Addition of Dinlkylzinc to Ketones in the Presence of Silylating Agents: Synthesis of Functionalized Tertiary Silyl Ethers

Full text of DOI:10.1021/jo971639x

1
330
J . Org. Chem. 1998, 63, 1330-1333
Ta ble 1. Ad d ition of Et2Zn to Acetop h en on ea
Ad d ition of Dia lk ylzin c to Keton es in th e
P r esen ce of Silyla tin g Agen ts: Syn th esis of
F u n ction a lized Ter tia r y Silyl Eth er s
solvent
time (h)
yield (%)b
hexane
Et2O
toluene
CH2Cl2
28
24
2
83
50
70
81
Chiara Alvisi, Sonia Casolari, Anna Luisa Costa,
Monica Ritiani, and Emilio Tagliavini*
2
Dipartimento di Chimica “G. Ciamician”, Universit a` di
a All the reactions were carried out at -20 °C with a ratio 1a :
Bologna, Via Selmi 2, 40126-Bologna, Italy
2a :3a ) 1:1:1.2. b Yield of 4a containing less than 2% of 1-[(tri-
methylsilyl)oxy]-1-phenylethane (5a ) as the only contaminant.
Received September 3, 1997
3
Tertiary alcohols are generally prepared in good yields
by the addition of alkyllithium or alkylmagnesium halide
reagents to ketones; their acidic hydroxyl function, on the
other hand, often requires protection if further chemical
transformation is to be undertaken in a multistep reac-
tion sequence, and silylation is often the protection of
choice. The major drawback to this classic procedure is
the limited number of functional groups compatible with
the high reactivity of organolithium and magnesium
reagents; the ester, halo, nitrile, and other electrophilic
moieties must be avoided either in the substrate or in
the organometallic reagent.
mote their reaction with aldehydes are well defined; the
addition of dialkylzinc to ketones, however, has remained
practically unexplored.4
We present here the simple and chemoselective reac-
tion of R
(CH OPiv] with a series of ketones 2a -j containing
various functional groups promoted by trialkylsilyl chlo-
SiCl; b Et SiCl; c t-BuMe
2
Zn 1a -c [a , R ) Et; b, R ) (CH
2 4
) OAc; c, R )
2 4
)
rides or triflates 3a -c (a Me
3
3
2
-
SiOTf), to give the corresponding tertiary silyl ethers
4a -n in good yields (eq 1).
Dialkylzinc compounds are stable, poorly reactive,
organometallic compounds.1 Although only Me
Zn and
Zn are commercially available, simple alkyl or func-
tionalized R Zn can be prepared by several methods
which tolerate the presence of a variety of functionalities,
2
Et
2
2
2
like halo, ester, nitrile, etc. R
2
Zn reagents are generally
inert toward carbonyl compounds, but methods to pro-
*
Corresponding author: Fax +(51)259456. E-mail temil@ciam.
unibo.it
A first set of experiments showed that dichloromethane
is the best solvent (Table 1); then the different ketones
(
1) (a) N u¨ tzel, K. In Houben-Weyl: Methoden der Organichen
Chemie; M u¨ ller, E., Ed.; Georg Thieme Verlag: Stuttgart; 1973, Vol.
3/2a, p 553. (b) Boersma, J . In Comprehensive Organometallic
Chemistry; Wilkinson, G., Ed.; Pergamon Press: Oxford, 1982; Vol. 2,
p 824. (c) Knochel, P. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, 1991, Vol. 1, p 211.
1
(
3
2a -j) were tested using Et
2
Zn 1a and the silyl promoters
a -c. The crude products obtained were contaminated
almost only by the secondary trialkylsilyl ethers 5a -j,
which are unavoidable byproducts in the case of aliphatic
substrates. The products can be purified by column
chromatography or distillation, but in the case of TMS
(2) (a) Knochel, P. Synlett 1995, 393. (b) Eisemberg, C.; Knochel, P.
J . Org. Chem. 1994, 59, 3760. (c) Ostwald, R.; Chavant, P.-Y.;
Stadtm u¨ ller, H.; Knochel, P. J . Org. Chem. 1994, 59, 4143. (d) Langer,
F.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. Synlett. 1994, 410.
(
e) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (f) Rozema, M.
5
ether products distillation was sometimes preferred.
J .; Eisemberg, C.; L u¨ tjens, H.; Ostwald, R.; Belyk, K.; Knochel, P.
Tetrahedron Lett. 1993, 34, 3115. (g) Rozema, M. J .; AchyutaRao, S.;
Knochel, P. J . Org. Chem. 1992, 57, 1956. (h) Srebnik, M. Tetrahedron
Lett. 1991, 32, 2449. (i) Seebach, D.; Behrendt, L.; Felix, D. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1008.
1
Data are collected in Table 2 and show that almost any
kind of ketone affords the additon product in very good
6
3
yield in combination with Me SiCl, the formation of 5
ranging from less than 2% with aromatics to ca. 10% with
aliphatic ketones.
(3) (a) Knochel, P.; Singer, R. D. Chem. Rev. (Washington, D.C.)
1
1
993, 93, 2117. (b) Soai, K.; Niwa, S. Chem. Rev. (Washington, D.C.)
992, 92, 833. (c) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49. (d) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y.
M. Tetrahedron 1994, 50, 4363.
The chemoselectivity of the addition is very good. The
ester, chloroaryl, nitroaryl, R-bromo, and R-chloro func-
tions are unaffected by the nucleophile (entries 2-5, 9,
(
4) (a) J ones, P. R.; Goller, E. J . J . Org. Chem. 1969, 34, 3566. (b)
Ibid. 1971, 36, 3311. (c) Marx, B. Compt. Rend. Acad. Sci., Ser. C 1967,
64, 527.
5) Some of the TMS ethers are not perfectly stabile to prolonged
1
0). This makes our procedure very useful for the
2
(
transformation of complex, multifunctional substrates.
The direct synthesis of triethylsilyl and TBS ethers
contact with silica gel, leading to partial decomposition. Their thermal
stability, on the other hand, is generally good.
(entries 10-12) in even better yields than the corre-
(
6) The behavior of R,â-unsaturated ketones is intriguing: while 1,3-
diphenylpropanone (chalcone) undergoes clean conjugate addition of
in the presence of 3a under usual conditions to afford the
sponding TMS ethers is also an important finding;
TBSOTf is preferred to the corresponding chloride in the
latter case to achieve a comparably fast reaction. The
high chemical stability of the TBS ethers makes their
direct preparation attractive for use in multistep syn-
theses. When the addition involves chiral ketones,
diastereomeric mixtures of products are obtained; a
certain degree of facial selectivity was observed with
1
a
corresponding 1-[(trimethilsilyl)oxy]-1,3-diphenylpentene, cyclohex-
enone gives rise to a more complex mixture of products, partially
coming from successive 1,4-addition of the initially formed silyl enol
2
ether to the substrate. On the other hand, the Michael addition of R -
Zn to enones has been described: (a) DeVries, A. H. M.; Meetsma, A.;
Feringa, B. L. Angew. Chem., Int. Ed. Engl. 1996, 35, 2374. (b) Reddy,
C. K.; Devasagayaraj, A.; Knochel, P Tetrahedron Lett. 1996, 37, 4495.
Also the addition of alkyl- and alkynylzinc halides is known: (c) Kim,
S.; Lee, J . M. Tetrahedron Lett. 1990, 31, 7627. (d) Hanson, M. V.;
Rieke, R. D. J . Am. Chem. Soc. 1995, 117, 10775. The conjugate
addition of R
H.; Seebach, D. Tetrahedron 1995, 51, 2305.
2
Zn to nitroolefins has also been reported: (e) Sch a¨ fer,
(7) No attempt has been made to determine the configuration of the
diastereomeric products.
S0022-3263(97)01639-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/23/1998

Notes
J . Org. Chem., Vol. 63, No. 4, 1998 1331
Ta ble 2. Rea ction s of R2Zn w ith Keton es in th e P r esen ce of Silyla tin g Agen ts R33SiX
R-substituted ketones (entries 6, 10), reaching a 5:1 dr
for 3-chloro-2-butanone.7
Having verified the chemoselective addition of simple
diethylzinc to functionalized ketones, we checked the
possibility of reacting functionalized dialkylzinc reagents.
The organometallic reagents 1b,c were prepared accord-
ing to Knochel2 and allowed to react with 2a in the
3
presence of Me SiCl. The reactivity of these reagents is

1
332 J . Org. Chem., Vol. 63, No. 4, 1998
Notes
significantly lower with respect to that of diethylzinc, and
higher temperatures and longer reaction times are
required to accomplish the addition. Nevertheless, ac-
2-[(Tr im eth ylsilyl)oxy]-2-p h en ylbu ta n e (4a ): bp 33 (0.08).
MS 222 (1), 207 (7), 193 (100), 105 (5), 73 (53). 1H NMR 0.10 (s,
9
H); 0.72 (t, 3H, J ) 7.5 Hz); 1.60 (s, 3H); 1.78 (q, 2H, J ) 7.5
13
Hz); 7.12-7.42 (m, 5H).
25.3, 126.1, 127.7, 145.1.
C NMR 2.4, 8.5, 29.2, 38.3, 77.7,
8
ceptable yields of 4n ,o are obtained (Table 2, entries 13,
1
1
4), and this result greatly extends the applicability of
2
-[(Tr im eth ylsilyl)oxy]-2-(4-ch lor op h en yl)bu ta n e (4b):
our procedure to many combinations of reagents.
Finally, if tertiary alcohols are the desired products,
bp 94 (0.7). MS 243 (1.5), 241 (4), 229 (32), 227 (100), 127 (4),
1
125 (14), 75 (40), 73 (87). H NMR 0.10 (s, 9H), 0.69 (t, 3H, J )
7
4H).
.4 Hz), 1.57 (s, 3H), 1.74 (q, 2H, J ) 7.4 Hz), 7.20-7.35 (m,
they can be easily obtained upon desilylation of 4 by
13
standard procedures.9 The process can be also carried
C NMR 2.3, 8.3, 29.5, 38.2, 77.5, 126.7, 128.0, 129.6,
1
2
47.1.
-[(Tr im eth ylsilyl)oxy]-2-(4-n itr oph en yl)bu tan e (4c): MS
52 (9), 238 (100), 73 (55). H NMR 0.17 (s, 9H), 0.69 (t, 3H, J
out in a single pot, upon quenching with methanol
followed by acid treatment (eq 2).
2
1
)
7.4 Hz), 1.64 (s, 3H), 1.80 (q, 2H, J ) 7.4 Hz), 7.55 (m, 2H),
13
8
1
.19 (m, 2H). C NMR 2.3, 8.2, 29.3, 38.0, 77.8, 123.0, 126.2,
46.3, 156.2.
2
-[(Tr im eth ylsilyl)oxy]-2-ph en yl-1-br om obu tan e (4d): MS
1
2
9
1
73 (53), 271 (52), 207 (79), 91 (37), 73 (100). H NMR 0.30 (s,
H), 0.77 (t, 3H, J ) 7.3 Hz), 2.05 (ABX , 2H), 3.69 (d, 1H, J )
0.2 Hz), 3.72 (d, 1H, J ) 10.2 Hz), 7.20-7.45 (m, 5H). C NMR
3
1
3
In conclusion, we believe that our findings significantly
extend the potential of dialkylzinc reagents. Indeed, we
have demonstrated that a variety of functional groups
can be present either in the electrophilic substrate or in
the organometallic reagent, offering to organic chemists
a useful tool for the synthesis of multifunctional mol-
ecules and reducing the necessity of extensive protec-
tion-deprotection sequences.
4.9, 10.9, 35.3, 45.9, 82.2, 128.5, 129.6, 130.5, 146.5.
-[(Tr im et h ylsilyl)oxy]-4-et h ylcycloh exa n eca r b oxylic
a cid eth yl ester (4e) (1:1 isomers mixture): bp 74 (30). MS
4
1
2
72 (3), 242 (78), 169 (55), 157 (100), 73, (73). H NMR (first
isomer) 0.11 (s, 9H), 0.85 (t, 3H, J ) 7.3 Hz), 1.25 (t, 3H, J )
.1 Hz), 4.12 (q, 2H, J ) 7.1 Hz); (second isomer) 0.12 (s, 9H),
0.88 (t, 3H, J ) 7.3 Hz), 1.26 (t, 3H, J ) 7.1 Hz), 4.13 (q, 2H, J
7
1
3
) 7.1 Hz); (both isomers) 1.4-1.9 (m), 2.35 (m, 1H). C NMR
both isomers) 2.4, 2.6, 7.3, 7.9, 14.1, 24.3, 25.3, 35.7, 35.9, 36.1,
1.5, 42.8, 59.9, 60.0, 75.1, 76.6, 175.5, 175.8.
-[(Tr im eth ylsilyl)oxy]-1-eth yl-2-m eth ylcycloh exa n e (4f)
3:1 isomers mixture): bp 72 (30). MS 214 (6), 185 (70), 157
(
4
We are currently working to control the absolute
stereochemistry of the addition reaction. These results
will be reported in due course.
1
(
(
1
57), 144 (44), 73 (100). H NMR (major isomer) 0.08 (s, 9H),
0
1
3
.76 (d, J ) 6.2 Hz, 3H), 0.80 (t, 3H, J ) 7.6 Hz); (minor isomer)
.70 (ABX 2H), 0.10 (s, 9H), 0.83 (t, 3H, J ) 7.6 Hz), 0.85 (d,
H, J ) 6.8 Hz); (both isomers) 1.10-1.65 (m). C NMR (major
3
Exp er im en ta l Section
1
3
All reactions were carried out under Ar in anhydrous sol-
isomer) 2.6, 8.9, 14.9, 22.0, 26.1, 30.3, 33.5, 36.0, 36.9, 77.7;
(minor isomer) 2.7, 6.9, 15.1, 23.6, 24.6, 31.4, 35.3, 41.7, 78.3.
3-[(Tr im eth ylsilyl)oxy]-2,3-d im eth ylp en ta n e (4g): bp 77
vents: CH
2
Cl
2
was distilled from CaH
2
1
, toluene, Et
2
13
O, and
hexane from sodium and benzophenone. H NMR and C NMR
spectra were recorded at 300 and 75.5 MHz, respectively, in
1
(3). MS 187 (0.1), 173 (12), 159 (47), 145 (74), 73 (100). H NMR
CDCl
3
and are reported in δ units. Mass spectra were obtained
0.10 (s, 3H), 0.83 (d, 3H, J ) 6.8 Hz), 0.86 (d, 3H, J ) 6.8 Hz),
through GC-MS at 70 eV EI ionization and are given as m/z (rel
int). Boiling points are in °C (pressure in mmHg). All com-
pounds gave correct C, H analysis.
3
0.87 (t, 3H, J ) 8.1 Hz), 1.10 (s, 3H), 1.47 (ABX , 2H), 1.70 (hept,
1
3
1H, J ) 6.8 Hz). C NMR 2.6, 8.1, 17.3, 17.4, 23.5, 32.4, 36.2,
78.4.
Ad d ition of Dieth ylzin c 1a . In a 25 mL flask under Ar a
solution of the ketone 2a -j (5 mmol) and the silyl promoter 3a -c
3-[(Tr im eth ylsilyl)oxy]-3-eth yln on a n e (4h ): bp 100 (2.5).
MS 244 (17), 215 (88), 159 (100), 103 (15), 73 (46). H NMR
1
(5 mmol) in CH
2
Cl
2
(6 mL) is cooled at -20 °C. To this stirred
0.10 (s, 9H), 0.81 (t, 6H, J ) 7.5 Hz), 0.89 (m, 3H), 1.20-1.35
1
3
mixture is added Et
2
Zn 1a (1 M in hexanes, 6 mL) within 2 min.
(m, 8H), 1.35-1.45 (m, 2H), 1.45 (q, 4H, J ) 7.5 Hz). C NMR
The resulting solution is kept at -20 °C until GC analysis shows
that the ketone is no longer present, and then water (3 mL) is
added; the mixture is filtered, extracted with ether (3 × 5 mL),
dried, and concentrated by rotary evaporation. The crude
product is analyzed by GC to establish the content of the tertiary
1.0, 8.8, 14.1, 22.7, 24.2, 30.3, 31.9, 33.4, 40.2, 77.2.
4-[(Tr im et h ylsilyl)oxy]-4-m et h ylh exa n oic a cid et h yl
ester (4i): bp 75 (4.8). MS 231 (18), 217 (35), 185 (16), 145
1
(92), 99 (96), 73 (100). H NMR 0.10 (s, 9H), 0.86 (t, 3H, J )
7.4 Hz), 1.18 (s, 3H), 1.27 (t, 3H, J ) 7.1 Hz), 1.48 (q, 2H, J )
7.4 Hz), 1.65-1.85 (m, 2H), 2.35 (t, 2H, J ) 7.6 Hz), 4.13 (q, 2H,
(
4) and secondary (5) silyl ethers, and the products 4a -n are
1
3
purified by distillation or silica gel chromatography.
J ) 7.1 Hz). C NMR 2.5, 8.6, 14.2, 26.6, 29.3, 34.9, 36.2, 60.2,
75.5, 172.2.
If the free alcohol is desired, after completion of the addition,
methanol (3 mL) is added to the CH
2
Cl
2
/hexane solution,
3-[(t -Bu t yld im e t h ylsilyl)oxy]-2-ch lor o-3-m e t h ylp e n -
ta n e (4j) (5:1 isomers mixture): MS 237 (1), 235 (3), 223 (5),
221 (17), 195 (38), 197 (12), 187 (42), 139 (31), 137 (90), 93 (65),
followed by Amberlyst 15 (H) resin (1 g), and the mixture is
stirred until no silyl ether can by seen by TLC analysis. After
filtration to remove the resin, the product is recovered and
purified by usual workup.
Ad d ition of F u n ction a lized Dia lk ylzin c Rea gen ts 1b,c.
The organometallic reagents have been prepared from pure Et
1
75 (80), 73 (100). H MNR 0.11 (s, 3H), 0.12 (s, 3H), 0.88 (s,
9H), 0.90 (t, 3H, J ) 7.6 Hz), 1.28 (s, 3H), 1.48 (d, 3H, J ) 6.7
Hz), 1.79 (ABX
, 2H), 3.86 (q, 1H, J ) 6.7 Hz). 13C NMR (major
3
isomer) -2.5, -2.0, 7.5, 18.4 19.3, 25.9, 33.1, 62.2, 77.8; (minor
2
-
isomer) 8.2, 18.4, 19.7, 23.9, 25.9, 32.0, 65.0, 78.6.
Zn and 1-acetoxy-4-iodobutane (for 1b) or 1-pivaloxy-4-iodobu-
2
c
2-[(Tr ieth ylsilyl)oxy]-2-p h en ylbu ta n e (4k ): bp 98 (1). MS
tane (for 1c) according to the literature. In the same reaction
flask containing 4 mmol of 1b or 1c, cooled at 0 °C, CH Cl (3
mL) is added, followed by 2a (0.38 mL, 3.3 mmol) and TMSCl
a (0.42 mL, 3.3 mmol). After 36 h, the reaction is quenched
1
2
6
64 (1), 235 (46), 115 (20), 103 (100), 75 (40). H NMR 0.70 (q,
2
2
H, J ) 7.6 Hz), 0.78 (t, 3H, J ) 7.4 Hz), 1.05 (t, 9H, J ) 7.6
Hz), 1.69 (s, 3H), 1.85 (ABX , 2H), 7.23-7.53 (m, 5H).
3
3
and worked up as above. The products 4m and 4n are purified
by chromatography on silica gel.
The following products were prepared:
2-[(ter t-Bu tyldim eth ylsilyl)oxy]-2-ph en ylbu tan e (4l): MS
1
249 (0.2), 235 (21), 207 (22), 115 (4), 75 (100). H NMR 0.00 (s,
3
3
1
H), 0.12 (s, 3H), 0.71 (t, 3H, J ) 7.4 Hz), 0.97 (s, 9H), 1.60 (s,
13
H), 1.79 (ABX
8.6, 26.2, 29.6, 38.4, 77.7, 125.4, 126.1, 127.7, 148.5.
-[(Tr im eth ylsilyl)oxy]-5-p h en ylh exa n -1-ol a ceta te (4m ):
3
, 2H), 7.15-7.45 (m, 5H). C NMR -1.9, 8.6,
(
8) RZnI reagents have also been tested: an attempted reaction with
R ) (CH OAc showed the formation of some 4m ; however, the rate
is too slow to make the reaction synthetically useful.
9) For example, treatment of 4a (Table 2, entry 1) with Amberlyst
5 (H) in MeOH gave the corresponding tertiary alcohol in 94% yield.
5
2 4
)
MS 293 (0.5), 194 (21), 193 (100), 177 (4), 117 (17), 91 (8), 73
1
(
(36). H NMR 0.88 (s, 9H), 1.0-1.6 (m, 4H), 1.57 (s, 3H), 1.65-
1
1.8 (m, 2H), 1.96 (s, 3H), 3.94 (t, 2H, J ) 6.7 Hz), 7.1-7.4 (m,

Notes
J . Org. Chem., Vol. 63, No. 4, 1998 1333
5
1
H). 13C NMR 2.4, 20.4, 20.9, 28.7, 29.7, 45.3, 64.3, 77.4, 125.1,
26.2, 127.8, 148.4, 171.1.
Ack n ow led gm en t. Investigation supported by Uni-
versity of Bologna (Funds for selected research topics).
5
-[(Tr im eth ylsilyl)oxy]-5-ph en ylh exan -1-ol pivaloate (4n ):
1
MS 335 (0.3), 193 (100), 159 (6), 117 (5), 73 (33). H NMR 0.11
(
(
2
1
s, 9H), 1.14 (s, 9H), 1.2-1.6 (m, 4H), 1.61 (s, 3H), 1.65-1.85
Su p p or tin g In for m a tion Ava ila ble: Elemental analysis
data for compounds 4a -n , 6 (2 pages). This material is
contained in libraries on microfiche, immediately follows this
article in microfilm version of the journal, and can be ordered
from the ACS; see any current masthead page for ordering
information.
1
3
m, 2H), 3.97 (t, 2H, J ) 6.5 Hz), 7.1-7.4 (m, 5H). C NMR
.4, 20.4, 27.1, 28.7, 29.7, 40.1, 45.4, 64.1, 77.3, 125.1, 126.1,
27.7, 148.3, 173.9.
3
,5-Dim eth yl-3-h exa n ol (6): MS 115 (8), 101 (19), 73 (100),
1
5
7 (33). H NMR 0.91 (t, 3H, J ) 7.4 Hz), 0.97 (d, 3H, J ) 6.7
Hz), 0.98 (d, 3H, J ) 6.7 Hz), 1.17 (s, 3H), 1.26 (br s, 1H), 1.38
d, 2H, J ) 7.4 Hz), 1.51 (q, 2H), 1.80 (hept, 1H, J ) 6.7 Hz).
(
J O971639X