Toluene
DME/water
Dioxane
90
60
60
90
90
90
90
60
90
90
90
90
90
90
90
90
90
40
40
40
40
16
16
40
40
16
40
40
40
40
40
40
40
40
50
78
100
93
100
100
83
78
100
30
–
69
55
81
43
68
–
Toluene
b
b
DME/water
DME/water
Dioxane
DME/water
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
9
10
11
12
13
14
15
16
17
Pd(PCy3)Cl2
Pd(PCy3)Cl2
Pd(OAc)2/PCy3
(Pd(PtBu2(OH))2Cl)2
(Pd(PtBu2(OH))2Cl)2
(Pd(PtBu2(OH))2Cl)2
(Pd(PtBu2(OH))Cl2)2
(Pd(PtBu2(OH))Cl2)2
Cs2CO3
CsF or KF
Dioxane
a DME=dimethoxyethane.
b dppf=diphenylphosphinoferrocene.
c Determined by GC analysis using HP-5 column.
Pd(PPh3)4 or Pd(dppf)Cl2
K2CO3
O
OH
O
B(OH)2
R
OH
Br
H
H
R
+
3:1 DME/H2O
90°C, 16-40 h
tBu
tBu
1
4a-i
2a-i
(2)
4a, 2a: R = H
4f, 2f: R =1-Benzofuranyl
4b, 2b: R = 4-OMe
4c, 2c: R = 4-NMe2
4d, 2d: R = 4-COOH
4e, 2e: R = 2,6-(OMe)2
4g, 2g: R = 2,4,6-tris(tert-butyl)phenyl (Mes*)
4h, 2h: R = 9-Anthracenyl
4i, 2i: R = 3,5-(tBu)2

M. A. Zhura6el, S. T. Nguyen / Tetrahedron Letters 42 (2001) 7925–7928
Table 2. 3-Aryl-5-tert-butyl salicylaldehydes via Suzuki coupling
7927
aArylboronic acid (1.1 equiv.), K2CO3 (1.5 equiv.), Pd(PPh3)4 (0.05 equiv.) heated at 90°C for 16–40 h in N2-degassed DME:H2O (3:1 v/v).
bArylboronic acid (1.1 equiv.), K2CO3 (1.5 equiv.), Pd(PPh3)4 (0.05 equiv.) heated at 90°C for 16–40 h in N2-degassed dioxane.
cYields are given for pure products isolated by flash chromatography on silica gel. The purity of products was assessed by 1H and 13C NMR
spectroscopy and GC analysis.

7928
M. A. Zhura6el, S. T. Nguyen / Tetrahedron Letters 42 (2001) 7925–7928
Scheme 1.
(Scheme 1). Thus, 2-hydroxy-5-tert-butylboronic acid
(6) was prepared and reacted with Mes*Br (7a) and
9-bromoanthracene (7b) using method A (Scheme 1).
However, this approach also did not yield the desired
products. Formation of small amounts of 8a was
observed by GC/MS but no 8b was detected. Analysis
of the reaction mixtures shows mostly starting materials
and, in the case of 7b, also some anthracene. We note
that Grubbs and co-workers have been able to prepare
2-(9-anthracenyl)phenol via Kumada coupling under
extended reaction time (4 days, THF reflux) albeit in
moderate yield.8,13
sen, E. N.; Pfaltz, A.; Yamamoto, H., Eds. Cyclopropa-
nation and CꢀH insertion with Cu; Springer: New York,
1999; Vol. 2, pp. 513–538.
2. Lydon, K. M.; McKervey, M. A. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds. Cyclopropanation and CꢀH inser-
tion with Rh; Springer: New York, 1999; Vol. 2, pp.
539–580.
3. Charette, A. B.; Lebel, H. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds. Cyclopropanation and CꢀH insertion with metals
other than Cu and Rh; Springer: New York, 1999; Vol. 2,
pp. 581–603.
In conclusion, we have shown that the Suzuki coupling
between a variety of arylboronic acids and 3-bromosal-
icylaldehydes is a general and direct method to access
several functionalized 3-arylsalicylaldehydes. While
highly efficient in the case of sterically hindered sub-
stituents, the reaction is unsuccessful when very bulky
aryls such as Mes* are used. A parallel strategy using
the Thermolyne 12-well heating block leads to a signifi-
cant reduction of time in the search for optimized
reaction conditions.
4. Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron 2000, 56,
3501–3509.
5. Uchida, T.; Irie, R.; Katsuki, T. Synlett 1999, 1793–1795.
6. Uchida, T.; Irie, R.; Katsuki, T. Synlett 1999, 1163–1165.
7. Jacobsen, E. N. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 1993; pp. 159–202.
8. Wang, C.; Friedrich, S.; Younkin, T. R.; Li, R. T.;
Grubbs, R. H.; Bansleben, D. A.; Day, M. W.
Organometallics 1998, 17, 3149–3151.
9. Tsuji, J. Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; Wiley: New York, 1995.
10. Lam, F.; Xu, J. X.; Chan, K. S. J. Org. Chem. 1996, 61,
8414–8418.
Acknowledgements
11. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020–4028.
12. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 9550–9561.
13. Bansleben, D. A.; Connor, E. F.; Grubbs, R. H.; Hender-
son, J. I.; Younkin, T. R.; Nadjadi, A. R. Supported
catalysts and olefin polymerization processes utilizing
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0056787, 2000; p. 36 (59 pp); CAN133:267225.
14. Li, G. Y. Angew. Chem., Int. Ed. Engl. 2001, 40, 1513–
1516.
We thank Dr. George Y. Li (DuPont Central Research)
for providing us with samples of (Pd(PtBu2(OH))2Cl)2
and (Pd(PtBu2(OH))Cl2)2.14 Financial support from the
Dreyfus Foundation, the DuPont Company, and the
Packard Foundation is gratefully acknowledged.
References
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