Direct formation of secondary and tertiary alkylzinc bromides and subsequent Cu(I)-mediated couplings

Article abstract of DOI:10.1021/jo952104b

Secondary and tertiary alkylzinc bromides can be generated from the direct oxidative addition of Rieke zinc to secondary and tertiary alkyl bromides in high yield. These organozinc reagents have been found to undergo copper-catalyzed conjugate addition, cross-coupling with acid chlorides, and carbocupration to activated alkynes.

Full text of DOI:10.1021/jo952104b

2
726
J . Org. Chem. 1996, 61, 2726-2730
Dir ect F or m a tion of Secon d a r y a n d Ter tia r y Alk ylzin c Br om id es
a n d Su bsequ en t Cu (I)-Med ia ted Cou p lin gs
Reuben D. Rieke,* Mark V. Hanson, and J effrey D. Brown
Department of Chemistry, University of NebraskasLincoln, Nebraska 68588-0304
Q. J ason Niu†
Rieke Metals, Inc., 6133 Heide Lane, Lincoln, Nebraska 68512
Received November 28, 1995X
Secondary and tertiary alkylzinc bromides can be generated from the direct oxidative addition of
Rieke zinc to secondary and tertiary alkyl bromides in high yield. These organozinc reagents have
been found to undergo copper-catalyzed conjugate addition, cross-coupling with acid chlorides, and
carbocupration to activated alkynes.
1
5
In tr od u ction
The first oxidative addition of zinc into a carbon-
strates, as in carbon-bromine bonds R to oxygen,
nitrogen,15 boron, or sulfur, â to phosphonates, and
for R-halo esters, nitriles, and amides. If the carbon-
16
17
18
19
halogen bond was demonstrated in 1849 by Frankland
by heating ethyl iodide and zinc metal to form diethyl-
zinc.1 Pursuant to this discovery, methods of metal
activation were employed with zinc to increase reaction
efficiency and to expand the scope of oxidative addition
to more unreactive carbon-halogen bonds. These meth-
bromine or chlorine bond is not sufficiently activated, the
oxidative addition is not effective. The zinc-copper
couples display only limited effectiveness for alkyl bro-
mides and tert-butyl bromides. There is evidence for the
5
generation of dialkylzincs using this procedure. How-
ever, a simple activation method was presented by
Knochel in which zinc halides were reduced on titanium
2
ods included washing with aqueous HCl, addition of 1,2-
3
4
5
dibromoethane and/or trimethylchlorosilane, Zn-Cu or
13
dioxide. Using this activated zinc, secondary alkyl- and
6
7
8
Zn-Cu-Ag couples, sodium-zinc and zinc-mercury
benzylzinc bromides could be prepared. There have been
no synthetically useful procedures to generate tertiary
alkylzinc bromides by direct oxidative addition in high
yield.
9
alloys, ultrasound irradiation, metal-solvent coconden-
sation,10 sacrificial zinc anodes, pulsed sonoelectro-
11
1
2
chemical reduction of zinc salts, and reduction of zinc
salts on titanium dioxide.13 The utilization of entrain-
ment methods for zinc metal in the generation of alkyl-
zinc halides from alkyl bromides and chlorides directly
has led to limited success. The ideal alkyl halide
In 1973, we reported a new method for the preparation
of a highly reactive zinc metal which involved the
2
0
reduction of zinc salts using sodium or potassium metal.
This reactive metal powder allowed for the first time the
direct oxidative addition to primary alkyl and aryl
bromides. In 1991, we published an improved method
which was safer and produced an even more reactive
zinc.21 Significantly, this approach provided a direct
route to highly functionalized organozinc halide reagents
from alkyl bromides, aryl iodides and bromides, as well
as vinyl iodides and bromides. We also reported a new
more reactive zinc which will undergo oxidative addition
substrates for oxidative addition, using entrainment
methods, have been alkyl iodides.14 However, activated
carbon-halogen bonds have proven to be useful sub-
†
Current address: Department of Chemistry, Cornell University,
Ithaca, NY 14853-1301.
X
Abstract published in Advance ACS Abstracts, March 15, 1996.
(
1) Frankland. E. Liebigs Ann. Chem. 1849, 71, 171.
(2) (a) Shriner, R. L. Org. React. 1942, 1, 1. (b) Cornforth, J . W.;
Cornforth, R. H.; Popj a´ k, G.; Gore, I. Y. Biochem. J . 1958, 69, 146.
3) (a) Erdik, E. Tetrahedron 1987, 43, 2203. (b) Knochel, P.; Yeh,
M. C. P.; Berk, S. C.; Talbert, J . J . Org. Chem. 1988, 53, 2390.
4) (a) Gawronski, J . K. Tetrahedron Lett. 1984, 25, 2605. (b) Picotin,
G.; Miginiac, P. J . Org. Chem. 1987, 52, 4796.
5) (a) Gladstone, J . H. J . Chem. Soc. 1891, 59, 290. (b) J ob, A.;
(
22
to alkyl chlorides. Recently, we reported that our highly
reactive zinc could also react directly with secondary and
tertiary alkyl bromides in high yield,23 and that these
reagents give the 1,4-conjugate addition product with R,â-
(
(
Reich, R. Bull. Soc. Chim. Fr. 1923, 33, 1414. (c) Kurg, R. C.; Tang, P.
J . C. J . Am. Chem. Soc. 1954, 76, 2262. (d) Renshaw, R. R.; Greenlaw,
C. E. J . Am. Chem. Soc. 1920, 42, 1472.
2
4
unsaturated ketones without the use of a Cu(I) catalyst.
(
6) (a) Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. Helv. Chim.
Acta 1987, 70, 1025. (b) Avignon-Tropis, M.; Pougny, J . R. Tetrahedron
Lett. 1989, 30, 4951.
(15) Knochel, P.; Chou, T.-S.; J ubert, C.; Rajagopal, D. J . Org. Chem.
1993, 58, 588.
(
7) See Methods of Elemento-organic Chemistry, Nesmeyanov, A. N.,
(16) Knochel, P. J . Am. Chem. Soc. 1990, 112, 7431.
(17) AchyuthaRao, S.; Tucker, C. E.; Knochel, P. Tetrahedron Lett.
1990, 31, 7575.
(18) Retherford, C.; Chou, T.-S.; Schelkun, R. M.; Knochel, P.
Tetrahedron Lett. 1990, 31, 1833.
(19) (a) Rathke, M. W. In Organic Reactions; Dauben, W. G., Ed.;
Wiley: New York, 1975; Vol. 22, p 423. (b) F u¨ rstner, A. Synthesis 1989,
571.
(20) Rieke, R. D.; Hudnall, P. M.; Uhm, S. J . J . Chem. Soc., Chem.
Commun. 1973, 269.
(21) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J . Org. Chem. 1991,
56, 1445.
(22) Hanson, M.; Rieke, R. D. Synth. Commun. 1995, 25, 101.
(23) Hanson, M. V.; Brown, J . D.; Niu, Q. J .; Rieke, R. D. Tetrahe-
dron Lett. 1994, 35, 7205.
Kocheshkov, K. A., Eds., North Holland: Amsterdam, 1967, Vol. 3, p
8
.
(
8) Elphimoff-Felkin, I.; Sarda, P. Organic Syntheses, Wiley: New
York, 1988; Coll. Vol. 6, p 769.
9) (a) Han, B.-H.; Boudjouk, P. J . Org. Chem. 1982, 47, 5030. (b)
For a general review see: Abdulla, R. F. Aldrichim. Acta 1988, 21, 31.
10) (a) Murdock, T. O.; Klabunde, K. J . J . Org. Chem. 1976, 41,
076. (b) Klabunde, K. J .; Murdock, T. O. J . Org. Chem. 1979, 44, 3901.
11) Sibille, S.; Ratovelomanana, V.; N e´ d e´ lec, J . Y.; P e´ richon, J .
Synlett 1993, 6, 425.
12) Durant, A.; Delplancke, J .-L.; Winand, R.; Reisse, J . Tetrahe-
dron Lett. 1995, 36, 4257.
13) Stadtm u¨ ller, H.; Greve, B.; Lennick, K.; Chair, A.; Knochel, P.
Synthesis 1995, 1, 69.
14) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(
(
1
(
(
(
(
(24) Hanson, M. V.; Rieke, R. D. J . Am. Chem. Soc. 1995, 117, 10775.
0
022-3263/96/1961-2726$12.00/0 © 1996 American Chemical Society

Direct Formation of Secondary and Tertiary Alkylzinc Bromides
J . Org. Chem., Vol. 61, No. 8, 1996 2727
Ta ble 1. Ter tia r y Alk ylzin c Br om id es
Ta ble 2. Secon d a r y Alk ylzin c Br om id es
a
Zn* 1.0-1.3 equiv, RBr 1.0 equiv, THF. b CuCN/LiBr 0.1
equiv, RZnBr 1.0 equiv, RCOCl 0.7 equiv, THF, -45 °C to rt.
Resu lts a n d Discu ssion
We have found that Rieke zinc readily yields alkylzinc
bromides efficiently under mild conditions from the direct
oxidative addition of Rieke zinc to secondary and tertiary
alkyl bromides. This method is good for hindered and
unhindered unactivated secondary and tertiary alkyl
bromides. The Rieke zinc used in these experiments was
generated by a two-pot procedure; to a mixture of lithium
(
2.1 equiv) and naphthalene (0.2 equiv) in THF was
added by drop a THF solution of anhydrous zinc chloride
1.0 equiv) over 2 h. This mossy form of zinc settled
a
Zn* 1.0-1.3 equiv, RBr 1.0 equiv, THF. b CuCN/LiBr 0.1
equiv, RZnBr 1.0 equiv, RCOCl 0.7-1.0 equiv, THF, -45 °C to rt.
(
rapidly and bore the same high reactivity as that of using
stoichiometric lithium naphthalenide. As was previously
reported,21 a mossy form of active zinc could be prepared
by allowing for a shortened reduction time. With the
resulting decreased settling times, the active zinc was
rapidly washed with THF to decrease the lithium chloride
and naphthalene content present from reduction, which
then simplified product purification. The rinsed active
zinc readily reacted with alkyl bromides to cleanly
produce an alkylzinc bromide. For instance, the addition
of 0.9 equiv of tert-butyl bromide to active zinc at room
temperature resulted in an exothermic reaction which
was complete within 1 h. The 13C NMR of the resulting
tert-butylzinc bromide revealed a strong singlet at δ 32.3
and a weak singlet at δ 21.7. This ability to generate an
alkylzinc bromide without an observable presence of a
dialkylzinc, or a product resulting from reductive cleav-
age, is significant. In contrast, a marked difference in
the ease of oxidative addition for 1-bromoadamantane
was observed. At ambient temperature, the oxidative
addition was slow. To effect a good conversion, an excess
amount of zinc (1.2 equiv) and refluxing conditions for 3
h was necessary. The oxidative addition of magnesium
Ta ble 3. F u n ction a lized Secon d a r y Alk ylzin c Br om id es
a
Zn* 1.0-1.3 equiv, RBr 1.0 equiv, THF. b CuCN/LiBr 0.1
equiv, RZnBr 1.0 equiv, RCOCl 0.7 equiv, THF, -45 °C to rt.
For example, cyclobutylzinc bromide can be prepared in
quantitative yield from cyclobutyl bromide. Although,
the cyclobutylzinc bromide could be generated at ambient
temperature in about 12-16 h using 1.1-1.2 equiv of
active zinc, the reaction time was reduced to 2 h by
refluxing in THF. A surprising result was that when the
oxidative addition of zinc was either performed at reflux
or at ambient temperature with cyclopropyl bromide, a
coupled product with benzoyl chloride using a copper
catalyst could not be achieved. The secondary acyclic
alkyl bromides formed the reagent in good yield with 1.1
equiv of active zinc. The oxidative addition was complete
in 2.5 h under refluxing conditions. Thus, the rate of
oxidative addition was faster for smaller chain lengths,
but longer chain lengths required longer reaction times,
up to 3 h at refluxing temperatures (cf. entry 7). This
procedure was able to accommodate remote functional
groups including ester and nitrile groups. The oxidative
addition of Rieke zinc to methyl 3-bromobutyrate (Table
(
turnings) to this halide is known to result in a significant
2
5
amount of reductive cleavage and homocoupling. Thus,
Rieke zinc was highly efficient in the oxidative addition
to this difficult alkyl bromide. The bulky nature of the
alkyl groups in these tertiary alkylzinc bromides was
evident as the copper-mediated coupling of acid chlorides
required longer reaction times than primary alkylzinc
reagents. The tertiary alkylzinc bromides (Table 1)
coupled slowly with benzoyl chloride using CuCN/LiBr26
as catalyst taking 4-8 h for completion.
The cyclic secondary alkyl bromides (Table 2, entries
1
-3) formed the alkylzinc bromide reagents in good yield.
3
, entry 1) was complete in 1 h at room temperature, but
(
25) Dubois, J . E.; Bauer, P.; Molle, G.; Daza, J . C. R. Hebd. Seances
Acad. Sci., Ser. C 1977, 284, 145.
26) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J . J . Org. Chem.
988, 53, 2390.
the ester functionality was stable to refluxing conditions
even after 2.5 h. The observed trend in the ease of
oxidative addition for unfunctionalized alkyl bromides
(
1

2
728 J . Org. Chem., Vol. 61, No. 8, 1996
Rieke et al.
Ta ble 4. Con ju ga te Ad d ition of Secon d a r y a n d Ter tia r y
Alk ylzin c Br om id es Med ia ted by Cop p er Sa lts
Sch em e 2
Sch em e 3
very sluggish at -78 °C, and only at 0 °C did the reaction
proceed slowly. Even at the elevated reaction tempera-
ture, the diasteriomeric excess for 18 was 85% in an
overall yield of 43% (Scheme 3).
Sch em e 1
Con clu sion
In summary, we have demonstrated a method for
preparing secondary and tertiary alkylzinc reagents from
the stable alkyl bromides. This result is significant, in
that tertiary alkylzinc bromides can be formed readily
from Rieke zinc insertion in high yield. The formation
of these organozinc reagents would be difficult or impos-
sible by other methodologies which do not tolerate
functionality. These organozinc reagents have been
found to undergo copper-catalyzed conjugate addition,
cross-coupling with acid chlorides, and carbocupration to
activated alkynes.
using Rieke zinc is tertiary >secondary >primary. This
progression is comparable to that of primary and second-
ary alkyl iodides.14
The conjugate addition of secondary and tertiary
alkylzinc bromides (Table 4) mediated by copper(I)
proceeds in good yield even though the reagents are bulky
nucleophiles (Scheme 1). The 1,4 addition reaction was
conducted as to previous literature procedure using the
soluble copper cyanide/lithium bromide complex in con-
junction with boron trifluoride diethyl etherate and
chlorotrimethylsilane.21 Under these conditions tert-
butylzinc bromide reacted with 2-cyclohexenone to give
Exp er im en ta l Section
Gen er a l In for m a tion . The manipulation of air-sensitive
reagents was conducted in a Vacuum Atmospheres Co. drybox
maintained with an argon atmosphere. Reactions were per-
formed on a dual manifold vacuum/argon system. Linde
prepurified grade argon was further purified by passing it
through a 150 °C catalyst column (BASF R3-11) and then
through a column of phosphorus pentoxide, followed by a
column of granular potassium hydroxide. THF was distilled
prior to use from NaK alloy under a blanket of argon.
Anhydrous zinc chloride was purchased from Cerac, Inc., and
was used as received.
1
5 in 75% yield. However, using copper iodide catalyti-
cally gave the product in 96% yield. The conjugate
addition involving 1-adamantylzinc bromide with 4-hexen-
3
6
3
-one using the previous Lewis acid combination gave a
3% isolated yield of the addition product 16. Methyl
-zinciobromobutyrate, a secondary alkylzinc reagent,
gave the addition product 14 in moderate yield with
cyclohexenone at 53% yield. The secondary and tertiary
organozinc reagents required longer reaction times than
primary alkylzinc reagents, usually 8-12 h for more
hindered systems.
The carbocupration reaction using stoichiometric ter-
tiary alkylzinc-copper reagents demonstrated their poor
nucleophilicity toward activated alkynes. Primary and
secondary organozinc reagents have been shown to be
Sta r tin g Ma ter ia ls. Functionalized alkyl bromides were
prepared as described below.
Eth yl 5-Hyd r oxyn on a n oa te. Prepared by literature pro-
2
1
cedure from the reduction of ethyl 5-oxononanoate in metha-
2
8
nol by NaBH
4
.
The product (43% yield) was isolated from
the crude reaction mixture by flash chromatography (EtOAc/
1
hexanes, 1:4). H NMR δ 4.12 (q, 2 H), 3.58 (m, 1 H), 2.32 (t,
highly stereoselective in the carbocupration of activated
2 H), 1.80-1.23 (m, 14 H), 0.91 (t, 3 H). 13C NMR δ 173.7,
alkynes.16
27
We have found that the reaction of 2,2-
71.4, 60.2, 37.2, 36.7, 34.2, 27.8, 22.7, 21.0, 14.2, 14.0. IR (neat)
-
1
dimethylpropylzinc bromide with the activated terminal
alkyne, methyl propiolate proceeded at -78 °C in 4 h
using copper cyanide/lithium bromide stoichiometrically
to give good stereoselectivity (Scheme 2). The product
1720, 1739 cm . Anal. Calcd for C11
Found: C, 65.48; H, 10.76.
22 3
H O : C, 65.31; H, 10.96.
2
9
5
-Hyd r oxyn on a n en itr ile. Prepared from 5-oxononane-
nitrile as procedure above.
3
0
1
7 was obtained in 77% yield with the E isomer pre-
dominating (E/ Z ) 86/13). In the case of the internal
alkyne ethyl 2-octynoate, the carbocupration reaction was
(28) Mancera, O.; Ringold, H. J .; Djerassi, C.; Rosenkranz, G.;
Sondheimer, F. J . Am. Chem. Soc. 1953, 75, 1286.
(29) O’Shea, M. G.; Kitching, W. Tetrahedron 1989, 45, 1177.
(
30) Cohen, N.; Rosenberger, M.; Saucy, G.U.S. Patent 3898264,
(27) Chou, T.-S.; Knochel, P. J . Org. Chem. 1990, 55, 4791.
1975.

Direct Formation of Secondary and Tertiary Alkylzinc Bromides
J . Org. Chem., Vol. 61, No. 8, 1996 2729
E t h yl 5-Br om on on a n oa t e. The above hydroxy com-
Cycloh exyl P h en yl Keton e (6). Reference 39.
2-Eth yl-1-P h en yl-1-Bu ta n on e (8). Reference 40.
3-Eth yl-8-ch lor o-4-octa n on e (9). The product was iso-
lated from the crude reaction mixture by flash chromatography
3
1
pounds were first converted to the mesylates and the crude
subjected to refluxing in a THF solution of lithium bromide.32
The product (27% yield) was isolated from the crude reaction
1
1
mixture by flash chromatography (EtOAc/hexanes, 5:95).
H
(EtOAc/hexanes, 5:95). H NMR δ 3.56-3.50 (m, 2 H), 2.47-
δ 4.14 (q, J ) 6.9, 2 H), 4.02 (m, 1 H), 2.33 (t, J ) 6.9, 2 H),
2.41 (m, 2 H), 2.33-2.30 (m, 1 H), 1.80-1.41 (m, 8 H), 0.87-
1
3
13
1
.9-1.7 (m, 6 H), 1.5-1.2 (m, 7 H), 0.90 (t, J ) 7.2, 3 H).
δ 173.2, 60.3, 57.7, 38.8, 38.3, 33.6, 29.7, 23.0, 22.1, 14.2, 13.9.
Anal. Calcd for C11 : C, 49.82; H, 7.98. Found: C,
C
0.78 (m, 6 H). H NMR δ 214.7, 56.1, 45.3, 42.0, 41.9, 32.7,
-1
24.9, 21.5, 21.5. IR (neat) 1709 cm . Anal. Calcd for C10
ClO: C, 62.98; H, 10.04. Found: C, 62.81; H, 9.89.
2-Meth yl-1-p h en yl-1-octa n on e (10). Reference 41.
19
H -
H
21BrO
2
5
0.11; H, 8.00.
5
-Br om on on a n en itr ile. 1H δ 4.00-3.92 (m, 1 H), 2.37-
.33 (m, 2 H), 1.97-1.71 (m, 6 H), 1.50-1.23 (m, 4 H), 0.86 (t,
Meth yl 3-Meth yl-4-oxo-4-p h en ylbu ta n oa te (11). The
2
product was isolated from the crude reaction mixture by flash
1
3
1
J ) 7.2, 3 H). C δ 119.0, 56.3, 38.6, 37.3, 29.3, 23.3, 21.8,
chromatography (EtOAc/hexanes, 15:85). H NMR δ 7.99 (m,
-
1
1
6.3, 13.6. IR (neat) 2244 cm . Anal. Calcd for C
9
H
16BrN:
2 H), 7.52 (m, 3 H), 3.95 (m, 1 H), 3.65 (s, 3 H), 2.97 (dd, J )
16.5, 4.2 Hz, 1 H), 2.47 (dd, J ) 16.9, 2.9 Hz, 1 H), 1.23 (d, J
C, 49.76; H, 7.43; N, 6.45. Found: C, 49.94; H, 7.60; N, 6.57.
Typ ica l P r ep a r a tion of Riek e Zin c. To a flask charged
with finely cut (ca. 0.75 × 1.0 × 5.0 mm) Li (0.11 g, 16 mmol),
naphthalene (0.20 g, 1.6 mmol), and THF (10 mL) under argon
was transferred via cannula a solution of zinc chloride (1.09
g, 8.00 mmol) in THF (15 mL) dropwise so addition was
complete in 1.5 h. The mixture was then vigorously stirred
for an additional 0.5 h until the lithium metal was consumed.
The stirring was then stopped and the zinc settled in ca. 10
min. The supernatant was removed via cannula. The Rieke
zinc was then washed with two consecutive portions of dry
THF (15 mL). A final portion of THF was added and the Rieke
zinc was ready for use.
1
3
) 3.06 Hz, 3 H). C NMR δ 202.8, 172.8, 135.9, 133.1, 128.8,
-1
128.5, 51.7, 37.2, 17.9. IR (neat) 1724, 1674 cm . Anal. Calcd
for C12 : C, 69.88; H, 6.84. Found: C, 69.72; H, 6.77.
14 3
H O
Eth yl 5-(1-Oxo-1-p h en ylm eth yl)n on a n oa te (12). The
product was isolated from the crude reaction mixture by flash
1
chromatography (EtOAc/hexanes, 1:9). H NMR δ 7.96 (m, 2
H), 7.52 (m, 3 H), 4.09 (d, J ) 7.2 Hz, 2 H), 3.44 (m, 1 H), 2.27
(m, 2 H), 1.82-1.43 (m, 6 H), 1.31-1.18 (m, 7 H), 0.84 (t, J )
1
3
6.6 Hz, 3 H). C NMR δ 204.1, 173.3, 137.5, 132.8, 128.6,
128.1, 60.22, 45.85, 34.3, 32.1, 31.5, 29.5, 22.9, 22.8, 14.1, 13.8.
-1
IR (neat) 1743, 1684 cm . Anal. Calcd for C18
H, 9.02. Found: C, 74.57; H, 9.13.
26 3
H O : C, 74.45;
P r ep a r a tion of ter t-Bu tylzin c Br om id e. To a slurry of
Rieke zinc (1.03 g) in THF (10.0 mL) under argon was added
via disposable syringe, 1.969 g of tert-butyl bromide. The
exothermic reaction was complete in 1 h. The zinc was allowed
to settle, and 0.5 mL of the supernatant was cannulated to an
NMR tube capped with a septum. A sealed capillary tube
5-(1-Oxo-1-p h en ylm eth yl)n on a n en itr ile (13). The prod-
uct was isolated from the crude reaction mixture by flash
chromatography (gradient elution: EtOAc/hexanes, 0:100,
2:98, 4:96, 6:94, 10:90). 1H NMR δ 7.92-7.90 (d, 2 H), 7.45 (s,
1 H), 7.44 (s, 2 H), 3.43 (s, 1 H), 2.27 (s, 2 H), 1.88 (s, 1 H),
1
3
1.74-1.62 (m, 6 H), 1.22 (s, 4 H), 0.88 (s, 3 H). C NMR δ
containing CDCl
3
inside the NMR tube was used to gain NMR
lock. C NMR (THF; δ 25.3) δ 32.3, 21.7.
203.3, 136.9, 133.0, 128.6, 127.9, 119.2, 45.1, 32.2, 30.6, 29.2,
1
3
-1
23.2, 22.6, 17.2, 13.7. IR (neat) 2244, 1677 cm . Anal. Calcd
Typ ica l P r oced u r e for Cop p er -Med ia ted Cou p lin g of
Alk ylzin c Br om id e Rea gen ts w ith Acid Ch lor id es. To a
slurry of Rieke zinc (7.98 mmol) in THF (25 mL) under a
blanket of argon was added 2-bromobutane (7.95 mmol), and
the mixture was refluxed for 2.5 h. The resulting light brown
solution was cooled to rt and was transferred via cannula to a
solution of CuCN (1.5 mmol) and LiBr (1.5 mmol) in THF (10
mL) at -45 °C. Benzoyl chloride (7.95 mmol) was added neat,
and the mixture was warmed slowly to rt over 4 h. The
reaction mixture was quenched with 3 M HCl (20 mL) and
extracted with ether (3×20 mL), and the combined layers were
for C16H21NO: C, 78.96; H, 8.70; N, 5.76. Found: C, 79.12;
H, 8.89; N, 5.67.
Typ ica l P r oced u r e for Cop p er -Med ia ted 1,4-Ad d ition
of Alk ylzin c Br om id es to R,â-Un sa tu r a ted Keton es. To
a slurry of Rieke zinc (12.9 mmol) in THF (25 mL) was added
methyl 3-bromobutyrate (11.6 mmol) neat via disposable
syringe and the mixture stirred for 4 h at rt. The Rieke zinc
was allowed to settle, the supernatant was transferred to a
THF (10 mL) slurry of CuI (15.5 mmol) at rt, and the mixture
was stirred for 10 min. The mixture was brought to -78 °C,
and BF
3
2
‚Et O (12.2 mmol), TMSCl (15.8 mmol), and 2-cyclo-
washed with water (20 mL), dried over MgSO
4
, and concen-
hexenone (7.54 mmol) were added neat. The reaction mixture
was then brought to -30 °C and maintained for 10 h. The
mixture was then warmed to rt and stirred for an additional
3 h. The reaction mixture was quenched with 3 M HCl (20
mL) and extracted with ether (3 × 20 mL), and the combined
3
3
trated. 2-Methyl-1-phenylbutanone 7 (7.52 mmol, 95%) was
isolated from the crude reaction mixture by flash chromatog-
raphy (EtOAc/hexanes, 5:95).
2
2
,2-Dim eth yl-1-p h en yl-1-p r op a n on e (1). Reference 34.
,2-Dim eth yl-1-p h en ylbu ta n on e (2). Reference 35.
2 2 3
organics were washed sequentially with aqueous Na S O
3
6
(20%, 20 mL), water (3 × 20 mL), brine (20 mL) and then dried
Ad a m a n tyl p h en yl k eton e (3). The product was iso-
over MgSO and concentrated. Methyl 3-(3-oxocyclohexyl)-
4
lated from the crude reaction mixture by flash chromatography
1
butanoate (14) (4.00 mmol, 53%) was isolated from the crude
(
gradient elution: EtOAc/hexanes, 0:100, 2:98, 5:95, 8:92). H
1
as a colorless oil from silica gel (EtOAc/hexanes, 3:7). H NMR
NMR δ 7.54-7.51 (m, 2 H), 7.42-7.36 (m, 3 H), 2.06-1.99 (m,
1
3
1
3
δ 3.68 (s, 3 H), 2.42-1.15 (m, 12 H), 0.97-0.93 (m, 3 H).
C
9
1
H), 1.73-1.72 (m, 6 H).
C NMR δ 210.0, 139.6, 130.0,
-
1
NMR δ 204.8, 173.4, 51.2, 45.6, 44.2, 43.3, 41.3, 38.8, 38.7,
4.6, 34.6, 28.9, 27.3, 25.30, 25.27, 16.3, 16.1. IR (neat) 1745,
27.8, 127.0, 46.8, 39.0, 36.4, 28.0. IR (neat)1670 cm
Cyclobu tyl P h en yl Keton e (4). Reference 37.
Cyclop en tyl P h en yl Keton e (5). Reference 38.
.
3
1
-
1
714 cm
18 3
. Anal. Calcd for C11H O : C, 66.64; H, 9.15.
Found: C, 66.25; H, 8.99.
3
5
-ter t-Bu tylcycloh exa n on e (15). Reference 42.
-(1-Ad a m a n tyl)h exa n -3-on e (16). The product was iso-
(
(
(
(
(
(
(
(
31) Crossland, R. K.; Servis, K. L. J . Org. Chem. 1970, 35, 3195.
32) McMurry, J . E.; Erion, M. D. J . Am. Chem. Soc. 1985, 107, 2712.
33) Al-Aseer, M. A.; Smith, S. G. J . Org. Chem. 1984, 49, 2608.
34) Posner, G. H.; Brunelle, D. J .; Sinoway, L. Synthesis 1974, 662.
35) Favorsky, M. Al. Bull. Soc. Chim. Fr. 1936, 3, 239.
lated from the crude by flash chromatography (gradient
elution: EtOAc/hexanes, 0:100, 5:95, 10:90). H NMR δ 2.55
(m, 1 H), 2.42 (m, 2 H), 2.05 (m, 1 H), 1.97 (s, 3 H), 1.66 (m, 7
1
36) Stetter, H.; Rauscher, E. Chem. Ber. 1960, 93, 1161.
H, 1.48 (s, 6 H), 1.05 (t, J ) 7.5 Hz, 3 H), 0.78 (d, J ) 7.0 Hz,
1
37) The Sadtler Standard Spectra: IR Grating 7962, H NMR 9894.
13
3
1
H). C NMR δ 212.5, 44.0, 39.4, 38.9, 37.3, 36.4, 34.3, 28.6,
1
38) Aldrich Library of FT-NMR Spectra, 2(2), 11D; Aldrich Library
-
3.6, 7.9. IR (neat) 1716 cm . Anal. Calcd for C16H26O: C,
of FT-IR Spectra, 1(2) 10A.
39) The Standard Sadtler Spectra: IR Grating 26867, 1H NMR
5606.
40) Kuhlmey, S.-R.; Adolph, H.; Rieth, K.; Opitz, G. Liebigs Ann.
Chem. 1979, 617.
41) Maruyama, K.; Iwamoto, H.; Soga, O.; Takuwa, A. Bull. Chem.
Soc. J pn. 1982, 55, 2161.
42) The Standard Sadtler Spectra: IR Grating 12458, 1H NMR
740.
(
81.99; H, 11.18. Found: C, 81.74; H, 11.34.
1
Typ ica l P r oced u r e for th e Cop p er Med ia ted Ad d ition
of Alk ylzin c Br om id es to Activa ted Alk yn es. To a slurry
of Rieke zinc (15.3 mmol) in THF (25 mL) was added methyl
-bromo-2-methylbutane (15.3 mmol), neat via disposable
syringe, and the mixture stirred for 2 h at rt. The Rieke zinc
was allowed to settle, and the supernatant was transferred to
(
(
2
(
5

2
730 J . Org. Chem., Vol. 61, No. 8, 1996
Rieke et al.
a THF (20 mL) solution of CuCN (30 mmol) and lithium
bromide (30 mmol) at 0 °C. The solution was stirred for 10
min, and the temperature was brought to -78 °C. Methyl
propiolate was added neat, and the reaction mixture was
stirred for 4 h at -78 °C. The reaction mixture was then
quenched with 3 M HCl at -78 °C and was stirred for 0.5 h.
The mixture was then warmed to rt over 2 h. The organics
were taken up in ether (20 mL), and the aqueous layer was
extracted with ether (2 × 20 mL). The combined organics were
washed sequentially with water (3 × 20 mL) and brine (20
dure as for compound 17, except bath temperature was
maintained at 0 °C for 18 h. The product was isolated (43%
yield, 85% de based on NMR) from the crude reaction mixture
by flash chromatography (gradient elution: EtOAc/hexanes,
1
0:100, 5:95). H NMR δ 5.56 (s), 5.63 (s), 4.15 (q), 2.48 (m),
1
3
1.59-1.26 (m), 1.15 (s), 1.07 (s), 0.92-0.85 (m), 0.73 (t).
C
NMR δ 170.6, 166.8, 114.5, 116.6, 60.1, 59.4, 41.6, 33.9,33.4,
32.9, 31.8, 30.4, 29.5, 29.2, 26.9, 26.36, 22.42, 14.3, 14.14, 14.05,
14.0, 9.0. IR (neat) 1720, 1627 cm-1. HRMS m/ z for C H28O2
1
5
calcd 240.2089, found 240.2088.
mL) and were dried over MgSO
4
. Chromatography of the
crude on silica gel (EtOAc/hexanes, 1:9) afforded methyl 4,4-
Ack n ow led gm en t. Financial support provided by
the National Institutes of Health (Grant GM 35153) is
gratefully acknowledged.
dimethylhex-2-enoate (17) (6.08 mmol, 77%) as a mixture of
1
isomers (E/Z ) 88/12 by NMR). Major isomer (E): H NMR δ
6
.92 (d, J ) 16 Hz, 1 H), 5.74 (d, J ) 16.5 Hz, 1 H), 3.74 (s, 3
H), 1.39 (q, J ) 7.5, 2 H), 1.03 (s, 6 H), 0.81, (t, J ) 7.5 Hz, 3
H). C NMR δ 167.6, 158.6, 117.5, 51.4, 36.9, 34.6, 25.8, 8.8.
1
3
Su p p or tin g In for m a tion Ava ila ble: Copies of both 1H
-
1
1
IR (neat) 1728, 1653 cm . Minor isomer (Z): H NMR 5.91
d, J ) 13.5 Hz, 1 H), 5.70 (d, J ) 13 Hz, 1 H), 3.69 (s, 3H),
13
and C NMR spectra of 17 and 18 (4 pages). This material is
(
1
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
.51 (q, J ) 7.5 Hz, 2 H), 1.13 (s, 6 H), 0.84 (t, J ) 7.5 Hz, 3
H). HRMS m/ z for C19
16 2
H O (both isomers) calcd 156.1150,
found 156.1151.
E t h yl 3-(1,1-Dim et h ylp r op yl)oct -2-en oa t e (18). The
reaction was performed using the same experimental proce-
J O952104B