Oxidative carbon-carbon bond formation via silyl bis-enol ethers: Controlled cross-coupling for the synthesis of quaternary centers

Article abstract of DOI:10.1021/ol702306z

(Chemical Equation Presented) Unsymmetrical silyl bis-enol ethers have been developed as effective substrates for synthesizing quaternary centers from tetralone derivatives through oxidative carbon-carbon bond formation. The derived products are shown to

Full text of DOI:10.1021/ol702306z

ORGANIC
LETTERS
2
007
Vol. 9, No. 22
667-4669
Oxidative Carbon−Carbon Bond
4
Formation via Silyl Bis-enol Ethers:
Controlled Cross-Coupling for the
Synthesis of Quaternary Centers
Michael D. Clift, Carla N. Taylor, and Regan J. Thomson*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208
r-thomson@northwestern.edu
Received September 22, 2007
ABSTRACT
Unsymmetrical silyl bis-enol ethers have been developed as effective substrates for synthesizing quaternary centers from tetralone derivatives
through oxidative carbon carbon bond formation. The derived products are shown to be highly versatile intermediates that may be used to
generate diverse structures such as cyclopentenones, 2H-pyrroles, and spirocyclic pyrrolidines.
−
The oxidative coupling of enolates, first reported in 1935,1
provides direct access to highly versatile 1,4-dicarbonyl
intermediates. A major limitation of this chemistry lies with
involved the use of enamines, which are preferentially
oxidized over enol silanes. MacMillan’s recently disclosed
5
2
catalytic enantioselective oxidative coupling uses enamine
6
the lack of methods that allow for selective and controlled
heterocoupling of two different enolates. For many cases a
mixture of both homo- and heterocoupled products are
obtained (Figure 1, eq 1). Recently, Baran and co-workers
demonstrated that a number of selective cross-couplings can
be achieved when the oxidation potential between the
substrates is significantly different, such as between an amide
catalysis to gain impressive selectivity. To date, no general
method for controlled oxidative ketone-ketone cross-
coupling has been reported.
3
or ester enolate and a ketone enolate. In the case of silyl
enol ethers, cross-coupling can typically only be achieved
4
by using an excess of one enol silane. Narasaka’s solution
(
(
1) Ivanoff, D.; Spasoff, A. Bull. Soc. Chim. Fr. 1935, 2, 76-78.
2) For additional early contributions, see: (a) H. Sch a¨ fer, A. A. Angew.
Chem., Int. Ed. Engl. 1968, 7, 474-475. (b) Brettle, R.; Parkin, J. G.;
Seddon, D. J. Chem. Soc. (C) 1970, 1317-1320. (c) Rathke, M. W.; Lindert,
A. J. Am. Chem. Soc. 1971, 93, 4605-4606. (d) Dessau, R. M.; Heiba, E.
I. J. Org. Chem. 1974, 39, 3457-3459. (e) Ito, Y.; Konoike, T.; Saegusa,
T. J. Am. Chem. Soc. 1975, 97, 2912-2914. (f) Ito, Y.; Konoike, T.; Harada,
T.; Saegusa, T. J. Am. Chem. Soc. 1977, 99, 1487-1493. (g) Kobayashi,
Y.; Taguchi, T.; Tokuno, E. Tetrahedron Lett. 1977, 3741-3742. (h) Frazier,
R. H.; Harlow, R. L. J. Org. Chem. 1980, 45, 5408-5411.
Figure 1. General approach toward controlled oxidative carbon-
carbon bond formation.
(
3) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006, 45,
7
083-7086.
1
0.1021/ol702306z CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/03/2007

As part of our program directed at synthesizing bioactive
polycyclic molecules, we became interested in using silyl
bis-enol ethers to generate quaternary centers through in-
tramolecular oxidative bond formation. We were encouraged
by a report in 1998 by Schmittel and co-workers who
revealed that symmetrical silyl bis-enol ethers will undergo
sponding chlorosilane 5 (R ) Me) and diethylacetamide as
indicated by H NMR spectroscopy. Enolization of 2-meth-
yltetralone (6) with LDA, followed the addition of the
chlorosilane 5 (R ) Me) generated from 4 (R ) Me), resulted
in clean formation of the desired unsymmetrical silyl bis-
enol ether 7a (Scheme 2). While purification of the silyl bis-
1
7
oxidative bond formation to generate 1,4-diketones. Despite
the potential utility of this process to generate unsymmetrical
8
1
,4-diketones, it has never been fully developed. We now
Scheme 2. Conditions for Oxidative C-C Bond Formation
describe the development of an efficient method for selective
ketone-ketone oxidative cross-coupling for the synthesis of
quaternary centers, which is based on the use of unsym-
metrical silyl bis-enol ethers. The basic concept is outlined
in eq 2 of Figure 1.
Our initial studies were directed at preparing unsym-
metrical silyl bis-enol ethers derived from 2-methyltetralone
(6) and a variety of methyl ketones. Rathke and Weipert have
reported a general method for the synthesis of unsymmetrical
silyl bis-enol ethers based on generating chlorosilanes (5)
in situ from enol silylamines (4) and acetyl chloride.
enol ether by flash chromatography may be achieved, we
found this to be unnecessary due to the effectiveness of the
synthesis. Only 1.1 equiv of enol silane 4 (R ) Me) was
used in relation to 2-methyltetralone (6). This stoichiometry
will have important consequences for the use of this
chemistry in carrying out complex fragment couplings in the
context of total synthesis.
9
Subsequent addition of NaI, triethylamine and the second
ketone afforded the desired product in good yield. These
conditions, however, led to mixtures of regioisomeric
products when ketones with two sets of enolizable positions
are used. Therefore, we developed a modified procedure
based on Corey’s conditions for selective kinetic generation
Our initial exploration of potential oxidants utilized enol
10
of enol silanes from methyl ketones. Thus, addition of the
methyl ketone 3 to a mixture of both LDA and chloro-N,N-
diethylamino-dimethylsilane at -78 °C affords excellent
regioselectivity for the desired enol ethers (i.e., 4). Evapora-
tion of the solvent, trituration with pentanes to remove LiCl,
and subsequent distillation provides good to excellent yields
for a range of enol silylamines 4 (Scheme 1).11
2g
silane 7a. Cu(OTf)
2
has been reported to be a good oxidant
for TMS-enol ether coupling but in our hands gave <10%
of the desired adduct 8a. Cerium(IV) ammonium nitrate
4a
(CAN)/NaHCO
3
was quickly found to be the oxidant of
choice, providing diketone 8a in an overall yield of 71%
from 2-methyltetralone (Scheme 2).
As a control experiment, a 1:1 mixture of the TMS-enol
silanes derived from 2-methyltetralone (i.e., 9) and acetone
(
i.e., 10) was exposed to the reaction conditions. The complex
Scheme 1. Regioselective Synthesis of Enol Silylamines
reaction mixture that resulted contained little or none of the
desired adduct 8a (Scheme 3).
Scheme 3. Control Experiment
The addition of acetyl chloride to a solution of 4 (R )
Me) resulted in rapid formation (<10 min) of the corre-
(
4) (a) Baciocchi, E.; Casu, A.; Ruzziconi, R. Tetrahedron Lett. 1989,
3
3
0, 3707-3710. (b) Fujii, T.; Hirao, T.; Ohshiro, Y. Tetrahedron Lett. 1992,
3, 5823-5826.
(
The scope of the methyl ketone component was explored
next and was general for a variety of substrates (Table 1).
Aliphatic substrates are well tolerated, providing moderate
to good yields of the 1,4-diketone products (entries 1-7).
As can be seen, increasing steric hindrance led to a decrease
in overall reaction efficiency. While â-substitution on the
methyl ketone fragment was well tolerated, providing 8e in
5) Narasaka, K.; Okauchi, T.; Tanaka, K.; Murakami, M. Chem. Lett.
1
992, 2099-2102.
(
6) (a) Jang, H. Y.; Hong, J. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2007, 129, 7004-7005. (b) Beeson, T. D.; Mastracchio, A.; Hong, J.
B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582-585.
(7) Schmittel, M.; Burghart, A.; Malisch, W.; Reising, J.; Sollner, R. J.
Org. Chem. 1998, 63, 396-400.
(8) Schmittel, M.; Haeuseler, A. J. Organomet. Chem. 2002, 661, 169-
1
1
79.
6
1% overall yield (Table 1, entry 5), R-substitution resulted
(9) Rathke, M. W.; Weipert, P. D. Synth. Commun. 1991, 21, 1337-
351.
in lower yields. Isopropyl and tertiary butyl substituents
afforded the corresponding products in 50% and 41% yield,
respectively (Table 1, entries 6 and 7). Aryl substituents
(
10) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495-498.
(11) For R ) Me and R ) t-Bu, enol silylamines prepared according to
ref. 9.
4668
Org. Lett., Vol. 9, No. 22, 2007

Table 1. Substrate Scope for 2-Methyltetralone Derived
Compoundsa
Scheme 4. Substrate Diversity from Dione 8a
entry
R
overall yield 8 (%)b
1
2
3
4
5
6
7
8
9
Me (7a)
Et (7b)
n-Pr (7c)
CH2CH2Ph (7d)
i-Bu (7e)
i-Pr (7f)
t-Bu (7g)
Ph (7h)
4-Cl-Ph (7i)
4-OMe-Ph (7j)
4-Me-Ph (7k)
CHdCHPh (7I)
C≡C-Ph (7m)
71 (8a)
62 (8b)
61 (8c)
51 (8d)
61 (8e)
50 (8f)
41 (8g)
81 (8h)
72 (8i)
73 (8j)
73 (8k)
75 (8l)
54 (8m)
Cyclopentenone 1712 was accessed from 8a by NaOH-
mediated aldol condensation (73% yield). Thus, the three-
step procedure from 2-methyltetralone (6) represents an
13
efficient strategy for cyclopentenone annulation. Condensa-
tion of 8a with ammonium acetate in acetic acid at 100 °C
afforded the corresponding 2H-pyrrole 19. We had initially
hoped to isolate the 3H-pyrrole, but under the acidic reaction
conditions a ring contraction of protonated 3H-pyrrole 18
ensued to generate the spirocycle 19. This interesting
transformation presumably proceeds through a selective [1,5]-
10
11
12
13
a
Reagents and conditions: (i) 1.5 mmol 6, LDA (1.1 equiv), -78 °C to
°C; then 4 (1.1 equiv)/MeCOCl (1.0 equiv); (ii) CAN (2.0 equiv), NaHCO3
4.0 equiv), MeCN, 0 °C. b Isolated yield.
0
(
14
sigmatropic alkyl shift. 2H-Pyrrole 19 was selectively
reduced (15:1 dr) to pyrrolidine 20 upon treatment with Pd/C
and H
2
. The X-ray crystal structure of the HCl salt of 20
provided good yields, with both electron-rich and electron-
poor systems behaving similarly (entries 8-11). Cross-
conjugated enol silanes derived from R,â-unsaturated ketones
confirmed that hydrogenation occurred anti to the large
1
5
aromatic ring. We are currently exploring the generality
of this ring contraction/hydrogenation sequence in order to
prepare stereochemically rich spirocyclic alkaloids
(i.e., 7l and 7m) were also suitable compounds (Table 1,
entries 12 and 13).
In summary, we have developed unsymmetrical silyl bis-
enol ethers as effective substrates for crossed-ketone oxida-
tive coupling reactions of tetralone derivatives. Using these
compounds provides a general method for the preparation
of quaternary centers in a convergent manner. Current and
future research is directed at expanding the scope of silyl
bis-enol ether-based transformations and applying this chem-
istry to the synthesis of bioactive polycyclic natural products.
Having established the methodology as useful for 2-meth-
yltetralone substrates, we investigated the use of other cyclic
aryl ketones (Figure 2). 2-Ethyltetralone was an effective
Acknowledgment. Support is provided by Northwestern
University (NU) and the NU Analytical Services Laboratory
(NSF Grants DMR0114235 and CHE9871268). We grate-
fully acknowledge Charlotte Stern (Northwestern University)
for X-ray crystallography and Prof. Karl Scheidt (North-
western University) for helpful discussions.
Figure 2. Variation of substituted enolate component.
reaction partner with both acetone and acetophenone derived
systems (11 and 12, respectively). 2-Methylindanone pro-
vided only 30% of dione 13 (R ) Me), whereas dione 14
Supporting Information Available: Experimental pro-
cedures, spectral data, and crystallographic data (PDF, CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(R ) Ph) was obtained in 76% yield. Such dramatic
differences in yield were also observed when 2-methylben-
zosuberone was used as a substrate. To date, 2-methylcy-
clohexanone has not proven to be a synthetically useful
reaction partner (<10% yield with acetophenone). We are
currently engaged in solving this issue in order to fully
expand the scope of this methodology.
OL702306Z
(
12) Snyder, L.; Meyers, A. I. J. Org. Chem. 1993, 58, 7507-7515.
(13) For a related strategy, see: Miyashita, M.; Yanami, T.; Yoshikoshi,
A. J. Am. Chem. Soc. 1976, 98, 4679-4681.
(
14) For related examples, see: (a) Chiu, P.-K.; Sammes, M. P.
Tetrahedron Lett. 1987, 28, 2775-2778. (b) Lui, K. H.; Sammes, M. P. J.
Chem. Soc., Perkins Trans. 1 1990, 457-468. (c) Shimkin, A. A.; Shirinian,
V. Z.; Nikalin, D. M.; Krayushkin, M. M.; Pivina, T. S.; Troitsky, N. A.;
Vorontsova, L. G.; Starikova, Z. A. Eur. J. Org. Chem. 2006, 2087-2092.
(15) See Supporting Information for details.
We were also interested in utilizing the versatility of the
1,4-diketone products by using straightforward reactions to
create a diverse array of structures (Scheme 4).
Org. Lett., Vol. 9, No. 22, 2007
4669