Acetyltrimethylsilane: A novel reagent for the transformation of 2H-pyran-2-ones to unsymmetrical biaryls

Article abstract of DOI:10.1021/jo052085y

An expeditious synthesis of unsymmetrical biaryls functionalized with electron-withdrawing or -donating substituents is described and illustrated by carbanion-induced ring transformation of 2H-pyran-2-one using acetyltrimethylsilane (ATMS) as a novel reag

Full text of DOI:10.1021/jo052085y

useful intermediate for nucleophilic acylation reactions.4 To the
best of our knowledge, none have demonstrated synthetic utility
in preparing functionalized biaryl compounds, which not only
are the central building motifs of a large number of natural
products5 and synthetic pharmaceuticals but also are useful as
versatile auxiliaries for asymmetric syntheses,6 as chiral phases
for chromatography,7 and as important substrates for advanced
materials.8
Acetyltrimethylsilane: A Novel Reagent for the
Transformation of 2H-Pyran-2-ones to
Unsymmetrical Biaryls†
Atul Goel,*,‡ Deepti Verma,‡ Manish Dixit,‡
Resmi Raghunandan,§ and P. R. Maulik§
DiVision of Medicinal and Process Chemistry and Molecular
and Structural Biology, Central Drug Research Institute,
Lucknow 226001, India
The regioselective palladium-catalyzed cross-coupling of
organosilicon compounds with organic halides has been devel-
oped as a viable alternative to the cross-coupling of copper,
magnesium, boron, tin, and zinc alkyls.9 The most commonly
used organosilicon reagent for the synthesis of symmetrical and
unsymmetrical biaryls is aryl silane, which has been extensively
studied by Hiyama and Hatanaka.10 The cross-coupling of aryl-
(halo)silanes with aryl halides in the presence of a palladium
catalyst is a general and practical route to symmetrical and
unsymmetrical biaryls. Symmetrical biaryls have recently been
prepared by Pd-catalyzed homocoupling of difluorosilanes in
the presence of a dibromide as an oxidant.11 Recently, phenyl-
(trialkoxy)silanes have been utilized to prepare functionalized
biaryls via hypervalent silicate anion intermediate or by using
palladium/imidazolium chloride system as a useful catalyst.12
Despite their efficiency, the interest in aryl(halo/alkoxy)silane
cross-coupling is limited by the difficulty of synthesizing such
compounds. Additionally, non-palladium-catalyzed13 reductive
coupling reactions have been reported using either TTMSS-
AIBN as promoters or in the presence of zinc dust and
ammonium formate. Other organosilicon reagents such as
silanols14 and silacyclobutanes15 were also proposed as useful
reagents for biaryl synthesis in good to excellent yields.
Nevertheless, the use of such reagents involves stoichiometric
amounts of expensive activators or palladium catalysts.
The tremendous synthetic potential of organosilicon reagents
in preparing regiospecifically substituted biaryls and difficulty
in existing protocols prompted us to develop a new simple,
agoel13@yahoo.com
ReceiVed October 5, 2005
An expeditious synthesis of unsymmetrical biaryls function-
alized with electron-withdrawing or -donating substituents
is described and illustrated by carbanion-induced ring
transformation of 2H-pyran-2-one using acetyltrimethylsilane
(ATMS) as a novel reagent in good yield. The novelty of
the reaction lies in the creation of an aromatic ring from
2H-pyran-2-ones via two-carbon insertion from ATMS used
as a source of carbanion.
The significant advancements in the chemistry of organo-
silicon reagents over the past few decades have opened new
avenues for their potential utility in regio- and stereochemical
organic syntheses.1 Among the various organosilicon reagents,2
acyl silanes are of particular interest due to their reactive
behavior and unusual physical and chemical properties associ-
ated with them. Chemically, alkanoyl- and benzoyl-alkyl/
arylsilanes (R3SiCOR′; R, R′ ) alkyl, aryl) behave like classical
ketones with some reagents, and their reactivity is quite different
depending upon the substituents attached to them.3 Although
acyl silanes are being considered as poor substrates for func-
tionalization due to high sensitivity toward basic conditions and
light, they have been successfully used as synthetic equivalents
of aldehydes provided with enhanced chemical stability and as
(4) (a) Wilson, S. R.; Hague, M. S.; Misra, R. N. J. Org. Chem. 1982,
47, 747. (b) Sato, T.; Arai, M.; Kuwajima, I. J. Am. Chem. Soc. 1977, 99,
5827.
(5) Torssell, K. G. B. In Natural Product Chemistry; Wiley: Chichester,
1983. (b) Thomson, R. H. In The Chemistry of Natural Products; Blackie:
Glasgow, 1985.
(6) (a) Noyori, R. Chem. Soc. ReV. 1989, 18, 187. (b) Andersen, N. G.;
Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1996, 61, 9556.
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(8) (a) Yamamura, K.; Ono, S.; Tabushi, I. Tetrahedron Lett. 1988, 29,
1797. (b) Yamamura, K.; Ono, S.; Ogoshi, H.; Masuda, H.; Kuroda, Y.
Synlett 1989, 18.
(9) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359.
(10) Hatanaka, Y.; Goda, K.-I.; Okahara, Y.; Hiyama, T. Tetrahedron
1994, 50, 8301. (b) Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1990, 31,
2719. (c) Hatanaka, Y.; Hiyama, T. Synlett 1991, 845. (d) Hiyama, T.;
Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471.
(11) Yamaguchi, S.; Ohno, S.; Tamao, K. Synlett 1997, 1199.
(12) (a) Shibata, K.; Miyazawa, K.; Goto, Y. J. Chem. Soc., Chem.
Commun. 1997, 1309. (b) Lee, H. M.; Nolan, S. P. Org. Lett. 2000, 2,
2053.
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hedron 2004, 60, 6217. (b) Abiraj, K.; Srinivasa, G. R.; Gowda, D. C.
Tetrahedron Lett. 2004, 45, 2081.
† CDRI Communication No. 6860.
‡ Division of Medicinal and Process Chemistry.
§ Molecular and Structural Biology.
(1) (a) Fleming, I. Organic Silicon Chemistry. In ComprehensiVe Organic
Chemistry; Barton, D. H. R., Ollis, W. D., Eds.; Pergamon Press: Oxford,
1979; Vol. 3, pp 541-659. (b) Colvin, E. W. Silicon in Organic Synthesis;
Butterworths: London, 1981; revised ed., Krieger Pub. Co.: Malabar, FL,
1985. (c) Horn, K. A. Chem. ReV. 1995, 95, 1317.
(2) (a) Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. ReV. 1990,
19, 147. (b) Honda, M.; Yamamoto, Y.; Tsuchida, H.; Segi, M.; Nakajima,
T. Tetrahedron Lett. 2005, 46, 6465.
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T. Org. Lett. 1999, 1, 299. (b) Hirabayashi, K.; Mori, A.; Kawashima, J.;
Suguro, M.; Nishihara, Y.; Hiyama, T. J. Org. Chem. 2000, 65, 5342.
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(3) Ricci, A.; Degl′Innocenti, A. Synthesis 1989, 647.
10.1021/jo052085y CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/22/2005
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J. Org. Chem. 2006, 71, 804-807

SCHEME 1
general, and inexpensive route for their synthesis. Herein we
describe synthesis of functionalized biaryls from the reaction
of aryllactones and acetyltrimethylsilane (ATMS) under mild
basic conditions. The novelty of the procedure lies in the
conversion of the 2H-pyran-2-one skeleton into an aromatic ring
via two-carbon insertion using ATMS as a useful reagent.
Our synthetic approach to preparing functionalized biaryls
3a-f is based on ring transformation of 6-aryl-3-methoxycar-
bonyl-4-methylsulfanyl-2H-pyran-2-ones 1a-f using ATMS as
a carbanion source. The 2H-pyran-2-ones 1a-f precursors have
been prepared by the reaction of methyl 2-methoxycarbonyl-
3,3-di(methylsulfanyl)acrylate with substituted acetophenones
under alkaline conditions in high yields.16 Lactones 1a-f have
three electrophilic centers: C2, C4, and C6 in which the latter
is highly reactive toward nucleophiles due to the extended
conjugation and the presence of the electron-withdrawing
substituent at position 3 of the pyran ring. These biaryl
compounds 3a-f were synthesized by stirring an equimolar
mixture of 2H-pyran-2-ones 1a-f, ATMS, and powdered KOH
in dry DMF under nitrogen atmosphere for 4-6 h at room
temperature (Scheme 1). The reaction was performed in the dark
to avoid decomposition of ATMS in light and was monitored
by TLC, which showed a blue spot when exposed to short-
wave UV radiation at 254 nm. After completion, the reaction
mixture was poured into ice water and neutralized with dilute
HCl. The crude product thus obtained was purified by silica
It was of interest to understand the mechanism of this hitherto
unobserved type of reaction. It has been well-documented that
acyl silanes are readily cleaved at room temperature by dilute
aqueous base into silanol and aldehyde.17 Although we carried
out the reaction in dry DMF under inert atmosphere, there may
be a possibility of hydrolysis of ATMS into acetaldehyde due
to the presence of traces of water. To shed light on the reactive
species (ATMS or acetaldehyde), we attempted the reaction in
alcoholic alkaline condition by replacing the solvent from dry
DMF to methanol, which should accelerate in situ formation
of acetaldehyde, and thus should analogously yield the biaryls.
However, this optimistic presumption was unsuccessful, and no
biaryl product was obtained. It is also apparent that alkyl and
aromatic groups attached to a silanoyl group dramatically
influence the reactivity as well as the reaction products.3 For
example, when benzoyltriphenylsilanes are treated with diazo-
methane, two products (â-ketosilanes and the isomeric siloxy-
alkenes) are usually obtained in equal quantities. On the
contrary, when acetyltriphenylsilanes are reacted with diazo-
methane, â-ketosilanes are obtained in major quantities.
After considering all the aspects, a plausible mechanism for
the formation of a biaryl is depicted in Scheme 1. The
transformation of 2H-pyran-2-one into a biaryl may proceed
by enolate addition of ATMS at position C-6 of lactone 1,
followed by intramolecular cyclization involving the carbonyl
functionality of ATMS and C-3 of the pyran ring to form a
bicyclic intermediate. The intermediate after elimination of
carbon dioxide formed an oxyanion, which on delocalization
of negative charge can undergo silylcarbinol-alkoxysilane-type
rearrangement, forming a silicon-oxygen bond, followed by
elimination of siloxy group through a carbanionic intermediate.
The resulting ester intermediate is smoothly transformed into
the corresponding silylester, which on hydrolysis under mild
basic conditions furnished a biaryl carboxylic acid (Scheme 1).
In addition to biaryls, heterobiaryls from heteroaryl-aryl
couplings have found a unique place in various therapeutic areas
1
gel chromatography. The H NMR spectroscopic analysis of
3a revealed one singlet at δ 2.49 for the SMe group, a doublet
at 7.98 for an aromatic proton, and two doublets in the range
of 7.72-7.54 for other aromatic protons. The absence of a
methoxy proton signal in the range 3.8-4.2 and the presence
of a carbonyl stretching peak at 1682 for aromatic carboxylic
acid in IR spectrum revealed that the ester group is hydrolyzed
to carboxylic acid under basic conditions. The molecular ion
peak at m/z 258 allowed us to propose the structure for isolated
compound as 3-methylsulfanyl-biphenyl-4-carboxylic acids 3a-
f. Finally, the structure of 3a was confirmed by a single-crystal
X-ray analysis (see Supporting Information).
(17) (a) Brook, A. G.; Schwartz, N. V. J. Org. Chem. 1962, 27, 2311.
(b) Brook, A. G.; Vandersar, T. J. D.; Limburg, W. Can. J. Chem. 1978,
56, 2758. (c) Brook, A. G. J. Am. Chem. Soc. 1957, 79, 4373. (d) Somer,
L. H.; Bailey, D. L.; Goldberg, G. M.; Buck, C. E.; Bye, T. S.; Evans, F.
J.; Whitmore, F. C. J. Am. Chem. Soc. 1954, 76, 1613.
(16) Tominaga, Y.; Ushirogochi, A.; Matsuda, Y. J. Heterocycl. Chem.
1987, 24, 1557.
J. Org. Chem, Vol. 71, No. 2, 2006 805

SCHEME 2
optimization studies were carried out by varying reaction
conditions and bases such as NaH, KOH, Et3N, DIPA, K2CO3,
LDA, DBU, and t-BuOK in suitable solvents. The potassium
hydroxide in dry DMF under nitrogen atmosphere in dark was
found to be the most appropriate. Unfortunately, our efforts to
obtain the compounds in higher yields were not successful.
To prepare biaryls exclusively, we attempted to reduce the
electrophilicity at position 4 of lactones 6a-e by replacing the
methyl sulfanyl group with a secondary amine such as piperi-
dine. With this consideration, we prepared 6-aryl-2-oxo-4-
piperidin-1-yl-2H-pyran-3-carbonitriles (8a-e) in high yields
by refluxing a solution of lactone 6a-e with piperidine in
methanol for 6-8 h as described earlier.21 The reaction of
lactones 8a-e and ATMS under the same reaction conditions
as described in Scheme 1 gave 3-piperidin-1-ylbiphenyl-4-
carbonitriles (9a-e) in good yields (Scheme 3). All the
synthesized compounds were characterized by spectroscopic
analyses.
In summary, we have developed a new reagent acetyltri-
methylsilane for the synthesis of unsymmetrical biaryls through
carbanion-induced ring transformation of 2H-pyran-2-ones under
mild basic conditions. This methodology is very simple,
economical, and does not require expensive palladium catalysts
that are normally used for C-C bond-forming reactions. The
novelty of the reaction lies in the conversion of the lactone ring
into an aromatic ring via two-carbon insertion involving the
-CH2CO unit of the ATMS, in the presence of a base.
as well as in generating molecular devices.9 Although the
chemistry of heterobiaryls is replete with various palladium-
catalyzed approaches, simple, inexpensive noncatalyzed meth-
odologies are still nonexistent. Recently, an interesting route
for preparing heterobiaryls has been developed by a straight-
forward anionic coupling of R-metalated heterocycles with
halobenzene.18 To demonstrate the utility of this route for
preparing heterobiaryls, we carried out a reaction of 6-furyl/
thienyl-3-methoxycarbonyl-4-methylsulfanyl-2H-pyran-2-
one16 (4a,b) with ATMS under the same reaction conditions
(Scheme 2). After the usual workup, we isolated the compounds
as 4-furan/thiophen-2-yl-2-methylsulfanylbenzoic acid 5a,b in
good yields.
To further expand the scope of this reaction, current interest
focuses on fabricating useful biaryl building blocks by utilizing
functionalized 2H-pyran-2-ones. Several studies19,20 have dem-
onstrated that the biaryl and teraryl synthons containing “cyano”
functionality in their molecular framework dramatically influ-
ence the photophysical and electroluminescent properties of light
emitting diode devices by lowering the energy of the LUMO,
thus exhibiting a relatively low threshold voltage and high
quantum efficiency. The paucity of the synthetic methodology
for constructing a cyano group containing biaryls prompted us
to exploit our methodology to prepare them.
Experimental Section
The synthetic procedures and characterization data for all the
new compounds are described in the Supporting Information. The
data for one of the representative compounds from each scheme is
described here. ATMS was purchased from a commercial supplier.
General Procedure for the Synthesis of 3a-e. A mixture of
6-aryl-3-methoxycarbonyl-4-methylsulfanyl-2H-pyran-2-ones16 1 (1
mmol), acetyltrimethylsilane (2, 1.1 mmol), and powdered KOH
(1.2 mmol) in dry DMF (5 mL) under dry nitrogen atmosphere
was stirred at room temperature in the dark for 4-6 h. At the end,
the reaction mixture was poured into ice water with vigorous stirring
and finally neutralized with dilute HCl. The solid thus obtained
was filtered, dried, and purified on a silica gel column using
chloroform/hexane (3:1) as eluent.
The cyano group containing precursors, 6-aryl-4-methylsul-
fanyl-2-oxo-2H-pyran-3-carbonitriles 6a-e, were synthesized
by reacting an equimolar mixture of methyl 2-cyano-3,3-di-
(methylsulfanyl)acrylate and substituted acetophenones in dry
DMSO.21 For ascertaining the course of reaction with these
precursors, the 2H-pyran-2-ones 6a-c were then reacted with
ATMS in the presence of a base to furnish 3-methylsulfanyl-
biphenyl-4-carbonitriles 7a-c in moderate yield as shown in
Scheme 3. To achieve higher yields of biaryls, a series of
SCHEME 3
806 J. Org. Chem., Vol. 71, No. 2, 2006

3-Methylsulfanylbiphenyl-4-carboxylic Acid (3a): White solid;
mp: 219-220 °C; MS (FAB): 244 (M+); IR (KBr): 1680 cm-1
3-Piperidin-1-ylbiphenyl-4-carbonitrile (9a): Viscous oil; MS
(FAB): 263 (M+ + 1); IR (neat): 2220 cm-1 (CN); 1H NMR (200
MHz, CDCl3) δ: 1.60-1.68 (m, 2H, CH2), 1.78-1.87 (m, 4H,
2CH2), 3.18-3.26 (m, 4H, 2CH2), 7.14-7.18 (m, 2H, ArH), 7.31-
7.64 (m, 6H, ArH); Anal. Calcd for C18H18N2: C, 82.41; H, 6.92.
Found: C, 82.26; H, 6.78.
1
(CO); H NMR (200 MHz, DMSO-d6) δ: 2.49 (s, 3H, SCH3),
7.36-7.54 (m, 5H, ArH), 7.72-7.78 (m, 2H, ArH), 7.98 (d, 1H, J
) 5.2 Hz, ArH), 13.01 (brs, 1H, COOH); Anal. Calcd for
C14H12O2S: C, 68.83; H, 4.95. Found: C, 68.47; H, 5.08.
General Procedure for the Synthesis of 7a-c and 9a-e. A
mixture of 6-aryl-4-methylsulfanyl/(piperidin-1-yl)-2-oxo-2H-pyran-
3-carbonitrile21 6a-c or 8a-e (1 mmol), acetyltrimethylsilane (1
mmol), and powdered KOH (1.2 mmol) in dry DMF (5 mL) was
stirred at room temperature for 6-8 h in the dark under dry nitrogen
atmosphere. At the end, the reaction mixture was poured into ice
water with vigorous stirring and finally neutralized with dilute HCl.
The solid thus obtained was filtered and purified on a silica gel
column using chloroform/hexane (1:9) as eluent.
Acknowledgment. This work was supported by the Depart-
ment of Science and Technology (DST), New Delhi, India. We
are thankful to RSIC, CDRI, Lucknow, for providing spectro-
scopic analyses of the synthesized compounds.
Supporting Information Available: Complete experimental
details and characterization data of all new compounds (3a-f, 6b,
1
7a-c, 8a-e, 9a-e). A copy of H NMR spectra of all the new
compounds. X-ray structure and packing diagrams of compound
3a including noncovalent interactions studies. This material is
available free of charge via the Internet at http://pubs.acs.org.
3-Methylsulfanylbiphenyl-4-carbonitrile (7a): Light yellow
solid; mp: 84-86 °C; MS (FAB): 226 (M+ + 1); IR (KBr): 2221
1
cm-1 (CN); H NMR (200 MHz, CDCl3) δ: 2.62 (s, 3H, SCH3),
7.36-7.70 (m, 8H, ArH); Anal. Calcd for C14H11NS: C, 74.63; H,
JO052085Y
4.92. Found: C, 74.21; H, 4.99.
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J. Org. Chem, Vol. 71, No. 2, 2006 807