An efficient synthesis of α-branched enones

Article abstract of DOI:10.1055/s-2004-829095

A new method for preparing α-branched enones from carboxylic acid derivatives is reported. The procedure commenced by the reaction of N,O-dimethylamides with a masked acyl anion equivalent, followed by the addition of (trimethylsilyl-methyl)cerium dichloride to give intermediates that undergo Lewis acid mediated olefination to produce enol ethers that are then hydrolyzed to afford simple α-branched enones in high overall yields.

Full text of DOI:10.1055/s-2004-829095

LETTER
1431
An Efficient Synthesis of a-Branched Enones
An
E
fficient Synth
a
esis of
a
-
Br
v
anched
E
non
i
es d A. Kummer, Jehrod B. Brenneman, Stephen F. Martin*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA
Fax +1(512)4714180; E-mail: sfmartin@mail.utexas.edu
Received 11 March 2004
Dedicated to Professor Clayton A. Heathcock for his many significant contributions to the art of synthesis and on the occasion of his
retirement
was transformed into a carbonyl group, the elimination of
the elements of TMS-OH was substantially more difficult.
Only ketones 5a,b could be converted to the desired
enones, while protodesilylation of 3a–h was an unavoid-
Abstract: A new method for preparing a-branched enones from
carboxylic acid derivatives is reported. The procedure commenced
by the reaction of N,O-dimethylamides with a masked acyl anion
equivalent, followed by the addition of (trimethylsilyl-methyl)ceri-
um dichloride to give intermediates that undergo Lewis acid medi- able side reaction when HF was used.
ated olefination to produce enol ethers that are then hydrolyzed to
afford simple a-branched enones in high overall yields.
Key words: enones, Peterson olefination, titanium, acyl anion
equivalents, homologation
In the context of designing novel approaches to complex
natural products using ring-closing metathesis as a key
step, we had occasion to require a procedure that allowed
for the synthesis of a-substituted enones from carboxylic
acid derivatives. A survey of the literature revealed that
there were few such methods of general applicability.1 We
were thus encouraged to develop a new synthetic method
for effecting such a construction and now report a conve-
nient three-step preparation of a-branched enones from
carboxylic acid derivatives.
Scheme 1 Reagents and conditions: i. 2-Ethoxyvinyllithium, THF,
–78 °C; ii. Cl2CeCH2SiMe3, PhMe, –78 °C; iii. TiCl4, 2,6-lutidine,
CH2Cl2, –45 °C, then H3O+.
Table 1 Preparation of a-Branched Enones 4a–h from Carboxylic
Acid Derivatives 1a–h
The starting point for our synthesis of a-branched enones
was the series of N,O-dimethylamides (1a–h), which were
prepared from the corresponding acid,2 acid chloride,3 or
ester4 according to standard methods. Treatment of
amides 1a–h with the lithium anion of ethyl vinyl ether5
afforded the intermediate enones 2a–h in high yield
(Scheme 1, Table 1).6 Addition of the organocerium re-
agent derived from transmetallation of commercially
available (trimethylsilylmethyl)lithium with anhydrous
CeCl3 provided the corresponding tertiary alcohols 3a–h.
Use of the cerium reagent was critical to obtaining good
yields in this addition.7
Entry
a
R =
Yield (%) Yield (%) Yield (%)
2
3
4
88
93
729
b
c
81
80
89
76
881,9
829
The stage was then set for forming the desired enones by
elimination of trimethylsilanol by a Peterson olefination
protocol,8 followed by acid-catalyzed hydrolysis of the
enol ether moiety. Experiments to induce the elimination
were first performed under standard basic conditions
(NaH/HMPA or KH) leading to the desired enones in
modest yields (40–62%) along with some unidentifiable
side-products. Attempts to effect the elimination under
acidic conditions (e.g., H2SO4 or HF) were unsuccessful
as hydrolysis of the enol ether function occurred compet-
itively with elimination to give 5a–h. Once the enol ether
d
e
95
88
94
81
869
8310
fa
g
93 (91)
69
98 (99)
93
93 (93)12
6311
h
87
94
8212
SYNLETT 2004, No. 8, pp 1431–1433
0
1.
0
7.
2
0
0
4
Advanced online publication: 22.06.2004
DOI: 10.1055/s-2004-829095; Art ID: Y02104ST
© Georg Thieme Verlag Stuttgart · New York
a Reaction conducted on 0.4 mmol and 4.0 mmol scales with identical
yields (4.0 mmol scale yields given in parentheses).

1432
D. A. Kummer et al.
LETTER
combined organic layers were dried (Na2SO4) and concentrated un-
der reduced pressure, and the residue was purified by flash chroma-
tography eluting with pentane–Et2O (3:1, containing 2% v/v Et3N)
to afford 1.15 g (91%) of pure enol ether 2f as a clear oil.
(Trimethylsilylmethyl)titanium dichloride has been used
in a process that results in the methylenation of aldehydes
via an intermediate titanium-alkoxide.13 This reaction in-
spired us to examine the use of titanium based reagents to
induce the elimination of 3a–h. After some experimenta-
tion, we found that the alcohols 3a–h could be rapidly and
cleanly converted to the corresponding enones 4a–h by
addition of a pre-mixed solution of TiCl4 and 2,6-lutidine
at –45 °C, followed by an aqueous acid workup. Use of
2,6-lutidine as an acid scavenger was generally essential
to maintaining the integrity of the enol ether function dur-
ing the elimination step. Only 5a,b could be converted
into 4a,b. We were unable to transform 5c–h into 4c–h
Representative Procedure for the Preparation of 3a–h
Anhyd CeCl3 (2.02 g, 8.20 mmol) was suspended in PhMe (41 mL)
and the mixture was sonicated for 1 h. The resulting finely divided
suspension was cooled to –78 °C, and then treated with a solution
of LiCH2TMS (0.95 M in pentane, 8.4 mL, 8.0 mmol) via syringe.
The resulting slurry was stirred for 1 h at –78 °C, whereupon a so-
lution of enol ether 2f (0.91 g, 3.90 mmol) in PhMe (5 mL) was add-
ed via cannula. The reaction mixture was stirred at –78 °C for 2 h,
and then MeOH (ca. 5 mL) was added. The reaction mixture was al-
lowed to warm to r.t. by removal of the cooling bath, and then fil-
under these conditions, presumably because generation of tered through a plug of Celite, and the filtrate was subsequently
washed with H2O (100 mL). The resulting layers were separated
and the aqueous phase was extracted with Et2O (3 × 30 mL). The
combined organic layers were dried (Na2SO4) and concentrated un-
der reduced pressure to provide a crude residue that was purified by
flash chromatography eluting with pentane–Et2O (4:1, containing
a b-silyl carbocation adjacent to a carbonyl via loss of the
hydroxyl group is unfavorable in substrates without
additional carbocation stabilizing functionalities like an
aromatic ring.
2% v/v Et3N) to afford 1.25 g (99%) of pure alcohol 3f as a clear oil.
As is evident from examination of the entries in Table 1,
the method may be successfully applied to substrates with
varying degrees of branching in the a-position, as well as
those having protected amine and alcohol functions. Less
Representative Procedure for the Preparation of 4a–h
Freshly distilled 2,6-lutidine (1.22 g, 11.4 mmol) in CH2Cl2 (60 mL)
was cooled to –45 °C, whereupon freshly distilled TiCl4 (1.08 g,
5.70 mmol) was added dropwise via syringe. The resulting bright
than 3% epimerization occurred during the conversion of
1g to 4g, so the method is applicable to the preparation of
yellow solution was stirred at –45 °C for 15 min, and then a solution
stereochemically pure enones.14 Additionally, the scale of of 3f (1.23 g, 3.80 mmol) in CH2Cl2 (15 mL) was added via cannula.
The resulting dark brown solution was stirred at –45 °C for 2.5 h,
the reaction sequence can be increased with ease and with
whereupon aq 1 N HCl (ca. 10 mL) was added, and the cooling bath
nearly identical yields to the small scale trials as was dem-
was removed. The mixture was stirred at r.t. for an additional 10
min, and then washed with H2O (100 mL). The resulting layers were
separated and the aqueous layer was extracted with CH2Cl2 (3 × 25
onstrated by the conversion of 1f to 4f on 4 mmol scale.
We also found that the efficiency of the three-step process
can be improved with only a slight (<10%) decrease in the
overall yield by directly treating the cerium alkoxide in-
termediates obtained by addition of (trimethylsilylmeth-
yl)cerium dichloride to 2a–h, with a pre-mixed solution of
TiCl4 and 2,6-lutidine at –45 °C. For substrates that are in-
compatible with TiCl4, standard KH-mediated olefination
conditions8a can be employed, although increased reaction
times are required and slightly lower yields of the prod-
ucts may be obtained.
mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure to provide a crude residue that was
purified by flash chromatography eluting with pentane–Et2O (4:1)
to afford 0.72 g (93%) of pure enone 4f12 as a light yellow oil.
General Procedure for the Preparation of 4a–h Directly from
2a–h
Anhyd CeCl3 (1.9 mmol) was suspended in PhMe (10 mL) and the
mixture was sonicated for 1 h. The resulting finely divided suspen-
sion was cooled to –78 °C, and then treated with a solution of
LiCH2TMS (0.95 M in pentane, 1.8 mmol) via syringe. The result-
ing slurry was stirred for 1 h at –78 °C, whereupon a solution of enol
ether 2a–h (0.9 mmol) in PhMe (3 mL) was added via cannula. The
resulting mixture was stirred at –78 °C until the reaction was judged
complete by TLC (2–12 h), and then transferred to a –45 °C bath.
The reaction mixture was allowed to equilibrate to this temperature
over a period of 10 min, and then treated with a pre-mixed solution
of freshly distilled 2,6-lutidine (7.2 mmol) and TiCl4 (3.6 mmol) in
PhMe (7 mL) at –45 °C via cannula. The resulting dark brown so-
lution was stirred at –45 °C until the reaction was judged complete
by TLC (2–4 h), whereupon aq 1 N HCl (ca. 5 mL) was added and
the reaction mixture was warmed to r.t. by removal of the cooling
bath. The mixture was stirred at r.t. for an additional 10 min, and
then isolated and purified by flash chromatography15 as previously
described to give pure enones 4a–h as light yellow or colorless oils.
In summary, a concise new method for preparing a-
branched enones from carboxylic acid derivatives has
been developed. Application of this method to the prepa-
ration of intermediates suitable for subsequent ring-clos-
ing metathesis and to natural products synthesis is
currently under investigation. The results of these studies
will be reported in due course.
Representative Procedure for the Preparation of 2a–h
A solution of tert-BuLi (1.5 M in pentane, 10.8 mL, 16.2 mmol) was
added dropwise to a stirred solution of freshly distilled ethyl vinyl
ether (1.28 g, 17.8 mmol) in THF (20 mL) at –78 °C. The resulting
bright yellow solution was stirred at –78 °C for 10 min, and then
placed into a 0 °C bath. After 5 min, the solution was recooled to
–78 °C, and a solution of 1f (1.21 g, 5.40 mmol) in THF (27 mL)
was added via cannula. The reaction mixture was stirred at –78 °C
for 2 h, whereupon MeOH (ca. 10 mL) was added and the reaction
mixture was warmed to r.t. by removal of the cooling bath. The re-
action mixture was subsequently washed with H2O (75 mL), and the
resulting aqueous layer was extracted with Et2O (3 × 20 mL). The
Acknowledgment
We are grateful to the National Institutes of Health, The Robert A.
Welch Foundation, Merck Research Laboratories, and Pfizer, Inc.
for their generous support of this research. We also thank Dr.
Rainer Machauer for helpful discussions.
Synlett 2004, No. 8, 1431–1433 © Thieme Stuttgart · New York

LETTER
An Efficient Synthesis of a-Branched Enones
1433
(11) For the previous synthesis and characterization of enone 4g
see: Bates, R. W.; Devi, T. R. Tetrahedron Lett. 1995, 36,
509.
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(12) Characterization data for new enones 4b, 4f, and 4h. Enone
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6.04 (d, J = 1.2 Hz, 1 H), 5.65 (d, J = 1.2 Hz, 1 H), 3.76 (s,
3 H), 2.26 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 200.3,
156.8, 148.4, 130.5, 130.1, 128.0, 124. 0, 121.2, 111.0, 55.7,
27.4. MS (CI): m/z = 177 [M + H+]. IR (neat): 2939, 1698,
1600, 1491, 1243, 1170, 1026 cm–1. Enone 4f: 1H NMR (400
MHz, CDCl3): d = 5.65 (s, 1 H), 5.23 (s, 1 H), 2.23 (s, 3 H),
2.00–1.96 (comp, 3 H), 1.80 (d, J = 2.9 Hz, 6 H), 1.73–1.64
(comp, 6 H). 13C NMR (100 MHz, CDCl3): d = 203.4, 159.1,
120.1, 40.9, 37.7, 37.0, 30.3, 28.8. MS (CI): m/z = 205 [M +
H+]. IR (neat): 2906, 1676, 1265, 1135 cm–1. Enone 4h: 1H
NMR (400 MHz, CDCl3): d = 7.37–7.25 (comp, 5 H), 6.00
(s, 1 H), 5.77–5.76 (m, 1 H), 4.50 (s, 2 H), 3.48 (t, J = 6.5 Hz,
2 H), 2.33 (s, 3 H), 2.30–2.25 (comp, 2 H), 1.67–1.58 (comp,
2 H), 1.55–1.45 (comp, 2 H). 13C NMR (100 MHz, CDCl3):
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70.4, 30.5, 29.7, 26.2, 25.2. MS (CI): m/z = 233 [M + H+]. IR
(neat): 2937, 2860, 1678, 1454, 1365, 1104 cm–1.
(6) All new compounds were purified (>95%) by flash
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NMR and 13C NMR, IR, and HRMS.
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Synlett 2004, No. 8, 1431–1433 © Thieme Stuttgart · New York