Facial-selective allylation of methyl ketones for the asymmetric synthesis of tertiary homoallylic ethers

Article abstract of DOI:10.1055/s-2004-829153

The stereoselective allylation of methyl ketones is described to give tertiary homoallylic ethers, which can easily be transformed into homoallylic alcohols by a Birch reduction. Reaction of methyl ketones 4 with allylsilane 5 in the presence of the chiral TMS ether 3a and a catalytic amount of trifluoromethanesulfonic acid led to homoallylic ethers 6 in high yield with a selectivity of 9:1 to >20:1. The TMS ether 3a was prepared from inexpensive mandelic acid, which is commercially available in both enantiomeric forms, in four steps.

Full text of DOI:10.1055/s-2004-829153

2236
PRACTICAL SYNTHETIC PROCEDURES
Facial-Selective Allylation of Methyl Ketones for the Asymmetric Synthesis of
Tertiary Homoallylic Ethers
Enantiopure
H
o
u
moallylic
E
t
t
hers an
z
d
A
lcohols F. Tietze,* Sören Hölsken, Jens Adrio, Tom Kinzel, Christoph Wegner
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2,
37077 Göttingen, Germany
Fax +49(551)399476; E-mail: ltietze@gwdg.de
PSP
Received 7 April 2004
Dedicated to Professor Axel Zeeck on the occasion of his 65th birthday
No27
Abstract: The stereoselective allylation of methyl ketones is described to give tertiary homoallylic ethers, which can easily be transformed
into homoallylic alcohols by a Birch reduction. Reaction of methyl ketones 4 with allylsilane 5 in the presence of the chiral TMS ether 3a
and a catalytic amount of trifluoromethanesulfonic acid led to homoallylic ethers 6 in high yield with a selectivity of 9:1 to >20:1. The TMS
ether 3a was prepared from inexpensive mandelic acid, which is commercially available in both enantiomeric forms, in four steps.
Key words: allylations, allylsilannes, amino alcohols, asymmetric synthesis, Birch reduction, homoallylic alcohols
1. AcCl, MeOH
rt, 12 h
1. BH3·THF, ∆, 12 h
2. CF3CO2Me, r.t., 12 h
Ph
Ph
Ph
COCF3
NH
Procedure 1
OH
NH2
HO
HO
TMSO
2. NH3(aq),
–4 °C, 12 h
3. TMSCl, NEt3,
CH2Cl2, r.t., 24 h
O
O
1
2
3a
Ph
COCF3
NH
TfOH, CH2Cl2
–78 °C, 6 h
O
Ph
COCF3
NH
O
TMS
+
+
Procedure 2
R
TMSO
R
R'
3a: R' = H
(3b:R' = CH3)
4a-d
5
6a-d
Ph
COCF3
NH
a: R = Et
b: R = iPr
Li, DBBP, THF
–40 °C, 2 h
OH
R
O
R
Procedure 3
c: R = CH2CH2Ph
t
d: R = CH2CH2OSiPh2 Bu
7a-d
Scheme 1
Introduction
for the allylation of simple aliphatic ketones are not satis-
fying.4
The facial-selective addition of allylmetals to carbonyl
groups to furnish homoallylic alcohols is a fundamental
transformation in chemistry and a widely used process in
organic synthesis.1 Typically, either chiral acetals, chiral
catalysts or an equimolar amount of a chiral allyl reagent
such as allylboranes or allyltitanium compounds are em-
ployed.2 Most of these reagents give excellent selectivities
with aldehydes but fail when applied to simple ketones.3
Some progress has been made using 20–30 mol% of
chiral titanium binol-based catalysts. However, the yields
Recently we have demonstrated that the reaction of ali-
phatic aldehydes with allylsilanes in the presence of the
trimethylsilyl ether of N-trifluoroacetylnorpseudoephe-
drine (3b) and a catalytic amount of trimethyl trifluo-
romethanesulfonate (TMSOTf) led to the corresponding
secondary homoallylic ethers with a >99:1 selectivity.5
The procedure using trifluoromethanesulfonic acid
(TfOH) instead of TMSOTf could also be applied to me-
thyl ketones 4 to give tertiary homoallylic ethers, with a
selectivity of 1:9 to >20:1 in a domino fashion,6 as the
only products (Scheme 1).7 The homoallylic ethers can
easily be transformed into the corresponding tertiary
alcohols by cleavage of the benzyl ether moiety using ei-
ther lithium in liquid ammonia or – as a much milder
SYNTHESIS 2004, No. 13, pp 2236–2239
x
x.
x
x
.
2
0
0
4
Advanced online publication: 14.07.2004
DOI: 10.1055/s-2004-829153; Art ID: E10904SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Enantiopure Homoallylic Ethers and Alcohols
2237
method – lithium in THF in the presence of 4,4¢-di-(tert- one as the most difficult substrate, which still allows a re-
butyl)-1,1¢-biphenyl (DBBP).8
markable facial selectivity of 11.9:1 at –96 °C (unpuri-
fied). Attention should be drawn to the temperature of the
reaction mixture. Having an external acetone bath, cooled
by a cryostat, the solvent volume should not exceed
250 mL. In general, two equivalents of the ketone and the
allylsilane are necessary, but it is possible to recover the
unused ketone after the reaction by column chromatogra-
phy nearly quantitatively. As an alternative, one can also
employ one equivalent of the ketone to be transformed
and one equivalent of ethyl isopropyl ketone, which does
not react under the used reaction conditions, but is neces-
sary to obtain good yields. The reason for this unusual be-
havior is not known yet. Although the starting materials,
the auxiliary and the products show similar Rf values, a
simple purification by column chromatography on silica
gel is sufficient to obtain pure products in most cases. It
should be noted that the obtained products are diastere-
omers, which can be further enriched using achiral adsor-
bents.
However, the general use of this procedure has so far been
hampered by the fact that only one of the enantiomers of
norpseudoephedrine is commercially available. We here-
in wish to report the synthesis of a modified auxiliary 3a
for the allylation of methyl ketones derived from inexpen-
sive mandelic acid (1) in four reaction steps. Since (R)-
and (S)-mandelic acid are commercially available, both
enantiomeric forms of the auxiliary 3a can be prepared. It
was shown that the influence of the methyl group in the 2-
position of 3b is negligible; thus, the use of 3a allows the
allylation of methyl ketones with the same facial selectiv-
ity as with 3b.
In this article we report the synthesis of the auxiliary 3a as
well as a general method for the facial selective allylation
of aliphatic methyl ketones 4 to give enantiopure tertiary
homoallylic ethers 6 in a highly diastereoselective fashion
and their transformation into enantiopure homoallylic al-
cohols 7.
Table 1 Synthesis of Tertiary Homoallylic Ethers 6a–d from Dif-
ferent Ketones 4a–d in the Presence of 3a (1 equiv)
Scope and Limitations
Entry
1: a
2: a
3: b
4: c
R in 4, 6 and 7
T (°C)
–78
Yield (%) dr (%)
The preparation of (S)-2,2,2-trifluoro-N-(2-phenyl-2-tri-
methylsilyloxyethyl)acetamide (3a) is described in detail
in Procedure 1. (S)-Mandelic acid (1) was transferred into
the amide 2 using acetyl chloride followed by addition of
ammonia. Reduction of the amide 2 employing the bo-
rane-THF complex gave the corresponding amine, which
without purification was protected at the nitrogen as N-tri-
fluoroacetyl group using CF3CO2Et and at the hydroxyl
group as TMS ether with TMSCl (Scheme 1). The ob-
tained product 3a was purified by a simple column chro-
matography and then used for the allylation reaction.
Et
89
72
82
68
87
8.8:1
Et
–96
11.9:1
13.6:1
10.7:1
>20:1
iPr
–78
CH2CH2Ph
–78
t
5: d
CH2CH2OSiPh2 Bu
–78
Cleavage of the benzyl ether moiety is detailed in Proce-
dure 3. The earlier used Birch conditions (lithium in liquid
ammonia) described previously7 gave no reliable results
of the reaction outcome. In several cases the allylic double
bond in 6 was partly or totally reduced, while using lithi-
um in THF with DBBP, no reduction of the allylic double
bond was observed.8 The commercially available, but ex-
pensive DBBP can be prepared in a single reaction step
starting from biphenyl, tert-butyl chloride and catalytic
amounts of aluminum chloride as reported by Timberlake
et al.9
The allylation reaction is described in Procedure 2. While
the auxiliary 3a works excellently with aliphatic methyl
ketones it is not suitable for the diastereoselective allyla-
tion of a,b-unsaturated and aromatic methyl ketones.
However, methyl ketones containing a double bond or an
aromatic substituent, which is not in conjugation with the
carbonyl moiety give excellent results; also other func-
tional groups such as esters or ethers are tolerated. Hy-
droxy ketones are unreactive probably due to an inhibition
caused by the hydroxyl group; in contrast protected hy-
droxy ketones react smoothly within 6 hours with high se-
lectivities. The type of the protecting group in the
substrate can have some influence on the selectivity; the
TBDPS (tert-butyldiphenylsilyl) group was found to give
good results.
Procedures
Herein we present the synthesis of the chiral auxiliary (S)-
2,2,2-trifluoro-N-(2-phenyl-2-trimethylsilanyloxyeth-
yl)acetamide (3a), the allylation of the methyl ketones
4a–d and the removal of the chiral auxiliary in the prod-
ucts 6a–d to give the homoallylic alcohols 7a–d. In Pro-
cedure 1 the four step synthesis of 3a starting from (S)-
mandelic acid (1) with formation of the amide, followed
by reduction and protection of the amino and hydroxyl
group is described, which takes place in an overall yield
of 68%. Procedure 2 illustrates as an example, the facial
As the allylation of the TBDPS-protected 4-hydroxybu-
tanone 4d leads to very interesting substrates 6d as well as
7d for further use in natural product synthesis,7 and shows
an excellent selectivity of >20:1 (unpurified), this com-
pound was chosen as substrate for the general experimen-
tal procedure. Further typical results employing other
aliphatic ketones are listed in Table 1 including butan-2-
Synthesis 2004, No. 13, 2236–2239 © Thieme Stuttgart · New York

2238
L. F. Tietze et al.
PRACTICAL SYNTHETIC PROCEDURES
tion!). The mixture was refluxed for 12 h and cooled to r.t., before
MeOH (60 mL) was carefully added (gas formation!) via an addi-
tion funnel. After evaporation of the solvent, the crude product was
diluted with MeOH (185 mL). CF3CO2Et (14.4 mL, 143 mmol) was
added dropwise and the mixture was stirred for 12 h at r.t. The sol-
vent was removed under reduced pressure, and the residue was di-
luted in CH2Cl2 (230 mL). Et3N (37.9 mL, 274 mmol) was added,
and the mixture was cooled to 0 °C with an ice-water bath followed
by addition of TMSCl (17.4 mL, 143 mmol). After stirring the mix-
ture for 3 d at r.t., it was quenched with H2O (150 mL), and the
crude product was extracted with CH2Cl2 (3 × 250 mL). The com-
bined organic layers were washed with brine (200 mL), dried
(MgSO4), and concentrated. The residue was purified by silica gel
column chromatography using pentane–tert-butyl methyl ether
(5:1) as eluent to afford 3a (27.5 g, 76% over three steps) as a col-
orless oil; [a]D20 +53.5 (c = 1.0, CHCl3).
selective allylation of 4-tert-butyldiphenylsilyloxybu-
tanone (4d) to give 6d in a yield of 87% and a selectivity
of >20:1. Procedure 3 describes the cleavage of the benzyl
ether moiety in 6d to afford the enantiopure homoallylic
alcohol 7d in 82% yield.
4,4¢-Di-(tert-butyl)-1,1¢-biphenyl (DBBP)
Anhyd AlCl3 (3.00 g, 22.5 mmol) was added to a 250 mL dry three-
neck round-bottom flask, equipped with a magnetic stirring bar,
condenser, addition funnel and a stopper, charged with ni-
tromethane (75 mL) and biphenyl (13.2 g, 85.0 mmol). The color of
the solution changed to deep violet. A solution of 2-chloro-2-meth-
ylpropane (17.4 g, 190 mmol) in nitromethane (20 mL) was then
added dropwise to the stirred mixture over 30 min. At the end of the
addition, the reaction started with vigorous evolution of HCl gas.
The reaction mixture was stirred overnight, poured onto crushed ice
in a 500 mL beaker and allowed to warm up to r.t. The organic layer
was extracted with a mixture of nitromethane–pentane (1:1,
3 × 50 mL), dried (MgSO4), and then filtered. The yellowish filtrate
was treated with silica gel (100 g) to provide a colorless solution,
which was concentrated in vacuo. The white powder was recrystal-
lized from nitromethane to give white needles of 4,4¢-di-(tert-bu-
tyl)-1,1¢-biphenyl; yield: 21.0 g (92%); mp 128 °C.
IR (NaCl): 3317, 3090, 3067, 3032, 2959, 1708, 1556, 1494, 1454,
1366, 1254, 1166, 1103, 1027, 963, 842, 756, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.18–7.31 (m, 5 H, 5 Harom), 6.60
(s, 1 H, NH), 4.74 (dd, 1 H, J = 8.4, 3.8 Hz, 1-H), 3.66 (ddd, 1 H,
J = 13.5, 7.5, 3.8 Hz, 2-Ha), 3.19 (ddd, 1 H, J = 13.5, 8.4, 4.5 Hz, 2-
Hb), –0.02 [s, 9 H, Si(CH3)3].
13C NMR (50 MHz, CDCl3): d = 140.9 (Carom), 128.5 (2 CHarom),
128.1 (CHarom), 125.8 (2 CHarom), 72.7 (C-1), 47.4 (C-2), –0.16
[Si(CH3)3].
1H NMR (300 MHz, CDCl3): d = 7.44–7.55 (m, 8 Harom), 1.37 [s,
18 H, 2 × C(CH3)3].
MS (DCI, 200 eV): m/z (%) = 628.5 (2), 340.3 (50), 323.3 (100).
13C NMR (50 MHz, CDCl3): d = 149.9 (Carom), 139.2 (Carom), 126.7
(CHarom), 125.6 (CHarom), 34.5 [2 C(CH3)3], 31.4 [2 C(CH3)3].
Anal. Calcd for C13H18F3NO2Si: C, 51.13; H, 5.94. Found: C, 51.38;
H, 5.96.
MS (EI, 70 eV): m/z (%) = 266.2 (41), 251.3 (100).
Procedure 2
(3S,1¢S)-1-tert-Butyldiphenylsiloxy-3-methyl-3-(1¢-phenyl-2¢-
trifluoroacetamido-1¢-ethoxy)hex-5-ene (6d)
Procedure 1
(S)-Mandelic Acid Amide (2)
An oven-dried 500 mL dry two-neck round-bottom flask, equipped
with a magnetic stirring bar, a stopper, and a three-way stopcock at-
tached to a balloon filled with argon was charged with 3a (13.8 g,
42.3 mmol), 4-tert-butyldiphenylsilyloxybutanone (4d; 25.8 g,
84.5 mmol) and CH2Cl2 (250 mL). The mixture was cooled to
–78 °C using a cryostat with an acetone bath. Allyltrimethylsilane
(14.4 mL, 84.5 mmol) was added via syringe at –78 °C, followed by
addition of TfOH (790 mL, 8.45 mmol). After stirring for 6 h at
–78 °C, the reaction was quenched with Et3N (18 mL) and MeOH
(200 mL). The crude product was extracted with CH2Cl2
(4 × 250 mL), dried (Na2SO4), and concentrated. The residue was
purified by silica gel column chromatography using pentane–Et2O
(9:1) as eluent to afford 6d as a colorless oil; yield: 21.5 g (87%),
[a]D20 +26.0 (c = 1.0, CHCl3).
A 1 L oven dried two neck round-bottom flask, equipped with a
magnetic stirring bar, and a three-way stopcock attached to a bal-
loon filled with argon was charged with (S)-mandelic acid (1;
25.0 g, 164 mmol) and anhyd MeOH (670 mL) and cooled to 0 °C
with an ice-water bath. Acetyl chloride (31.5 mL, 443 mmol) was
added dropwise to the flask via syringe at 0 °C. After stirring 12 h
at r.t., the solvent was evaporated on a rotary evaporator. The resi-
due was dissolved in MeOH (125 mL), and aq ammonia solution
(310 mL) was added. The flask was stored in the fridge overnight.
After evaporation of the solvent a white solid was obtained, which
was recrystallized from EtOH–pentane to afford white crystals;
yield: 22.0 g (89%); mp 120 °C; [a]D20 +78.0 (c = 1.7, acetone).
IR (NaCl): 3357, 3187, 2927. 1681, 1495, 1452, 1422, 1295, 1190,
1102, 1056, 928, 895, 859, 763, 710 cm–1.
1H NMR (300 MHz, DMSO): d = 7.22–7.43 (m, 6 H, 5 Harom, NH),
7.13 (s, 1 H, NH), 5.95 (d, 1 H, J = 4.7 Hz, 2-H), 4.83 (d, 1 H,
J = 4.7 Hz, OH).
13C NMR (50 MHz, DMSO): d = 174.5 (C-1), 141.3 (Carom), 127.8
(2 CHarom), 127.2 (CHarom), 126.4 (2 CHarom), 73.4 (C-2).
IR (NaCl): 3331, 3072, 2932, 1716, 1548, 1428, 1168, 1111, 917,
823, 739, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.58–7.64 (m, 4 H, 4 Harom), 7.33–
7.45 (m, 6 H, 6 Harom), 7.20–7.30 (m, 5 H, 5 Harom), 6.62 (s, 1 H,
NH), 5.75 (ddt, 1 H, J = 16.9, 10.2, 7.3 Hz, 5-H), 5.00–5.08 (m,
2 H, 6-H2), 4.60 (dd, 1 H, J = 8.3, 4.1 Hz, 1¢-H), 3.53–3.74 (m, 3 H,
1-H2, 2¢-Ha), 3.17 (ddd, 1 H, J = 13.1, 8.3, 4.5 Hz, 2¢-Hb), 2.23 (d,
2 H, J = 7.1 Hz, 4-H2), 1.70 (t, 2 H, J = 7.0 Hz, 2-H2), 1.00 [s, 9 H,
C(CH3)3], 0.95 (s, 3 H, 3-CH3).
MS (EI, 70 eV): m/z (%) = 151.1 (10), 107.0 (100).
HRMS (EI, 70 eV): m/z calcd: 151.0633; found: 151.0633.
13C NMR (50 MHz, CDCl3): d = 156.9 (q, JCF = 36.2 Hz, C=O),
2
(S)-2,2,2-Trifluoro-N-(2-phenyl-2-trimethylsilyloxyethyl)aceta-
mide (3)
141.6 (Carom), 135.5*, 133.7*, 129.6*, 127.9*, 127.6*, 126.1* (C-5,
2 Carom, 15 CHarom), 118.3 (C-6), 78.0 (C-1¢), 71.8 (C-3), 60.0 (C-4),
46.7 (C-2¢), 44.1 (C-2), 42.2 (C-4), 26.8 [C(CH3)3], 23.9 (3-CH3),
19.1 [C(CH3)3].
An oven-dried 500 mL dry three-neck round-bottom flask,
equipped with a magnetic stirring bar, addition funnel, a stopper,
and a reflux condenser with a three-way stopcock attached to a bal-
loon filled with argon was charged with (S)-mandelic acid amide (2;
22.0 g, 146 mmol). A solution of borane-THF complex (1 M,
300 mL, 300 mmol) was added via an addition funnel (gas forma-
MS (DCI, 200 eV): m/z (%) = 601.6 (100), 584.6 (5).
HRMS (ESI): m/z calcd for 606.2622; found: 606.2623.
Synthesis 2004, No. 13, 2236–2239 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Enantiopure Homoallylic Ethers and Alcohols
2239
Procedure 3
References
(S)-1-(tert-Butyldiphenylsilyloxy)-3-methylhex-5-en-3-ol (7d)
An oven-dried 1 mL dry two-neck round-bottom flask, equipped
with a magnetic stirring bar, a stopper and a three-way stopcock at-
tached to a ballon filled with argon was charged with THF
(420 mL), and the solvent was degassed three times by freezing
with a dry ice acetone bath in vacuo. DBBP (13.3 g, 49.9 mmol) and
Li granulates (approx. size 1 mm) were added, and the mixture was
vigorously stirred at r.t. until the solution showed a deep blue co-
lour. After cooling down to 0 °C with an ice-water bath, the mixture
was stirred for an additional 2 h before the solution was cooled to
–78 °C using a cryostat with an acetone bath. A solution of 6d
(36.4 g, 62.3 mmol) in THF (100 mL) was added dropwise. After
stirring for 1 h at –78 °C, the mixture was allowed to warm to –50
to –40 °C and was stirred for an additional 2 h. The reaction was
quenched by adding solid NH4Cl at –40 °C (until the black solution
turned yellow), and allowed to warm to r.t. The solid residues were
filtered off before adding a half-saturated solution of NH4Cl
(400 mL), and the crude product was extracted with Et2O
(3 × 300 mL). The combined organic layers were washed with brine
(200 mL), dried (Na2SO4), filtered, and concentrated. The residue
was purified by silica gel chromatography using first pentane to
elute DBBP, and then a gradient of pentane–Et2O (15:1 to 3:1) as
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20
eluent to afford 7d (18.8 g, 82%) as a yellow oil; [a]D –5.8
(c = 0.5, CHCl3).
IR (NaCl): 3444, 3072, 2928, 1640, 1429, 1112, 913, 822, 737, 702
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.64–7.73 (m, 4 H, 4 Harom),
7.35–7.48 (m, 6 H, 6 Harom), 5.86 (ddt, 1 H, J = 17.0, 10.4, 7.4 Hz,
5-H), 5.01–5.10 (m, 2 H, 6-H2), 3.89 (t, 2 H, J = 6.0 Hz, 1-H2),
2.24–2.37 (m, 2 H, 4-H2), 1.80 (dt, 1 H, J = 14.5, 6.1 Hz, 2-Ha),
1.68 (dt, 1 H, J = 14.5, 5.6 Hz, 2-Hb), 1.23 (s, 3 H, 3-CH3), 1.05 [s,
9 H, C(CH3)3].
13C NMR (50 MHz, CDCl3): d = 135.5 (2 CHarom), 134.5 (C-5),
132.7 (Carom), 129.9 (CHarom), 127.8 (2 CHarom), 117.8 (C-6), 72.4
(C-3), 61.7 (C-1), 47.0 (C-4), 41.1 (C-2), 26.8 [C(CH3)3], 26.6 (3-
CH3), 19.0 [C(CH3)3].
MS (DCI, 200 eV): m/z (%) = 369.4 (100), 386.4 (18).
Anal. Calcd for C23H32O2Si: C, 74.95; H, 8.75. Found: C, 75.12; H,
8.66.
(8) Tietze, L. F.; Völkel, L. Angew. Chem. Int. Ed. 2001, 40,
901.
(9) Hossain, M. T.; Timberlake, J. W. J. Org. Chem. 2001, 66,
6282.
Acknowledgment
This work was supported by the DFG (Sonderforschungsbereich
416) and the Fonds der Chemischen Industrie. We are grateful to
Wacker-Chemie GmbH for supplying chlorotrimethylsilane and
tert-butyldiphenylchlorosilane.
Synthesis 2004, No. 13, 2236–2239 © Thieme Stuttgart · New York