A facile and highly efficient route to a traceless pi-arene chromium linker. Applications to synthetic and combinatorial chemistry.

Article abstract of DOI:10.1021/ol0166000

[reaction--see text] A simple and efficient method for the attachment of functionalized arene chromium carbonyls to a polymeric support has been developed. A highly efficient solid-phase synthesis of tertiary alcohols and esters was performed in a traceless manner using this strategy. The linker-fabrication protocol permits simultaneous immobilization of various substrates on the solid support.

Full text of DOI:10.1021/ol0166000

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3683-3686
A Facile and Highly Efficient Route to a
Traceless π-Arene Chromium Linker.
Applications to Synthetic and
Combinatorial Chemistry
James H. Rigby* and Mikhail A. Kondratenko
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
jhr@chem.wayne.edu
Received August 16, 2001
ABSTRACT
A simple and efficient method for the attachment of functionalized arene chromium carbonyls to a polymeric support has been developed. A
highly efficient solid-phase synthesis of tertiary alcohols and esters was performed in a traceless manner using this strategy. The linker-
fabrication protocol permits simultaneous immobilization of various substrates on the solid support.
Over the past decade, polymer-supported reactions have
been the subject of considerable study as a result of the
increasing significance of combinatorial chemistry and
multiple parallel synthesis.1 The design of new linkers has
been important to the success of this endeavor since linker
diversity permits a broader scope of substrates and reagents
to participate in solid-phase chemistry. Currently, many
groups are focused on developing so-called “traceless”
linkers, which are designed to leave a minimal vestige of
the solid support upon release of the product.2,3 In this
context, the use of π-arene chromium complexes for loading
the substrates onto a solid support offers attractive opportuni-
ties,4 because the arene-chromium moiety is compatible
with most functional groups. Recently, the Gibson and
Maiorana laboratories have reported on the preparation
of resin-bound π-arene chromium carbonyl complexes.5
However, these approaches have, to date, afforded only
modest yields of the polymer-attached complexes, and they
are characterized by significant decomposition and side
product formation. Herein we disclose a simple and efficient
method for incorporating arene chromium carbonyls onto
a polystyrene-based resin and demonstrate the utility of
the resultant material in preparative and combinatorial
chemistry.
(3) For some recent publications, see: (a) Tumelty, D.; Cao, K.; Holmes,
P. Org. Lett. 2001, 3, 83. (b) Kirchhoff, J. H.; Brase, S.; Enders, D. J.
Comb. Chem. 2001, 3, 71. (c) Horton, J. R.; Stamp, L. M.; Routledge,
A. Tetrahedron Lett. 2000, 41, 9181. (d) Lormann, M.; Dahmen, S.;
Brase, S. Tetrahedron Lett. 2000, 41, 3813. (e) Pourbaix, C.; Carreaux,
F.; Carboni, B.; Deleuze, H. Chem. Commun. 2000, 1275. (f) Schiemann,
K.; Showalter, H. D. H. J. Org. Chem. 1999, 64, 4972. (g) Stieber, F.;
Grether, U.; Waldmann, H. Angew. Chem., Int. Ed. 1999, 38, 1073.
(h) Comely, A. C.; Gibson, S. E.; Hales, N. J. Chem. Commun. 1999,
2075.
(1) Obrecht, D.; Villalgordo, J. M. In Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound Libraries;
Baldwin, J. E., Williams, R. M., Eds.; Tetrahedron Organic Chemistry
Series. Pergamon: Oxford, 1998.
(4) Semmelhack, M. F.; Hilt, G.; Colley, J. H. Tetrahedron Lett. 1998,
39, 7683.
(2) For recent reviews, see: (a) Comely, A. C.; Gibson, S. E. Angew.
Chem., Int. Ed. 2001, 40, 1013. (b) Guillier, F.; Orain, D.; Bradley, M.
Chem. ReV. 2000, 100, 2091. (c) Zaragoza, F. Angew. Chem., Int. Ed. 2000,
39, 2077. (d) Bra¨se, S.; Dahmen, S. Chem. Eur. J. 2000, 6, 1899.
(5) (a) Gibson, S. E.; Hales, N. J.; Peplow, M. A. Tetrahedron Lett. 1999,
40, 1417. (b) Maiorana, S.; Baldoli, C.; Licandro, E.; Casiraghi, L.; De
Magistris, E.; Paio, A.; Provera, S.; Seneci, P. Tetrahedron Lett. 2000, 41,
7271.
10.1021/ol0166000 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/13/2001

Polystyrene-supported arene chromium carbonyls 9-14
were prepared from complexes 1-6 via intermediate com-
plex 7 using a two-step protocol,5b,6,7 (Scheme 1).
(arene)Cr(CO)2 fragment loading was determined in two
ways: (1) on the basis of isolated weighs of 9-14 (84-
95%) and (2) on the basis of the amount of substrate released
after subsequent cleavage of the arene-chromium bond (82-
92%). Both methods showed similar results.
Ketones 9, 10 and esters 11, 12 were exposed to Grignard
reagents in order to study the reactivity and synthetic utility
of these polymer-bound species. It was found that ethyl-
magnesium bromide underwent addition to 9-12 to furnish
the corresponding tertiary alcohols 18-20 in 76-82% yields
(Scheme 2). The structures assigned to 18-20 were consis-
Scheme 1
Scheme 2
tent with their IR spectra. Disappearance of the CdO
stretches at 1736-1714 cm-1 and the appearance of OH
absorptions at 3571-3562 cm-1 indicated that the CdO
groups were converted into the desired alcohols. Reaction
of 11 with i-PrMgCl followed by decomplexation afforded
a mixture of 3-methyl-1-phenyl-2-butanone 21 and 2-iso-
propyl-3-methyl-1-phenyl-2-butanol 22 in a ratio of 3:1
and 63% overall yield (Scheme 3), suggesting that mono-
In contrast to the resin-bound benzene and toluene
chromium carbonyls,6 the synthesis of 9-14, each of which
exhibits an oxygen in the side chain, resulted in partial
decomposition, thereby contaminating the final products with
polymer-bound chromium pentacarbonyl phosphine 17
(Scheme 1). This problem was successfully overcome by
using a large excess of cyclooctene (70-80 equiv). Under
conditions found to be optimal (toluene, 0 °C, hν, 8 min),
complexes 9-14 were obtained in high yields (84-95%),
and no evidence of decomposition was noted. In the
decomposition pathway it is likely that Cr(CO)5 fragment
16, derived from putative intermediate 15, successfully
competes with cyclooctene complex 7 to form the undesired
phosphine 17. Upon photolysis the chromium-oxygen bond
in 15 is formed by attack of readily available heteroatom
lone pair at the vacant coordination site on chromium. A
large quantity of cyclooctene suppresses this chromium-
oxygen bond formation, ensuring the preferred formation of
the required intermediate 7.
Scheme 3
additions to ester functions may be possible under certain
circumstances. More importantly, no starting materials
were detected in the crude products depicted in Schemes 2
and 3.
It is important to emphasize that the addition of the
Grignard reagent to polymer-attached ketones 9 and 10 and
esters 11 and 12 proceeded chemoselectively. No evidence
Products 9-14 were isolated as yellow beads, and their
structures were assigned by IR spectroscopy.8 The level of
(8) Compounds 9-14 exhibited two intense bands at 1885-1827 cm-1
that corresponded to a [Cr(CO)2(PR3)] fragment. Additionally, ketones 9
and 10, esters 11 and 12, and alcohols 13 and 14 revealed the keto- (1716-
(6) Rigby, J. H.; Kondratenko, M. A.; Fiedler, C. Org. Lett. 2000, 2,
3917.
(7) Jaouen, G. Tetrahedron Lett. 1973, 52, 5159.
1714 cm-1), ester- (1736-1733 cm-1), and hydroxy-group (3568 cm-1
)
absorptions, respectively.
3684
Org. Lett., Vol. 3, No. 23, 2001

of competitive additions to the metal-bound CO groups was
observed. Furthermore, addition of RMgX to the carbonyl
groups was not accompanied by enolization.9 The high
chemoselectivity of 9-12 toward Grignard reagents may be
attributed to steric hindrance created by the polymeric
scaffold.
Scheme 6
The crucial role of the solid support in the selective
formation of 18-20 was supported by the fact that only
starting material was recovered when unbound 3 was treated
with EtMgBr or i-PrMgCl and subsequently quenched with
aqueous NH4Cl (Scheme 4). Employing D2O instead of
Scheme 4
a Based on 9-14. b Based on 1-6.
Products 27-31 were released from the solid support by
oxidative cleavage of the Cr-arene bond with iodine or simply
by decomplexation with acetonitrile (Scheme 6). The spectra
of 27-31 were identical to those described in the litera-
ture.11 It must be noted, that the yields of the recovered
products 27-31 based on resin-bound substrates 9-14
(76-86%) were comparable to those reported previously;5
however, the yields obtained in the current work are fully
3-fold higher than in previous reports when they were
based on the original nonsupported precursors 1-6 (61-
78%).
aqueous NH4Cl as the quenching agent led to R-deuterated
(η6-methyl phenylacetate)Cr(CO)3 24 in 95% yield. These
results suggest that the Grignard reagents readily deprotonate
the unsupported ester 3 to give enolate 23, whereas addition
is the primary reaction channel for the supported substrate.
In addition to the possible influence of steric hindrance on
the different behavior of 11 and 3, one must also consider
the impact of the electronic differences between a phosphine
and a CO ligand.
Although the frequently used iodine decomplexation
method gave satisfactory results in this study, removal of
excess iodine complicated the workup and resulted in
decreased yields of final products 27-31. To simplify the
recovery protocol, an acetonitrile-assisted methodology was
developed. As depicted in Scheme 6, the use of acetonitrile
required slightly elevated temperature (50 °C); however, this
approach may be the method of choice in solid-supported
chemistry because of the ease of workup and higher final
product yields.
The resin-bound alcohols 13 and 14 were also found to
be amenable to derivatization. As expected, treatment of
alcohols 13 and 14 with an acetyl chloride/triethylamine
mixture in the presence of DMAP led to the corresponding
acetates 25 and 26 (Scheme 5).10 Cleavage from the resin
Scheme 5
The importance of combinatorial chemistry stems from
the ability to rapidly generate a vast number of compounds.
From this point of view, the linker formation technique
described above could be applied to advantage in the realm
(9) (a) Negishi, E. In Organometallics in Organic Synthesis; Wiley: New
York, 1980; Vol. 1. (b) Imamoto, T.; Takiyama. N.; Nakamura, K.;
Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392.
(10) In addition to the chromium carbonyl stretching at 1887-1829 cm-1
,
the IR spectra of 25 and 26 revealed absorptions at 1741 and 1737 cm-1
that correspond to the CdO stretches of the acetates.
(11) (a) Wrobel, D.; Tacke, R.; Wanuagat, U.; Harder, U. Chem. Ber.
1982, 115, 1694. (b) Katritzky, A. R.; Qi, M. J. Org. Chem. 1997,
62, 4116. (c) Suzuki, N.; Rousset, C. J.; Aoyagi, K.; Kotora, M.; Takahashi,
T. J. Organomet. Chem. 1994, 473, 117. (d) Patel, V. F.; Pattender,
G. J. Chem. Soc., Perkin Trans. 1 1990, 2703. (e) Chandrasekhar, S.;
Ramachandar, T.; Reddy, M. V.; Takhi, M. J. Org. Chem. 2000, 65,
4729.
afforded free esters 25 and 26 in 80-86% yield based on
13 and14 and 74-76% based on the nonsupported alcohols
5 and 6 (see Scheme 6).
Org. Lett., Vol. 3, No. 23, 2001
3685

diverse libraries. A control experiment was conducted in
order to determine if single-pot loading of numerous
substrates onto the resin would be possible and to observe
whether these multicomponent reagents would be amenable
to further chemical manipulation. In the event, irradiation
of equimolar quantities of 1-4 with excess cyclooctene in
toluene followed by treatment with resin-bound phosphine
8 afforded the resin 32 containing four different substrates
(Scheme 7).12 The polymer-bound ketoester 32 was reacted
with excess ethylmagnesium bromide to give the mixed
polymeric alcohol 33. The subsequent acetonitrile-assisted
cleavage of the linker furnished a mixture of tertiary alcohols
27, 28, and 29 in a ratio of 1:2:1 (by 1H NMR spectroscopy)
in an overall yield of 84% based on 32 and 75% based on a
mixture of 1-4.
Scheme 7
In conclusion, a convenient and efficient protocol for
making an arene-chromium carbonyl linker has been devel-
oped, and its utility in solid-phase synthesis was evaluated.
This process displayed several useful attributes including
high substrates loading (84-95%), high chemical yields,
a simple recovery procedure, and multicomponent capabili-
ties. The proposed methodology represents a valuable tool
for accessing a variety of resin-bound products and could
find broad application in the generation of combinatorial
libraries.
Acknowledgment. The authors wish to thank the Na-
tional Institutes of Health (grant GM-30771) for their
generous support of this research.
OL0166000
of combinatorial or parallel synthesis. This loading meth-
odology allows for the simultaneous incorporation of a
variety of starting materials onto the solid support. Therefore,
considerable time could be saved in preparing and testing
(12) The IR spectrum of 32 exhibited chromium carbonyl stretching
frequencies at 1886 and 1831 cm-1 and two bands at 1738 and 1721 cm-1
corresponding to the ester and keto groups, respectively, which is consistent
with the proposed structure.
3686
Org. Lett., Vol. 3, No. 23, 2001