Neopentyl and neophyl groups: New nontransferable groups for organocopper and organozinc chemistry

Article abstract of DOI:10.1055/s-1999-3387

Neopentyl and Neophyl groups have been found to be excellent nontransferable groups for organozinc and organocopper chemistry. We have shown that mixed diorganozincs of the type FG-R-Zn(CH₂CMe₂R) can be used advantageously for the enantioselective addition to aldehydes. These mixed copper or zinc reagents are also found to be very efficient in the Michael addition to various activated alkenes.

Full text of DOI:10.1055/s-1999-3387

3
12
PAPER
Neopentyl and Neophyl Groups: New Nontransferable Groups
for Organocopper and Organozinc Chemistry
Christian Lutz, Philip Jones, Paul Knochel*
Fachbereich Chemie der Philipps-UniversitŠt Marburg, Hans-Meerwein-Stra§e, 35032 Marburg, Germany
Fax +49(6421)282189; E-mail: Knochel@ps1515.chemie.uni-marburg.de
Received 24 July 1998; revised 15 September 1998
after 16 h at Ð20¡C (S)-1-phenylpropanol (7a) in 79 %
Abstract: Neopentyl and Neophyl groups have been found to be ex-
cellent nontransferable groups for organozinc and organocopper
chemistry. We have shown that mixed diorganozincs of the type
FG-R-Zn(CH CMe R) can be used advantageously for the enan-
yield and an excellent 97%ee. A similar reaction with
7
bis(neophyl)zinc (5) gave (S)-1-phenylpropanol (7a) in
8
9 % yield and 94 %ee. In both cases no migration of the
2
2
tioselective addition to aldehydes. These mixed copper or zinc re- neopentyl and neophyl groups was observed.
agents are also found to be very efficient in the Michael addition to
various activated alkenes.
Key words: mixed zinc reagents, asymmetric synthesis, conjugate
addition, organocuprates, nontransferable groups
Organometallic chemistry has become a cornerstone of
modern organic synthesis, and today hardly any total syn-
theses are published without a key step involving some
nucleophilic organometallic reagent. Despite this, the
search for improvements in functional group compatibili-
ty, efficiency and specificity of existing methods is never
ending. Whilst organozinc reagents offer high functional
Scheme 1
group tolerance these reagents suffer from notable draw-
1
backs. Diorganozinc reagents, R Zn are highly reactive
2
This method constitutes an improvement on methods us-
ing diorganozincs as these typically employ 2Ð3 equiva-
lents of diorganozinc, (FG-R) Zn, corresponding to 4Ð6
equivalents of the FG-R group, whereas this procedure
uses 0.8Ð1.2 equivalents of diorganozinc, (FG-R) Zn, so
only 1.6Ð2.4 equivalents of the FG-R group.
species, however, in most cases only one of the two alkyl
groups is transferred, essentially wasting 50% of the pre-
cious reagent. Alkyl zinc halides, RZnX, offer alterna-
tives, the zinc carrying only one alkyl side chain,
however, these species are less reactive and often necessi-
tate the use of additional catalysis. We have recently
shown that mixed diorganozinc reagents of the type FG-
4
2
2
The reaction with both mixed neopentyl and neophyl di-
organozinc reagents is quite general and tolerates a wide
variety of aldehydes and functionalised alkyl groups (Ta-
ble 1). Both unfunctionalised alkyl groups can be trans-
ferred (entry 1) in good yield and excellent enantioselec-
tivity, but also highly functionalised zinc reagents (entries
2
R-Zn-CH SiMe offer distinct advantages. With these
2
3
species the zinc carries one transferable functional alkyl
group and one nontransferable trimethylsilylmethyl
group. The advantage that these species offer over exist-
ing methodology is that they maintain reactivity, albeit
2
6
Ð5). Also, both aromatic and aliphatic aldehydes (entry
) are tolerated. In all cases the yields are good, 69Ð92 %,
slightly less than R Zn, and have the efficiency of RZnX.
2
To complement this work we became interested in inves-
tigating the role of the nontransferable group, we were
particularly interested due to the prohibitive cost of tri-
as are the enantioselectivities, 86Ð96 %ee. The yields ob-
tained with the neopentyl group are in general slightly
higher than in the case of the neophyl group, compare en-
tries 3 with 4, and 7 with 8, but the enantioselectivities are
comparable.
3
methylsilylmethyl compounds. In particular, we looked
at the all-carbon variant, the neopentyl group (CH CMe )
2
3
and the structurally similar neophyl group (CH CMe Ph).
2
2
The transfer of the methyl group is also extremely diffi-
cult due to its small size, so usually poor selectivities are
The enantioselective addition of functionalised diorga-
nozincs to aldehydes catalysed by (1R,2R)-bis(trifluo-
romethanesulfonamido)cyclohexane (1) and titanium(IV)
alkoxides constitutes an excellent method for the prepara-
obtained when using Me Zn, typically 23%ee with
2
8
Ti(OiPr) . However, by using a mixed zinc reagent bear-
4
4
ing a neopentyl or neophyl group this can be drastically
improved to 93 %ee (entries 7 and 8), showing that the
neopentyl and neophyl groups are involved in the stereo-
determining step.
tion of secondary alcohols. This was deemed an excellent
5
test reaction. Accordingly, bis(neopentyl)zinc (2) was
mixed with diethylzinc (3) at r.t. to give rise to a mixed
6
ethyl(neopentyl)zinc reagent (4a) (Scheme 1). Addition
of this mixed zinc reagent to benzaldehyde (6) in the pres- In parallel studies the roles of the neopentyl and neophyl
ence of Ti(OiPr) and the bis-sulphonamide ligand 1 gave groups in Michael addition reactions were also investi-
4
Synthesis 1999, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart á New York

PAPER
Neopentyl and Neophyl Groups
313
Table 1 Reaction of Mixed Zinc Reagents with Aldehydes
Table 2 Conjugate Addition Reactions using Mixed Dialkylzincs
Entry Zinc
Reagenta
RCHOb Product
Yield ee d
(%)c (%)
Entry Zinc
Reagenta
Michael
Acceptor
Product
Yield
(%)b
1
2
PentZnNp
A
A
89
79
>95
86
1
2
PentZnNp
63
95
PivO(CH ) ZnNp
2
3
c-HexZnNp
3
4
PivO(CH ) ZnNp
A
A
82
71
89
89
2
4
PivO(CH ) ZnNf
2
4
3
c-HexZnNp
78
a
Np = Neopentyl.
Isolated yield of analytically pure products.
b
5
6
PivO(CH ) ZnNp
A
B
81
91
95
96
2
5
Transfer of primary systems (Table 2, entry 1) also pro-
ceeds well, and the reaction is compatible with unsatu-
rated esters (entry 2) and acyclic enones (entry 3).
EtZnNp
The mixed alkyl(neophyl)zinc reagents were also pre-
pared by treatment of neophyllithium (13) with cyclo-
hexylzinc iodide (9), using similar conditions, 3-cyclo-
hexylcyclohexanone (12a) was isolated in a moderate
7
8
MeZnNp
MeZnNf
A
A
92
69
93
94
10
4
2% yield (Scheme 2). Further reactions using mixed
a
b
c
d
alkyl(neophyl) zinc reagents demonstrated the lower reac-
tivity of the neophyl zinc reagents over their neopentyl
counterparts.
Np = Neopentyl, Nf = Neophyl.
A = Benzaldehyde, B = Hydrocinnamaldehyde.
Isolated yield of analytically pure products.
Determined by chiral GC or chiral HPLC analysis (see experimen-
tal section).
We were also interested in investigating the application of
neopentyl and neophyl groups for organocopper chemis-
1
1
try (Scheme 3).
9
5
gated (Scheme 2). Neopentyllithium (8) was treated with
cyclohexylzinc iodide (9) at Ð40¡C to yield the mixed
neopentyl(cyclohexyl)zinc reagent 10. Addition of
N-methyl-2-pyrrolidinone (NMP), TMSBr and then cy-
clohex-2-enone (11) at Ð40¡C gave, after warming to r.t.,
3-cyclohexylcyclohexanone (12a) in 78 % yield, with no
products corresponding to neopentyl transfer.
Scheme 3
Accordingly, copper(I) iodide was treated with
5
neopentyllithium (8) and then butyllithium to yield the
mixed neopentyl(butyl)cuprate 19. Treatment of this ma-
terial with cyclohex-2-enone (11) at Ð78¡C gave, within
1
0 min, 84 % yield of 3-butylcyclohexanone (12c). Again,
no neopentyl migration was observed. Similarly, a mixed
neophyl(butyl)cuprate 20 was prepared. This material was
treated likewise with cyclohex-2-enone (11). After 10 min
at Ð78¡C, 3-butylcyclohexanone (12c) was isolated in
Scheme 2
Synthesis 1999, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart · New York

3
14
C. Lutz et al.
PAPER
7
0% yield together with recovered starting material. Preparation of Functionalized Dialkyzinc Compounds; General
Procedure
Again, no transfer of the neopentyl group was observed.
Et Zn (7.7 mL, 75 mmol) was slowly added dropwise to a stirrred
mixture of an iodoalkane (50 mmol) and CuI (29 mg, 0.3 mol %) at
2
The origin of the nontransferable effect of these neopentyl
and neophyl groups is not fully understood. We believe r.t. under Ar. Upon complete addition the mixture was heated to 50¡C
that the role of these groups is purely steric and the large for 4Ð12 h. The conversion of the iodoalkane was checked by GC
bulk of the nontransferable group serves so as to orientate
the neophyl or neopentyl ligand away from the corre-
analysis of hydrolyzed and iodolyzed aliquots. Finally, the formed
ethyl iodide and excess diethylzinc were removed in vacuo (0.1 Torr,
5
5¡C), using two cooling traps cooled with liquid N . After 2 h, de-
2
sponding electrophile, thereby placing the second alkyl
rest in closer geometrical proximity to the electrophilic re-
action partner. We further believe that this work shows
that in the mixed alkyl(trimethylsilylmethyl)zinc reagents
cane (1.5 mL) was added and the evaporation was continued. This co-
evaporation procedure was repeated three times. The resulting di-
alkylzinc reagent was dissolved in Et O (10 mL) and was ready to use.
2
The distilled diethylzinc collected in cooling traps was quenched by
addition of mixtures of hexanes/acetone and warmed to r.t.
1
2
there is no b-silyl effect due to the similar reactivity of
these reagents to the mixed alkyl(neopentyl) zinc re-
agents.
Enantioselective Addition to Aldehydes; General Procedure
A solution of (1R,2R)-1,2-bis(trifluoromethanesulfonamido)cyclo-
In summary, we have developed two new nontransferable
groups for organozinc and organocopper chemistry. The
i
hexane 1 (61 mg, 0.16 mmol) and Ti(O Pr) (0.36 mL, 1.2 mmol) in
4
Et O (3 mL) was prepared and cooled to Ð20¡C. Meanwhile, the di-
2
resulting mixed FG-R-Zn-CH CMe R reagents have been
2
2
alkylzinc and the inert dialkylzinc were mixed at 25¡C in another
flask. The resulting mixed zinc reagent was slowly added to the cat-
demonstrated to be highly efficient in the asymmetric ad-
dition reaction to aldehydes and also in the 1,4-addition to alyst solution. After 10 min, the aldehyde was added. The reaction
a range of Michael acceptors.
mixture was stirred at Ð20¡C for 14Ð26 h. The reaction was
quenched by cautious addition of 10% aqueous HCl solution and
subsequently extracted with Et O. The combined organic extracts
were washed with brine, dried and concentrated under reduced pres-
sure. The crude product was purified by chromatography (hex-
2
Unless otherwise indicated, all reactions were carried out under Ar.
THF and Et O were dried and freshly distilled over Na/benzophenone
2
and N-methyl-2-pyrrolidinone (NMP) was distilled from CaH . Zn
anes:Et O).
2
2
dust (~325 mesh) was purchased from Aldrich or Riedel-de-Ha‘n
(
Germany). Et Zn and Me Zn were used as supplied by Chemetall
(S)-1-Phenylpropanol (7a)2b
Yield (295 mg, 79 %, 97 %ee) using Et Zn (0.33 mL, 2.5 mmol),
2
2
(
Germany). Ti(OiPr) was freshly distilled before use and stored un-
4
2
der Ar. Reactions were monitored by gas chromatography (GC) anal-
ysis of reaction aliquots and enantiomeric excesses were determined
either by GC or HPLC analysis. FTIR were recorded on a Nicolet 5
(
neopentyl) Zn (0.37 g, 1.8 mmol) and PhCHO (292 mg,
2
2
.75 mmol) following the general procedure. Purified by chroma-
tography (hexanes/Et O= 4:1). The e.r. was determined by chiral
2
1
13
1
13
DXB spectrometer. H and C NMR spectra ( H and C NMR) were
recorded on a Bruker AC-300 (300 MHz and 75.5 MHz, respectively)
or a Bruker AX-200 (200 MHz and 50 MHz, respectively). MS and
exact mass calculations were recorded on a VG-70-250 S mass spec-
trometer. The ionization methods used were desorption chemical ioni-
sation (CI) and electron impact ionisation (EI).The following starting
materials were prepared according to literature procedures: bis(neopen-
GC analysis; Chirasil CD; 120¡C isotherm; 100 kPa (H ); 7.23 min.
minor, 7.43 min. major isomer. [a] = Ð48.5 (c = 1.19, CHCl ).
2
25
D
3
Yield (295 mg, 89 %, 94 %ee) using Et Zn (0.21 mL, 1.6 mmol),
2
(
neophyl) Zn (0.59 g, 1.8 mmol) and PhCHO (234 mg, 2.21 mmol)
2
25
following the general procedure. [a]D = Ð46.1 (c = 4.91, CHCl3).
(S)-1-Phenylhexanol (7b)2b
Yield (357 mg, 89 %, >95 %ee) using Pent Zn (0.33 g, 1.6 mmol),
2
5
5
10
tyl)zinc, neopentyllithium, neophyllithium, (1R,2R)-1,2-bis(trifluo-
4,13
13
romethanesulfonamido)cyclohexane,
3-pivaloxypropyl iodide,
-pivaloxybutyl iodide, 5-pivaloxypentyl iodide,13 dipentylzinc.
14
15
(neopentyl) Zn (0.37 g, 1.8 mmol) and PhCHO (239 mg,
4
2
2
.25 mmol) following the general procedure. Purified by chroma-
Bis(neophyl)zinc (5)7
A solution of neophyl chloride (25.29 g, 150 mmol) in Et O
tography (hexanes/Et O= 4:1). The e.r. was determined by chiral
2
GC analysis; Chirasil CD; 145¡C isotherm; 100 kPa (H ); 7.53 min.
2
2
25
major, 7.95 min. minor isomer. [a]D = Ð35.9 (c = 2.83, CHCl3).
(100 mL) was added dropwise to a stirred mixture of Mg (4.0 g,
1
65 mmol) in Et O (25 mL) at r.t. under Ar. During the addition the
2
(
S)-4-Hydroxy-4-phenylbutyl Pivalate (7c)2b
Yield (359 mg, 79 %, 86 %ee) using bis(3-pivaloxypropyl) zinc
2.3 mmol) [prepared from 3-pivaloxypropyl iodide using the stan-
dard procedure], (neopentyl) Zn (0.37 g, 1.8 mmol) and PhCHO
mixture was allowed to reflux gently. Upon complete addition the
reaction was heated at reflux for a further 1.5 h. Meanwhile, ZnBr2
(
(16.9 g, 75.0 mmol) was dried at 140¡C, 0.1 mm Hg, 2 h, then
cooled to r.t. and dissolved in Et O (100 mL). The ZnBr solution
2
2
2
(0.193 g, 1.82 mmol) following the general procedure. Purified by
was cooled to 0¡C and then the neophylmagnesium chloride solu-
tion added slowly by cannula. It was then warmed to r.t. and stirred
for 14 h. The resulting magnesium salts were removed by filtration,
chromatography (hexanes/Et O= 4:1). The e.r. was determined by
2
chiral HPLC analysis; Chiracel OD, heptane/ isopropanol = 90:10;
flow 0.6 mL/min; 12.6 min. major, 15.3 min. minor isomer. [a]2
5
=
under Ar, through a frit (pore size D3) and washed with Et O (2 ×
D
2
Ð19.8 (c = 4.19, CHCl3).
4
0 mL). The solvent was removed by distillation and the crude res-
idue dried under vacuum (< 0.1 mm Hg) for 1 h. The resulting res-
idue was condensed into a new flask over an ether bridge under
vacuum, 1.7 × 10 mbar using a heat gun to yield bis(neophyl)zinc
(S)-5-Hydroxy-5-phenylpentyl Pivalate (7d)2b
Yield (438 mg, 82 %, 89 %ee) using bis(4-pivaloxybutyl)zinc
(0.61 g, 1.6 mmol) [prepared from 4-pivaloxybutyl iodide using the
Ð4
(14.6 g, 61%).
standard procedure], (neopentyl) Zn (0.37 g, 1.8 mmol) and PhCHO
1
2
H NMR (200 MHz, CDCl ): d = 7.51Ð7.30 (10H, m, Ar), 1.45
3
(0.214 g, 2.02 mmol) following the general procedure. Purified by
[
12H, s, C(CH ) ], 0.96 (4H, s, CH Zn).
3
2
2
chromatography (hexanes/Et O= 4:1). The e.r. was determined by
2
1
3
C NMR (75 MHz, CDCl ): d = 154.4, 129.0, 125.8, 125.0, 38.2,
chiral HPLC analysis; Chiracel OD, heptane/isopropanol = 95:5,
3
3
7.7, 34.9, 29.5.
Synthesis 1999, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Neopentyl and Neophyl Groups
315
flow 0.6 mL/min.; 23.95 min. major, 26.41 min. minor isomer.
lution of the Michael acceptor (4.0 mmol) in THF (5 mL) were add-
ed to this mixture at Ð40¡C. The reaction was stirred at Ð40¡C for 3
h, then warmed to r.t. and stirred overnight.
25
[
a] = Ð22.4 (c = 4.19, CHCl3).
D
Yield (391 mg, 71 %, 89 %ee) using bis(4-pivaloxybutyl)zinc
1.6 mmol) [prepared from 4-pivaloxybutyl iodide using the stan-
dard procedure], (neophyl) Zn (0.59 g, 1.8 mmol) and PhCHO
(
The mixture was poured into aq sat. NH Cl (40 mL) and conc. HCl
4
(10 drops) added and the mixture was then stirred at r.t. for 10 min.
2
(
0.221 g, 2.08 mmol) following the general procedure. (hexanes/
The resulting solution was extracted with Et O (3 × 70 mL), and the
2
2
5
Et O= 4:1). [a] = Ð21.9 (c = 2.91, CHCl3).
combined organic extracts were washed with brine (50 mL), dried
and finally concentrated under reduced pressure. The crude residue
was purified by column chromatography on silica.
2
D
(
S)-6-Hydroxy-6-phenylhexyl Pivalate (7e)
Yield (438 mg, 81 %, 95 %ee) using bis(5-pivaloxypentyl)zinc
1.6 mmol) [prepared from 5-pivaloxypentyl iodide using the stan-
dard procedure], (neopentyl) Zn (0.37 g, 1.8 mmol) and PhCHO
(
3-Cyclohexylcyclohexan-1-one (12a)2d
Yield (560 mg, 78 %) using cyclohexyl iodide (1.26 g, 6.0 mmol),
neopentyllithium (6.0 mmol), NMP (1 mL), cyclohex-2-enone
(387 mL, 4.0 mmol) and TMSBr (1.06 mL, 8 mmol) following the
2
(
0.206 g, 1.94 mmol) following the general procedure. Purified by
chromatography (hexanes/Et O= 2:1).The e.r. was determined by
chiral HPLC analysis; Chiracel OD, heptane/isopropanol = 95:5,
flow 0.6 mL/min.; 18.72 min. major, 20.06 min. minor isomer.
2
general procedure. Purified by chromatography using 10% v/v Et O-
2
hexanes.
2
5
[
a] = Ð22.4 (c = 4.19, CHCl3).
D
Yield (300 mg, 42 %) using cyclohexyl iodide (1.26 g, 6.0 mmol),
neophyllithium (6.0 mmol), NMP (1 mL), cyclohex-2-enone
(387 mL, 4.0 mmol) and TMSBr (1.06 mL, 8 mmol) following the
general procedure.
IR (neat): v = 3680, 3030, 2940, 1880, 1540, 1220 cmÐ1.
1
H NMR (300 MHz, CDCl ): d = 7.25Ð7.08 (5H, m, Ar), 4.00 (2H,
3
t, J = 6.6 Hz, CH OPiv), 3.59 (1H, m, CHOH), 2.74Ð2.59 (2H, m,
2
CH ), 1.74Ð1.35 (6H, m, CH ), 1.14 (9H, s, C(CH ) ).
2
2
3 3
3
-Pentylcyclohexan-1-one (12b)9
1
3
C NMR (75 MHz, CDCl ): d = 178.6, 142.0, 128.4, 128.3, 125.8,
3
Yield (420 mg, 63 %) using pentyl iodide (1.18 g, 6.0 mmol), neo-
pentyllithium (6.0 mmol), NMP (1 mL), cyclohex-2-enone
(387 mL, 4.0 mmol) and TMSBr (1.06 mL, 8 mmol) following the
general procedure. Purified by chromatography using 10% v/v
7
1.1, 64.2, 39.1, 37.0, 32.0, 28.6, 27.2, 21.9.
+
LRMS (EI): m/z = 278 (M , 0.6), 158 (26), 143 (25), 115 (100).
Anal. Calcd for C H O (278.39): C, 73.34; H, 9.42; found: C,
1
7
26
3
Et O-hexanes.
2
7
3.46; H 9.59.
Butyl 3-Cyclohexylpropanoate (17)2d
Yield (810 mg, 95 %) using cyclohexyl iodide (1.26 g, 6.0 mmol),
S)-1-Phenylpentan-3-ol (7f)2b
Yield (300 mg, 91 %, 96 %ee) using Et Zn (0.15 g, 1.6 mmol), (neo-
(
2
neopentyllithium (6.0 mmol), NMP (1 mL), butylacrylate (572 mL,
pentyl) Zn (0.37 g, 1.8 mmol) and hydrocinnamaldehyde (271 mg,
2
4.0 mmol) and TMSBr (1.06 mL, 8.0 mmol) following the general pro-
2
.0 mmol) following the general procedure. Purified by chromatog-
cedure. Purified by chromatography using 2.5% v/v Et O-hexanes.
2
raphy (hexanes/Et O= 2:1). The e.r. was determined by chiral GC
2
analysis; Chirasil CD; 120¡C isotherm; 100 kPa (H ); 14.70 min.
2
4-Cyclohexylbutan-2-one (18)2d
Yield (480 mg, 78 %) using cyclohexyl iodide (1.26 g, 6.0 mmol),
2
5
major, 15.12 min. minor isomer. [a] = + 23.8 (c = 3.01, CHCl3).
D
S)-1-Phenylethanol (7g)2b
Yield (229 mg, 92 %, 93 %ee) using Me Zn (0.15 g, 1.6 mmol),
neopentyllithium (6.0 mmol), NMP (1 mL), methyl vinyl ketone
(
(
358 mL, 4.0 mmol) and TMSBr (1.06 mL, 8.0 mmol) following the
2
general procedure. Purified by chromatography using 5% v/v Et OÐ
2
(
neopentyl) Zn (0.37 g, 1.8 mmol) and PhCHO (217 mg,
2
hexanes.
2
.04 mmol) following the general procedure. Purified by chroma-
tography (hexanes/Et O = 4:1). The e.r. was determined by chiral
2
Michael Addition Reaction of Mixed Diorganocuprates:
3-Butylcyclohexan-1-one (12c)2
A solution of neopentyllithium (1.0 mmol) in pentane (0.93 mol L ,
GC analysis; Chirasil CD; 120¡C isotherm; 100 kPa (H ); 4.32 min.
2
d
2
5
major, 4.75 min. minor isomer. [a] = Ð39.3 (c = 4.92, CHCl3).
D
Ð1
Yield (229 mg, 69 %, 94 %ee) using Me Zn (0.15 g, 1.6 mmol),
2
1
.07 mL) was added dropwise over 1 min to a stirred suspension of
(
neophyl) Zn (0.59 g, 1.8 mmol) and PhCHO (287 mg, 2.7 mmol)
2
CuI (190.5 mg, 1.0 mmol) in THF (8 mL) at Ð78¡C under Ar. The
mixture was stirred at Ð78¡C for 10 min and then warmed to 0¡C
2
5
following the general procedure. [a] = Ð39.2 (c = 2.32, CHCl3).
D
and immediately cooled back to Ð78¡C. A solution of BuLi
Michael Addition Reaction with Mixed Dialkylzincs; General
Procedure
Ð1
(
1.0 mmol) in pentane (1.33 mol L , 750 mL) was added over 1 min
and then warmed slowly to 0¡C over 10 min and then recooled to
1
,2-Dibromoethane (0.2 mL) was added dropwise to a stirred mix-
Ð78¡C. Cyclohex-2-enone (100 mL, 1.0 mmol) was added and
ture of Zn dust (24.0 mmol) in THF (6 mL) at r.t. under Ar, whilst
heating with a heat gun to gently boil the solvent. Upon complete
addition the mixture was cooled to r.t. and then trimethylsilyl chlo-
ride (0.2 mL) was added dropwise over 5 min, again with gentle
heating of the solvent. After complete addition, the mixture was
stirred at r.t. for a further 5 min. The alkyl iodide (6.0 mmol) was
then added dropwise over 5 min, and then the mixture was heated at
stirred for 10 min. Aq sat. NaHCO (3 mL) was added and the mix-
3
ture was extracted with Et O (3 × 70 mL), and the combined organic
2
extracts washed with brine (50 mL), dried and finally concentrated
under reduced pressure. Purified by chromatography using 8% v/v
Et O-hexanes to give the ketone (130 mg, 84%).
2
Yield (325 mg, 70%) using neophyllithium (3 mmol), BuLi
(3 mmol), CuI (571 mg, 3 mmol) and cyclohex-2-enone (300 µL,
5
0¡C for 3 h, the zinc insertion reaction monitored by GC analy-
3
.0 mmol) following the general procedure. Purified by chromatog-
sis.When the insertion reaction was complete, the mixture was
cooled to r.t. and the excess zinc dust allowed to settle for 15 min.
The pale grey solution was then transferred to a flame dried flask
and cooled to Ð40¡C. A solution of neopentyl/neophyllithium
raphy using 8% v/v Et O-hexanes.
2
Acknowledgement
(
6.0 mmol) in pentane was added dropwise over 3 min to the stirred
solution of alkyl zinc iodide at Ð40¡C and then stirred at Ð40¡C for
h. NMP (1 mL), trimethylsilyl bromide (8.0 mmol) and then a so-
The authors wish to thank the DFG (SFB 260 and Leibniz prize)
for generous Þnancial support. C.L. thanks Chemetall (Frankfurt)
1
Synthesis 1999, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart · New York

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16
C. Lutz et al.
PAPER
and Sipsy (AvrillŽ, France) for a fellowship, whilst P. J. thanks the
Royal Society for an award under the European Science Exchange
Programme. We also acknowledge WITCO AG (Bergkamen),
BASF AG (Ludwigshafen) and BAYER AG (Leverkusen) for the
generous gift of chemicals.
(6) For the preparation of some other mixed diorganozincs see:
(a) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449.
(b) Oppolzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993,
115, 1593.
(c) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990,
9
37.
(7) Wissing, E.; Kleijn, H.; Boersma, J.; van Koten, G. Recl. Trav.
Pays-Bas 1993, 112, 618.
References
(
(
8) For the use of mixed methyl(alkyl)zinc in synthesis see ref. 6a
9) For the use of diorganozincs in 1,4-addition ractions see: Red-
dy, C. K.; Devasagayaraj, A.; Knochel, P. Tetrahedron Lett.
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1) Knochel, P.; Almena Perea, J. J.; Jones, P. Tetrahedron 1998,
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1
(
(
(
3) Trimethylsilylmethyl lithium and trimethylsilylmethyl
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yashi, S. Tetrahedron 1992, 48, 5691.
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(
(
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Synthesis 1999, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart · New York