Expedient, high-yielding synthesis of silyl-substituted salen ligands

Article abstract of DOI:10.1021/ol0713436

Described is an efficient synthesis of silyl-substituted salen ligands, used for the preparation of enantioselective catalysts. The salicylaldehyde precursors are synthesized from the silyl ethers of 2,6-dibromophenols via a one-pot double lithium halogen

Full text of DOI:10.1021/ol0713436

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3873-3876
Expedient, High-Yielding Synthesis of
Silyl-Substituted Salen Ligands
Avinash N. Thadani, Yong Huang, and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Vrawal@uchicago.edu
Received June 6, 2007
ABSTRACT
Described is an efficient synthesis of silyl-substituted salen ligands, used for the preparation of enantioselective catalysts. The salicylaldehyde
precursors are synthesized from the silyl ethers of 2,6-dibromophenols via a one-pot double lithium halogen exchanges, to induce an
intramolecular retro-Brook rearrangement and allow introduction of the aldehyde group. Condensation of the salicylaldehyde products with a
chiral diamine affords the silyl-substituted salen ligands in high yields. The use of other electrophiles allows easy access to silyl-substituted
phenolic esters, ketones, and boronic acids.
Asymmetric catalysis has grown explosively over the past
two decades. It is no exaggeration to say that all important
classes of reactions can now be rendered enantioselective.
Fueling the rapid growth of this field has been the continual
development of numerous and varied chiral ligands, the
molds that impart asymmetry to the reactants.1 Among the
many broadly effective ligand types are the salen-derived
metal complexes, which have been found to promote a range
of asymmetric processes and, for this reason, have earned
the designation “privileged ligands”.2 Salen ligands are easily
prepared by condensation of a salicylaldehyde and a chiral
1,2-diamine. The salicylaldehyde precursors are typically 3,5-
dialkyl substituted, with the 3,5-di-t-butyl variant being the
most common.
Among the other substituted salens, those prepared from
salicylaldehydes having a silyl group at the 3-position have
been found to have useful properties. Burrows and co-
workers developed such salen molybdenum catalysts for the
epoxidation and aziridination of olefins.3 Related chromium
complexes were used by Jacobsen et al. for the asymmetric
kinetic resolutions of meso-aziridines.4 Silyl-salen ruthenium
complexes were used by the Katsuki group for catalytic
aerobic oxidation of diols.5 In connection with our studies
on the enantioselective cycloaddition chemistry of amino-
substituted dienes,6 we sought to enhance the subtle asym-
metric topology of the standard 3,5-di-t-butyl-salen frame-
work and found the corresponding silyl-substituted salen
cobalt complexes to be superb catalysts for Diels-Alder
reactions.6d The higher effectiveness of silyl-salen com-
plexes, which allowed the catalysts to be used at loadings
as low as 0.05 mol %, was rationalized to be a result of
sterics-based distortion of the otherwise almost flat salen
framework. Through similar reasoning, we recently identified
triisobutylsilyl (TIBS) substituted Co-salen complexes as
excellent catalysts for the carbonyl ene reaction of various
1,1-disubstituted and trisubstituted alkenes with ethyl gly-
oxylate.7
(4) Li, Z.; Fernandez, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611-
1613.
(5) Miyata, A.; Furukawa, M.; Irie, R.; Katsuki, T. Tetrahedron Lett.
2002, 43, 3481-3484.
(1) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vols. 1-3.
(2) (a) Ito, Y. N.; Katsuki, T. Bull. Chem. Soc. Jpn. 1999, 72, 603-619.
(b) Larrow, J. F.; Jacobsen, E. N. Top. Organomet. Chem. 2004, 6, 123-
152.
(3) O’Conner, K. J.; Wey, S. J.; Burrows, C. J. Tetrahedron Lett. 1992,
33, 1001-1004.
(6) (a) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000,
122, 7843-7844. (b) Huang, Y.; Iwama, T.; Rawal, V. H. Org. Lett. 2002,
4, 1163-1166. (c) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J.
Am. Chem. Soc. 2002, 124, 4628-4641. (d) Huang, Y.; Iwama, T.; Rawal,
V. H. J. Am. Chem. Soc. 2002, 124, 5950-5951. (e) Takenaka, N.; Huang,
Y.; Rawal, V. H. Tetrahedron 2002, 58, 8299-8305. (f) McGilvra, J.;
Rawal, V. H. Synlett 2004, 13, 2440-2442.
10.1021/ol0713436 CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/01/2007

Despite their unique capabilities, silyl-salen complexes
have not been widely adopted as catalysts, due in part to the
challenges associated with their preparation. The reported
syntheses of 3-silyl-substituted salicylaldehydes require
several steps, some of which are low yielding.3,4 Our standing
interest in silyl-salens led us to devise a more efficient route
to them. We report here a general, high-yielding synthesis
of various 3-silyl-substituted salicylaldehydes as well as the
corresponding salen ligands.8 We also show the trapping of
the intermediate lithiated phenoxide with other electrophiles
to produce silyl-substituted phenolic esters, ketones, biaryls,
and boronic acids.
Our route to 3-silyl-substituted salicylaldehydes capitalized
on known metal-halogen exchange chemistry as well as on
the intramolecular transfer of silyl groups from phenolic
oxygens to the ortho-carbon, a type of retro-Brook rear-
rangement (Scheme 1).3,9,10 On the basis of literature
Table 1. Protocol Optimization: Synthesis of
2-Trimethylsilyl-Substituted Salicylaldehyde 4a
entry
base
solvent
yield [%]a
1
2
3
4
5
6
7
n-BuLi
Et2O
Et2O
Et2O
Et2O
Et2O
THF
DME
51
66
71
70
96
92
92
n-BuLi, 4 equiv of TMEDA
n-BuLi, 4 equiv of HMPA
n-BuLi, 4 equiv of DMPU
t-BuLi
t-BuLi
t-BuLi
a
Isolated yield.
Scheme 1
HMPA, or DMPU were used as additives. The salicylalde-
hyde product was obtained in considerably higher yield when
the metal-halogen exchange was accomplished using tert-
butyllithium, irrespective of the solvent used (Table 1, entries
5-7). Four equivalents of tert-butyllithium was ultimately
used to ensure that the second lithium-halogen exchange
proceeded to full conversion.
The optimized conditions were then utilized for the synthe-
sis of assorted 3-silyl-substituted salicylaldehydes (Table 2).
The requisite silyl ethers (2) were prepared via standard
procedures and in most cases subjected directly, without
purification, to the one-pot procedure. A variety of silyl
phenol ethers successfully underwent the intramolecular silyl
transfer and subsequent trapping with DMF. In the case of
the more sterically demanding silyl groups (tBuPh2Si,
precedents, the silyl ether of a 2,6-dibromophenol (2) was
expected to be converted to the corresponding dilithio
intermediate upon treatment with excess butyl lithium.
Intramolecular silyl transfer followed by trapping of the
resultant aryllithium intermediate 3 with dimethylformamide
would then give the desired 3-silyl-substituted salicylalde-
hyde (4). Subsequent condensation with an appropriate chiral
diamine would then afford the salen ligand.
Table 2. One-Pot Synthesis of 3-Silyl-Substituted
Salicylaldehydes
Initial exploratory studies were carried out on the tri-
methylsilyl (TMS) ether of 2,6-dibromo-4-methylphenol
(2a).11 The transformation was optimized by examining the
effect of various reaction parameters, including the base,
solvent, and additives (Table 1). Both n-butyllithium and tert-
butyllithium were found to be effective for the one-pot silyl-
salicylaldehyde synthesis. In the case of n-butyllithium,
somewhat higher yields were obtained when TMEDA,
entry
R′
SiR3
yield [%]a
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
H
SiMe3
96 (4a)
91 (4b)
93 (4c)
82 (4d)b,c
91 (4e)
87 (4f)b,d
96 (4g)
92 (4h)
94 (4i)
t
SiMe2 Bu
SiiPr3
SitBuPh2
SiPh3
(7) See accompanying publication: (a) Hutson, G. E.; Dave, A. H.;
Rawal, V. H. Org. Lett. 2007, 9, 3869-3872. (b) Hutson, G.; Rawal, V. H.
Abstracts of Papers, 233rd ACS National Meeting, Chicago, IL, United
States, March 25-29, 2007; American Chemical Society: Washington, DC,
2007; ORGN-557 (Chemical Abstracts: 2007:296584).
(8) Taken in part from: Huang, Y., Ph.D. Dissertation, University of
Chicago, 2002.
SiPh2Me
SiMe3
tBu
tBu
tBu
F
t
SiMe2 Bu
SiiPr3
SiMe3
10
92 (4j)
(9) (a) Simchen, G.; Pfletschinger, J. Angew. Chem., Int. Ed. Engl. 1976,
15, 428-429. (b) Habich, D.; Effenberger, F. Synthesis 1979, 841-876.
(c) Billedeau, R. J.; Sibi, M. P.; Snieckus, V. Tetrahedron Lett. 1983, 24,
4515-4518. Maruoka, K.; Itoh, T.; Araki, Y.; Shirasaka, T.; Yamamoto,
H. Bull. Chem. Soc. Jpn. 1988, 61, 2975-2976.
a
Isolated yield. b Reaction conducted in THF and warmed to rt during
c
the lithium-halogen exchange. Monobromide 4dBr was isolated (7%
yield). Monobromide 4fBr was isolated (6% yield).
d
3874
Org. Lett., Vol. 9, No. 20, 2007

Ph2MeSi, and Ph3Si), the reaction mixture was allowed to
warm to room temperature to promote the silyl transfer step.
The 3-silyl salicylaldehyde products were obtained in
uniformly high yields. In a few instances, we isolated a small
amount of a byproduct (2-bromo-6-silylphenol) that resulted
from incomplete lithium-halogen exchange. Phenolic pre-
cursors (2) having a substituent other than methyl at the
4-position were also examined as substrates (entries 6-10).
Precursors having a hydrogen, t-Bu, or fluorine at the
4-position were tolerated well, whereas nitro and trifluo-
romethyl substituents on the aromatic ring proved incompat-
ible with the reaction conditions.
than DMF in the reaction protocol. Thus, after addition of
t-BuLi to 2a and allowing time for the silyl transfer step,
the reaction mixture was treated with methylchloroformate
rather than DMF. The product of the reaction was methyl
salicylate 6, obtained in 85% isolated yield (eq 1).
The purpose of developing a high-yielding synthesis of
silyl-substituted salicylaldehydes (4) was to eventually trans-
form these compounds into the corresponding silyl-substi-
tuted salen ligands (5). Having achieved the initial objective,
we next explored the feasibility of a direct, purification-free
synthesis of the silyl salens. A protocol was developed for
the transformation of various dibromophenol ethers (2) into
the corresponding salen ligands (5), and the results are
summarized in Table 3. The crude salicylaldehydes, obtained
In a related reaction, treatment of the intermediate aryl-
lithium species (3) with aldehydes led to an unexpected
outcome. Specifically, quenching of the aryllithium inter-
mediate from 2a with excess para-anisaldehyde led to the
isolation of ketone 7 rather than the expected diaryl carbinol.
Ketone 7 is believed to arise through an Oppenauer oxidation
of the expected carbinol anion by anisaldehyde. Attempts
to avoid the oxidation product by reducing the number of
equivalents of para-anisaldehyde proved unsuccessful, giving
only lower yields of 7, with none of the expected secondary
benzylic alcohol product.
Table 3. Direct Synthesis of Silyl-Substituted Salen Ligands
entry
R′
SiR3
yield [%]a
To expand the scope of this versatile one-pot protocol,
we explored the possibility of converting the monolithio in-
termediate to the corresponding boronic acid. The desired
transformation was achieved by treating the putative aryl-
lithium intermediate (3) with trimethyl borate, followed by
an acid quench. Although the expected aryl boronic acid 8
was formed, it proved difficult to isolate. For this reason,
the crude aryl boronic acid was utilized directly in a Suzuki-
Miyaura cross-coupling reaction, as illustrated in Scheme
2. The desired cross-coupled product 10 was obtained in 69%
isolated yield based on 4-bromoanisole.
1
2
3
4
5
Me
tBu
tBu
tBu
F
SiMe3
SiMe3
SiMe2 Bu
84 (5a)
83 (5b)
88 (5c)
81 (5d)
80 (5e)
t
SiiPr3
SiMe3
a
Isolated yield.
as described in Table 2, were directly subjected to condensa-
tion with the representative chiral diamine, (1R,2R)-diami-
nocyclohexane. It is noteworthy that this diamine was
generated in situ from its cost-effective l-tartrate salt precur-
sor. The combined procedure allowed for the synthesis of
several silyl-substituted salen ligands in high overall yields,
without the necessity for any purification beyond simple
filtration.
Scheme 2
Finally, given that the intermediate after the intramolecular
silyl transfer reaction is an aryllithium species (3), we briefly
examined the possibility of incorporating electrophiles other
(10) Intramolecular silyl transfer on 2,6-dibromophenols has been
previously described. See: (a) Razuvaev, G. A.; Vasileiskaya, N. S.;
Khrzhanovskaya, I. L. J. Gen. Chem. USSR, Engl. Trans. 1975, 45, 2392-
2395. (b) Razuvaev, G. A.; Vasileiskaya, N. S.; Oleinik, E. P.; Vavilina,
N. N.; Muslin, D. V. J. Gen. Chem. USSR, Engl. Trans. 1976, 46, 2595-
2598. (c) Muslin, D. V.; Lyapina, N. Sh. Bull. Acad. Sci. USSR DiV. Chem.
Sci., Engl. Trans. 1984, 33, 2141-2143. Review: (d) Moser, W. H.
Tetrahedron 2001, 57, 2065-2084.
(11) For a general procedure for the preparation of 2, please see the
Supporting Information.
Org. Lett., Vol. 9, No. 20, 2007
3875

An alternate synthetic route to biaryl compounds such as
10 could involve the direct cross-coupling of aryllithium
species 3 under the Negishi cross-coupling conditions. In
the event, the aryllithium intermediate 3 was converted to
the aryl-zinc. The reaction mixture was then treated with
bromobenzene, the palladium catalyst, and copper(I) iodide
and heated. The nature of a palladium catalyst and the
amount of copper iodide proved critical to the success of
this cross-coupling reaction. Functionalized biaryl 11 was
obtained in 70% isolated yield based on starting silyl ether
2a.
the silyl-substituted salicylaldehydes in good to excellent
yields. Subsequent condensation with an appropriate chiral
diamine affords the silyl salen ligands without the necessity
of any further purification. This one-pot silyl salen synthesis
is convenient to carry out, even on a multigram scale. The
ease of this protocol should encourage others to further
explore the unique steric and electronic properties of silyl
salen complexes. The above studies also illustrated the use-
fulness of the lithiation/intramolecular silyl transfer protocol.
Reaction of the aryllithium intermediate with other electro-
philes allowed for the synthesis of various functionalized,
silyl-substituted phenols in good overall yields.
Acknowledgment. Financial support of this work by the
National Institutes of Health is gratefully acknowledged.
A.N.T. thanks the National Science and Engineering Re-
search Council of Canada for a postdoctoral fellowship.
Supporting Information Available: Preparation proce-
dures and characterization data for 2-4. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed an expedient, high-
yielding synthesis of silyl-substituted salen ligands. Double
lithiation of a 2,6-dibromosilylphenol ether followed by
intramolecular silyl transfer and trapping with DMF affords
OL0713436
3876
Org. Lett., Vol. 9, No. 20, 2007