Effect of Ethers on Reactions of Butylcoppers with α,β-Unsaturated Ketones in Toluene

Article abstract of DOI:10.1021/jo970831w

Mixtures of butyllithium and copper iodide prepared in toluene react with α,β-unsaturated ketones predominantly in a 1,2-fashion. Addition of various ethers to the system results in some preference for the 1,4-product. The structural characteristics of ethers which influence 1,4-addition have been revealed. Reactions with chiral ethers did not alter the stereochemistry of the product. The results are correlated with the current views on the mechanism of organocuprate reactions.

Full text of DOI:10.1021/jo970831w

J . Org. Chem. 1997, 62, 7637-7643
7637
Effect of Eth er s on Rea ction s of Bu tylcop p er s w ith
r,â-Un sa tu r a ted Keton es in Tolu en e
Celia L. Kingsbury and Robin A. J . Smith*
Department of Chemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand
Received May 8, 1997X
Mixtures of butyllithium and copper iodide prepared in toluene react with R,â-unsaturated ketones
predominantly in a 1,2-fashion. Addition of various ethers to the system results in some preference
for the 1,4-product. The structural characteristics of ethers which influence 1,4-addition have been
revealed. Reactions with chiral ethers did not alter the stereochemistry of the product. The results
are correlated with the current views on the mechanism of organocuprate reactions.
In tr od u ction
The organocopper-mediated 1,4-(conjugate) addition
reaction to R,â-unsaturated ketones (enones) is a widely
used reaction for selective carbon-carbon bond forma-
tion.1 This extensive synthetic application of organocop-
per reagents has promoted efforts to understand the
mechanism of the reaction2 and also the effect of external
influences such as silyl halides3-5 and solvents.5-7 In a
previous paper8 we described the dramatic effect of
diethyl ether (Et2O) on 1,4-addition reactivity of 1:2 CuI/
BuLi mixtures prepared in toluene. This procedure is
exemplified by the reaction of 4,4a,5,6,7,8-hexahydro-4a-
F igu r e 1. Effect of Et2O on 1,2-/1,4-addition to 1 with 1:2
CuI/BuLi in toluene.
methyl-2(3H)-naphthalenone (1) to give various amounts
of the 1,2- and 1,4-addition products, 2 and 3, as depicted
in Scheme 1.
These findings were in accordance with the theoretical
predictions9,10 that a suitable ligand is required to
stabilize a formally copper(III) reaction intermediate (4,
R ) Me,9 Et8) which has been postulated to be on the
1,4-addition reaction mechanistic pathway. It was also
suggested that Et2O could activate an existing organo-
metallic species or facilitate the creation of an entirely
new reagent.
Sch em e 1
In reactions carried out with between 1 and 2 molar
equiv (ME) of Et2O, the amount of 3 which was formed
correlated with the amount of Et2O (Figure 1).
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) Recent Reviews: Perlmutter, P. Conjugate Addition Reactions
in Organic Synthesis; Pergamon Press: Oxford, 1992. Lipshutz, B.
H.; Sengupta, S. Org. React. 1992, 41, 135-631. Kozlowski, J . A. In
Comprehensive Organic Chemistry; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 4, Chapter 1.4.
(2) Smith, R. A. J .; Vellekoop, A. S. Advances in Detailed Reaction
Mechanisms, Vol. 3; Coxon, J . M., Ed.; J AI Press: Greenwich, CT, 1994;
pp 79-130 and references therein.
Given that Et2O does not have any special chemistry,
it was anticipated that other ethers could have similar
influences on the reaction system. Therefore, studies
were undertaken to investigate the effect that variation
of ether structure and basicity had on 1,4-addition
reactivity. Information gained from these studies was
expected to provide further insight into the 1,4-addition
mechanism. An additional aim was to identify chiral
ethers that affected the 1:2 CuI/BuLi mixture in a
manner similar to that of Et2O. It was envisaged that
the use of enantiomerically enriched chiral ethers could
provide a stereochemical mechanistic probe and possibly
lead to an enantioselective 1,4-addition reaction protocol.
(3) Corey, E. J .; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019-6022.
Alexakis, A.; Berlan, J .; Besace, Y. Tetrahedron Lett. 1986, 27, 1047-
1050. Lipshutz, B. H.; J ames, B. Tetrahedron Lett. 1993, 34, 6689-
6692. Bertz, S. H.; Miao, G.; Rossiter, B. E.; Snyder, J . P. J . Am. Chem.
Soc. 1995, 117, 11023-11024. Eriksson, M.; J ohansson, A.; Nilsson,
M. Olsson, T. J . Am. Chem. Soc. 1996, 118, 10904-10905. Bertz, S.
H.; Eriksson, M.; Miao, G.; Snyder, J . P. J . Am. Chem. Soc. 1996, 118,
10906-10907.
(4) Bertz, S. H.; Smith, R. A. J . Tetrahedron 1990, 46, 4091-4100.
(5) Christenson, B.; Ullenius, C.; Håkansson, M.; J agner, S. Tetra-
hedron 1992, 48, 3623-3632 and references therein.
(6) House, H. O.; Wilkins, J . M. J . Org. Chem. 1978, 43, 2443-2454.
(7) Hallnemo, G.; Ullenius, C. Tetrahedron 1983, 39, 1621-1625.
(8) Kingsbury, C. L.: Smith, R. A. J . J . Org. Chem. 1997, 62, 4629-
4634.
(9) Dorigo, A. E.; Wanner, J .; Schleyer, P. von R. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 476-478.
(10) Snyder, J . P. J . Am. Chem. Soc. 1995, 117, 11025-11026.
S0022-3263(97)00831-1 CCC: $14.00 © 1997 American Chemical Society

7638 J . Org. Chem., Vol. 62, No. 22, 1997
Kingsbury and Smith
Ethers have previously been used to achieve enantio-
selectivity in the 1,4-addition reactions of organolithium
compounds with R,â-unsaturated aldimines.11 Of par-
ticular interest for this work was the high selectivity
obtained using (R,R)-1,2-dimethoxy-1,2-diphenylethane
in toluene (Scheme 2).
Sch em e 2
F igu r e 3. 1,2-/1,4-Addition variation with tert-butyl methyl
ether.
Resu lts a n d Discu ssion
Various amounts (ME) of ethers were mixed with a 1:2
CuI/BuLi mixture prepared in toluene, and then 1 was
added as described previously.8 The reactions were
initially carried out with 2 and 5 ME of each ether.
Further investigation of any ether was undertaken if a
significant amount of 1,4-addition was noted. The results
are tabulated in the Experimental Section.
Acyclic Eth er s. 1-Methoxybutane was investigated
as it is structurally similar to Et2O, and the results are
summarized in Figure 2.
F igu r e 4. 1,2-/1,4-Addition variation with diisopropyl ether.
small structural changes to the larger alkyl group of the
ether appeared to cause no significant reactivity modi-
fication.
To further investigate the effect of alkyl branching,
reactions with tert-butyl methyl ether and diisopropyl
ether were undertaken. The results are outlined in
Figures 3 and 4. The amount of 3 produced gradually
increased with increasing amounts of tert-butyl methyl
ether, to a maximum (56%) with 5 ME, which is signifi-
cantly less than that obtained in reactions with 1- or
2-methoxybutane. Presumably the increased steric hin-
drance of the tert-butyl compared with the 2-butyl
component has reduced the effectiveness of the coordina-
tion and as a consequence reduced the 1,4-reactivity. The
deleterious effect of extensive branching is illustrated in
the results from reactions with diisopropyl ether. Al-
though 1,4-addition reactivity was observed, it was less
predominant with only 42% of 3 obtained with 5 ME of
ligand. The alkyl chain length effect, noted previously
with dibutyl ether, may also be a significant factor in this
latter set of reactions.
The scope of the effect of chain length was further
evaluated by carrying out studies with 2-ethoxybutane
and 2-methoxyoctane. The results for these two ethers
were very similar, with 2 predominating in the reactions
using 2 or 5 ME. These data are in sharp contrast with
those obtained with 2-methoxybutane and indicate that
the structural “window” of reactivity enhancement is
quite narrow with respect to the molecular size of the
ether ligand.
F igu r e 2. 1,2-/1,4-Addition variation with 1-methoxybutane.
The results were similar to those obtained with Et2O
(Figure 1). Although the increase in the amount of 3 with
a ME of 1-methoxybutane was less abrupt than with
Et2O, the ultimate maximum yield was comparable. This
indicated that the 1,4-reactivity enhancement was not
unique to Et2O. In contrast, it was surprising to find that
reactions containing either 2 or 5 ME of dibutyl ether
gave predominantly 2. Therefore, it appears that the
alkyl chain length within the ether ligand plays an
important role in promoting 1,4-reactivity.
The effect of alkyl chain branching but without chain
length extension was examined with 2-methoxybutane.
As 2-methoxybutane is chiral the results were particu-
larly significant for the stereochemical aspects of the
research. The product distributions from reactions with
2-methoxybutane were very similar to those obtained
with 1-methoxybutane. Hence, it was concluded that
The product distributions which were observed can be
interpreted in terms of the organometallic system requir-
ing an accessible, ether oxygen, which is only possible
using a ligand containing at least one small alkyl group.
The relatively strong electron-donating effect of the
(11) Tomioka, K.; Shindo, M.; Koga, K. J . Am. Chem. Soc. 1989, 111,
8266-8268.

Effect of Ethers on Reactions of Butylcoppers
J . Org. Chem., Vol. 62, No. 22, 1997 7639
methyl group enhances the donor ability of an ether
oxygen, and from these considerations methyl ethers
were judged to be probably the most useful for further
study. On the basis of this premise, a series of aryl-
substituted alkyl methyl ethers were prepared and
examined. The incorporation of an aryl group makes the
ethers more readily recoverable from the reaction and
provides an opportunity for ligand recycling which is a
desirable feature in asymmetric reactions. Only minor
amounts of 3 were detected from the reactions with
phenyl methyl ether, and a significant amount of 1 was
recovered at high ME. These results presumably reflect
the poor coordinating ability of oxygen directly bound to
an aromatic ring. Reactions with benzyl methyl ether
returned substantial amounts of 1, indicating severe
inhibition of butyl activity, perhaps by preferential direct
reaction of the ligand with the organometallic species.
Several unidentified products were detected in these
reaction product mixtures. The 1,2-/1,4-addition reactiv-
ity with phenethyl methyl ether was similar to that
observed with tert-butyl methyl ether, apart from the
occurrence of some recovered 1 at high ME.
There was minimal effect with less than 1 ME of THF.
However, the amount of 3 detected rapidly increased with
1 to 2 ME of THF and reached a maximum with 3 ME.
Some 1 was recovered from the reactions with amounts
greater than 2 ME. With increasing ME of THF the
amount of 1 recovered appears linked to a decline in the
amount of 3 which is consistent with the notion of
preferential lithium coordination by the additional THF
as discussed previously. The result with 5 ME of THF
illustrates that only minimal additional amounts of
strongly Lewis basic solvents are required to disrupt the
“usual” cuprate activity observed at loadings of 2-3 ME.
The substituted chiral THF derivative, 2-methyltet-
rahydrofuran (2-MeTHF) was also examined in detail,
and the results are presented in Figure 6. Generally,
In summary, for acyclic ethers, the 1,4-activation is not
confined to Et2O although there are quite narrow struc-
tural limits on the types of molecules which are effective.
The two major structural requirements for effective 1,4-
activation are a relatively unencumbered ether oxygen
and a size restriction in terms of allowable alkyl chain
length. Cyclic ethers have less conformational mobility
than acyclics and hence allow examination of basicity
effects without the potential size/conformational compli-
cations revealed in the previous section.
Cyclic Alk yl Eth er s. Tetrahydrofuran (THF) is a
ubiquitous solvent being less conformationally flexible
but a considerably stronger Lewis base than dialkyl
ethers.12 It has been well documented that THF and
other basic solvents tend to decrease the rate of the
diorganocuprate 1,4-addition reaction and also the yield.6,7
An explanation for these influences is that these solvents
effectively compete with the enone for lithium. Coordi-
nation of the enone with lithium is a common feature in
all cuprate mechanistic scenarios.
Reaction of 1 with a 1:2 CuI/BuLi mixture prepared
in THF gave 60 mol % of 2 and 40 mol % of recovered 1.
This product ratio is comparable with that obtained from
the related reaction between methyl cuprate and 14 and
is consistent with the general inhibiting effect of this
solvent on cuprate 1,4-addition reactions. The effect of
stoichiometric amounts of THF on the reactivity of the
1:2 CuI/BuLi mixture in toluene was investigated, and
the results are presented in Figure 5.
F igu r e 6. 1,2-/1,4-Addition variation with 2-MeTHF.
the amount of 3 obtained from these reactions was
greater than that observed with THF. The amount of
recovered 1 from reactions with a high ME of 2-MeTHF
was also significantly lower than with THF, and this may
be associated with the decreased dipolarity-polarizability
of 2-MeTHF compared with THF.13
These results suggest that the cyclic ethers have a dual
role in influencing the 1,4-addition reactivity of the 1:2
CuI/BuLi toluene system. With stoichiometries between
1 and 3 ME, the ligand enhances 1,4-addition, presum-
ably by intermediate stabilization, and behaves similarly
to sterically uncluttered acyclic ethers. At higher ME’s
butyl addition decreases can be related to preferential
lithium coordination with the ether. In order to deter-
mine the effect of strongly donating ethers on the 1,4-
reactivity and especially to probe the necessity of lithium
availability for useful levels of reaction, a series of
potentially strongly coordinating dialkoxyalkanes was
examined.
Dim eth oxya lk a n es. In all of the above reactions at
least 2 ME of an ether was required for maximum 1,4-
addition. This implies that the 1:2 CuI/BuLi mixture in
toluene requires at least two ether oxygens for effective
reaction. Reactions involving dialkoxy compounds in-
troduce two ether oxygens for each ME of additive. 1,2-
Dimethoxyethane (DME) can be considered to be com-
parable in size to 1-methoxybutane and thus allow for
comparison of bidentate effects within the size limitation
disclosed earlier in this report. DME has been included
in studies on the effect of solvent on the ability of
methylcuprate to add to various enones.6 It was found
that increased amounts of enone were recovered from
reactions performed in 1:5 Et2O/DME compared with
(12) Maria, P.-C.; Gal, J .-F. J . Phys. Chem. 1985, 89, 1296-1304.
(13) Abraham, M. H.; Whiting, G. S.; Doherty, R. M.; Shuely, W. J .
J . Chromatogr. 1991, 587, 213-228.
F igu r e 5. 1,2-/1,4-Addition variation with THF.

7640 J . Org. Chem., Vol. 62, No. 22, 1997
Kingsbury and Smith
pure Et2O and that the product ratios from reactions
performed in the Et2O/DME solvent mixture were similar
to that obtained from using 1:5 Et2O/THF. It has been
suggested14 that the basicity of DME should lie between
dioxolane (∆H°(BF3) -68.6 kJ mol-1) and THF (∆H°(BF3)
-90.4 kJ mol-1) because of the inductive effect of the
second oxygen two carbons removed from the first. Given
that the recovery of 1 in reactions containing THF was
attributed to Lewis basicity, it was not surprising to find
that DME displayed a similar effect (Figure 7). The
F igu r e 9. 1,2-/1,4-Addition variation with 1,4-dimethoxybu-
tane.
The influence of 1,3-dimethoxypropane on 1,4-addition
is less than that of DME although appreciable 1,4-activity
was still noted below 1 ME. The addition of greater than
0.5 ME of 1,3-dimethoxypropane to the black 1:2 CuI/
BuLi mixture resulted in the formation of a dense, black
precipitate with a colorless supernatant. A yellow solu-
tion formed instantly upon the addition of 1, which
quickly darkened to orange and then to black as the
precipitate dissolved. The addition of 1 to methylcuprate
in Et2O at -78 °C also immediately produces an orange
solution15 which is considered to be related to the
formation of a cuprate(3d) f alkene(π*) complex.16
Reactions using 1,4-dimethoxybutane, over the 0-3 ME
range, gave similar product distributions to that of
1-methoxybutane (Figure 2). At least 1 ME was required
for significant production of 3, and this was interpreted
as resulting from effective coordination by only one of
the ether oxygens in each molecule of the additive. In
summary, the relative reactivity of the 1,ω-dimethoxy-
alkanes are in accordance with their relative bidentate
chelate stability and especially with DME there is strong
indications that a bidentate chelation to a metal center
is taking place and influencing the 1,4-reactivity.
(S)-2-Meth oxybu ta n e. Two of the ethers which gave
considerable amounts of 1,4-addition over the stoichiom-
etries examined were chiral, and reactions with optically
active 2-methoxybutane were undertaken to examine
stereochemical outcomes. Prochiral enone substrates
were identified for the initial segment of the stereochem-
ical investigation. The influence of Et2O on the reactions
of 1:2 CuI/BuLi in toluene with trans-4-phenyl-3-buten-
2-one (5) or 3,5,5-trimethyl-2-cyclohexen-1-one (6) were
similar to that observed with 1.8 A series of reactions
were carried out with 5 and 6 and a 1:2 CuI/BuLi mixture
containing appropriate stoichiometric amounts of 2-meth-
oxybutane. The 1,2-/1,4-addition ratios obtained are
presented in Table 1 together with the results from
F igu r e 7. 1,2-/1,4-Addition variation with DME.
striking differences between the data for THF and DME
are that significant 1,4-activity is noted with less than 1
ME of DME and the amount of 3 reaches a maximum
with lower ME of DME compared with THF. Reactions
involving 1,2-dimethoxypropane also showed a maximum
in the production of 3; however in this case the maximum
yield was only 50% and was obtained with 1 ME. This
reactivity difference presumably reflects steric hindrance
around the oxygen as noted earlier. The trend of inhibi-
tion of 1,4-reactivity with substitution near the ether
oxygen was continued with 2,3-dimethoxybutane which
gave <30% of 3 and required high ME. Reaction with
1,2-dimethoxy-1,2-diphenylethane gave no detectable
amounts of 3, in concert with the results using phenyl
methyl ether. Given the significant production of 3 with
1 ME of DME and the parallel trends in reactivity of the
substituted 1,2-dimethoxyalkanes with the acyclic ethers,
it seems reasonable to assume that DME is coordinating
and possibly as a bidentate chelate ligand.
The chelation aspect was investigated by using 1,3-
dimethoxypropane and 1,4-dimethoxybutane, which are
progressively less inclined to offer stable chelation op-
portunities. The effects of 1,3-dimethoxypropane and 1,4-
dimethoxybutane on the reactivity of the 1:2 CuI/BuLi
mixture are illustrated in Figures 8 and 9.
Ta ble 1. Effect of 2-Meth oxybu ta n e on 1,2-/1,4-Ad d ition
Ra tio w ith En on es
toluene
CuI + 2BuLi
8 [ ]
en on e8 products
w(2-methoxybutane)
1,2-/1,4-addition ratio
en on e
w ) 0
w ) 2
w ) 3
w ) 4
w ) 5
1
5
6
98/2
91/9
95/5
63/37
20/80
12/88
21/79
13/87
9/91
15/85
3/97
6/94
10/90
reactions with 1 for comparison. Predominant 1,4-addi-
F igu r e 8. 1,2-/1,4-Addition variation with 1,3-dimethoxypro-
pane.
(14) J ackman, L. M.; Petrei, M. M.; Smith, B. D. J . Am. Chem. Soc.
1991, 113, 3451-3458.

Effect of Ethers on Reactions of Butylcoppers
J . Org. Chem., Vol. 62, No. 22, 1997 7641
the benefit of hindsight one can only speculate on how
rapidly organocuprate chemistry with applications to
organic synthesis would have developed if it had not been
carried out with methyllithium in Et2O during its forma-
tive stage.
Exp er im en ta l Section
tion to 5 or 6 was achieved with 2 ME of 2-methoxybu-
tane while a similar selectivity with 1 required about
twice the amount of the ether. These results reinforce
the view that enone 1 is a severe test of 1,4-addition
regioselectivity.
General experimental conditions have been described previ-
ously.8 Chiral GC analysis was carried out using a 30 m ×
0.25 mm i.d., 0.25 µm film thickness, J &W CYCLODEX-B
column, helium carrier gas at 1.1 mL min-1, 25:1 injector split.
HPLC analysis was carried out on a Daicel Chiralcel OD 250
× 4.0 mm column using 10% 2-propanol/hexane, flow rate 0.2
mL min-1 and UV detector (220 nm).
All alcohols were obtained commercially except for 1,4-
butanediol. Dibutyl ether, tert-butyl methyl ether, diisopropyl
ether, and 2-methyltetrahydrofuran were distilled from sodium
under nitrogen. Phenyl methyl ether was vacuum distilled
(95 °C/100 mmHg). THF and DME were freshly distilled from
a sodium/potassium amalgam under argon. 1,2-Dimethoxy-
1,2-diphenylethane was prepared by Dr A. S. Vellekoop.
1,4-Bu ta n ed iol. 2-Butyne-1,4-diol (11.62 g, 135 mmol),
ethyl acetate (250 mL), and platinum(IV) oxide (≈0.3 g) were
shaken under hydrogen (150 psi) for 3 h. The resulting
mixture was filtered through a Celite pad, and the solvents
were removed under reduced pressure. The resulting brown
liquid was distilled using a Kugelrohr apparatus to give 1,4-
butanediol (8.81 g, 72%) (bp 120 °C/10 mmHg) (lit.19 bp 230
°C) as a colorless liquid: 1H NMR δ (ppm) 3.67 (4H, m), 2.98
(2H, broad s, OH), 1.68 (4H, m).
Optically active 2-methoxybutane was prepared from
(S)-(+)-2-butanol in high yield (83%) of excellent, appar-
ent ee (≈94%)17 (cf. Experimental Section). Reactions of
the 1:2 CuI/BuLi mixture and 4 ME of (S)-2-methoxybu-
tane with the enones 5 and 6 were carried out and GC
analyses of the reaction mixtures indicated that the 1,2-
addition products were only minor (<10%) components.
The ee values for the butyl 1,4-addition products to 5 and
6 were obtained by chiral HPLC and GC analyses,
respectively. In both cases the product was found to be
racemic. Five ME of (S)-2-methoxybutane was added to
the 1:2 CuI/BuLi mixture in toluene for the reaction with
1. A 100% excess of 1 was added to the reaction to allow
for the possibility of kinetic resolution. In order to obtain
the complete stereochemical profile of this reaction it was
necessary to obtain the ee of both the product (3) and
enone (1). Chiral GC separated the enantiomers of 1
while it was necessary to form the silyl enol ether of 3
for satisfactory chiral GC separation of the enantiomers.
In this reaction both 1 and the silyl ether from 3 were
found to be racemic. These results demonstrate that
although some of the ethers studied are highly beneficial
for promoting 1,4-addition they do not influence the
stereochemical outcome. The overall stereochemistry
may well be determined during the formation of the
cuprate(3d) f alkene(π*) complex with the ether acting
at a later stage in the overall sequence. The formation
of mixtures of diastereoisomeric cuprate(3d) f alkene(π*)
complexes with 1 has been proposed previously,16 and it
may well be that the high product diastereoselection
observed results from one of the complexes being more
reactive. These results contrast with those obtained
using amino ethers derived from tartaric acid.18 It may
well be that the polydentate features of these chiral
solvents/ligands are a key factor in influencing the
stereochemistry of the reaction.
Eth er P r ep a r a tion . The ethers were prepared20 by the
reaction of sodium methylsulfinyl carbanion21 in dimethyl
sulfoxide (DMSO) with the distilled alcohol followed by treat-
ment with a dialkyl sulfate. Ethers with a boiling point above
120 °C were extracted. The DMSO reactions mixture was
quenched by slow, dropwise addition of water and then
extracted with Et2O. The combined organic phase was washed
with brine and water and dried (MgSO4), and the solvents were
removed under reduced pressure. The crude reaction product
was then vacuum distilled using a Kugelrohr apparatus.
Ethers with boiling points lower than 120 °C were recovered
in low yields using the above extraction procedure; therefore,
an alternate extraction method involving applying a vacuum
(0.4 mmHg) to the briskly stirred DMSO reaction mixture was
used. The volatile materials were collected in a receiver cooled
in liquid nitrogen. Sodium metal was added to the distillate,
and after 1 h, the product was vacuum distilled.
The following ethers were prepared and stored over sodium
under argon: 1-methoxybutane19 (68%), 2-methoxybutane19
(80%), 2-ethoxybutane19 (77%), 2-methoxyoctane22 (bp 50 °C/
20 mmHg, 43%), benzyl methyl ether19 (bp 100 °C/100 mmHg,
81%), phenethyl methyl ether23 (bp 65 °C/16 mmHg, 84%), 1,2-
dimethoxypropane19 (57%), 2,3-dimethoxybutane24 (87%), 1,3-
dimethoxypropane25 (54%), and 1,4-dimethoxybutane26 (bp 120
°C/16 mmHg, 45%).
Con clu sion
Gen er a l Meth od for Or ga n om eta llic Rea ction s. (De-
ta ils of En on e a n d Eth er Ar e Given w ith Ea ch Exa m p le.)
Unless specified otherwise, reactions were as follows: CuI
(0.228 g, 1.2 mmol) was weighed into a dry Schlenk tube, which
was evacuated for 5 min then filled with argon. Dry, degassed
toluene (10 mL) was added, and the resulting white suspension
was cooled to -78 °C, with stirring. BuLi (2.2 mmol) was
added, and the mixture was stirred for 30 min at -78 °C and
The variability in 1,4-/1,2-addition reactivity of the 1:2
CuI/BuLi mixture in toluene with ethers is clearly related
to steric and perhaps electronic effects; however the
reason for the inhibition with long alkyl chains remains
unclear. The proposed 1,4-addition mechanism requires
ether involvement at the reactive intermediate stage and
clearly from this work the essential coordination places
quite definite steric demands on the ligand. Et2O seems
to be one of the best ligands for promoting the transfor-
mation although it is not unique in this respect. With
(19) CRC Handbook of Chemistry and Physics; Lide, D. R., Editor
in Chief; CRC Press: Boca Ratan, FL 1994.
(20) Sjo¨berg, B.; Sjo¨berg, K. Acta Chem. Scand. 1972, 26, 275-278.
(21) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1962, 84, 866-
867. Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1965, 87, 1345-
1353.
(22) Toy, A. D. F. J . Am. Chem. Soc. 1944, 66, 499.
(23) McKillop, A,; Ford, M. E. Tetrahedron 1974, 30, 2467-2475.
(24) Blomberg, C.; Coops, C. Recl. Trav. Chim. 1964, 83, 1083-1095;
Chem. Abstr. 1965, 63, 522b.
(15) Vellekoop, A. S.; Smith, R. A. J . J . Am. Chem. Soc. 1994, 116,
2902-2913.
(16) Bertz, S. H.; Smith, R. A. J . J . Am. Chem. Soc. 1989, 111, 8276-
8277.
(17) Tarbell, D. S.; Paulson, M. C. J . Am. Chem. Soc. 1942, 64,
2842-2844.
(18) Seebach, D.; Hibder, A. Org. Synth. 1983, 61, 24-34 and
references cited therein.
(25) Hogan, J . C.; Gandour, R. D. J . Org. Chem. 1992, 57, 55-61.
(26) Ger. Patent 894,110; Chem. Abstr. 1956, 50, 4201a.

7642 J . Org. Chem., Vol. 62, No. 22, 1997
Kingsbury and Smith
Ch a r t 1

Effect of Ethers on Reactions of Butylcoppers
J . Org. Chem., Vol. 62, No. 22, 1997 7643
then for 15 min at -20 °C. Over this period the suspension
darkened through grey to black. The mixture was then cooled
to -40 °C, inoculated with various amounts of eth er , and
stirred for 10 min. This mixture was cooled to -78 °C; then
en on e (1.0 mmol) and GC internal standard (1.0 mmol) were
added by syringe over 5-10 s. The mixture was stirred for
30 min at -40 °C and then quenched at -40 °C with an
aqueous mixture of saturated ammonium chloride/ammonia
(NH4+/NH3). The resulting biphasic mixture was allowed to
warm to room temperature when two aliquots (≈0.5 mL) were
removed from the organic phase and were added to separate
sample tubes, each containing NH4+/NH3 (≈0.5 mL), and
diluted with hexane (2 mL). The mixtures were shaken until
all solid had dissolved and was allowed to settle, and the
organic phase was analyzed by GC.
by NMR analysis of the (R)-(-)-O-methylmandelic acid ester
(98 ( 2%) and by GC analysis using a â-cyclodextrin column
(98 ( 1%) (cf. Supporting Information).
(S)-(+)-2-Meth oxybu ta n e. This compound was prepared
from (S)-(+)-2-butanol by following the standard volatile ether
preparation method described above and gave (S)-(+)-2-
methoxybutane (83%) (≈94% ee (vide infra)), RD ) +1.668°,
neat, 0.1 dm length, which based on density ) 0.742 g mL-1
,
gives [R]22D ) +22.5°. (lit.17 RD ) +12.2° (neat) from 2-butanol
RD ) +7.5° (neat), i.e. 69% ee). The estimated specific rotation
for pure (S)-(+)-2-methoxybutane, assuming no racemization
during alkylation, is [R]D ) +23.8°.
cis-8a -Bu t yl-3,4,4a ,5,6,7,8,8a -oct a h yd r o-4a -m et h yl-2-
((tr im eth ylsilyl)oxy)n a p h th a len e. The General Method for
Organometallic Reactions using Et2O (230 µL, 2 ME) and 1
(155 µL, 1.0 mmol) was followed except that after 30 min at
-40 °C the reaction mixture was not quenched but cooled to
-78 °C. Et2O (10 mL) was added dropwise over 10 min, and
the solution was warmed to -40 °C when chlorotrimethylsi-
lane (382 µL, 3.0 mmol) and triethylamine (418 µL, 3.0 mmol)
were added. The mixture was removed from the bath, stirred
for 2 h, and then quenched with NH4+/NH3 as usual. The total
Rea ction s of 1:2:w Cu I/Bu Li/Eth er Mixtu r es w ith 1.
All reactions were run using the General Method, eth er
(w(ME)), 1 (155 µL, 1.0 mmol), and n-C12 as the GC internal
standard (227 µL, 1.0 mmol). A black precipitate was obtained
#
after the addition of some diethers, indicated by (Chart 1).
Rea ction of a 1:2 Cu I/Bu Li Mixtu r e w ith 1 in THF . The
procedure was followed as for the General Method, except
freshly distilled, dry degassed THF (10 mL) was used as the
solvent and the entire reaction was carried out at -78 °C. The
reaction mixture went black 30 min after BuLi addition. GC
analysis of the reaction product showed 1 (40 mol %) and 2
(60 mol %).
Rea ction s of 1:2:w Cu I/Bu Li/2-Meth oxybu ta n e Mix-
tu r e w ith 5 or 6. All reactions were carried out using the
General Method, 2-methoxybutane (w(ME)) added directly,
and 5 (0.146 g, 1.0 mmol, in toluene (2 mL)) or 6 (150 µL, 1.0
mmol).
n-Dodecane (n-C12) (227 µL, 1.0 mmol) was used as the GC
internal standard for reactions with 5. The GC column was
programmed 90 f 175 °C, 15 °C min-1. Retention times (tR)
and response factors (Rf) for 5, 1,2-27 and 1,4-addition28
products were
reaction mixture was poured into a separatory funnel, and the
+
reaction Schlenk tube was washed consecutively with NH4
/
NH3 (10 mL) and hexane (10 mL) and shaken until a deep
blue developed and all solids had dissolved. The layers were
then separated. The aqueous layer was extracted with hexane
(2 × 20 mL), and the combined organic extracts were washed
with water (50 mL) and then dried (MgSO4). The mixture was
filtered after approximately 15 min, and solvents were evapo-
rated under reduced pressure to give the product (0.292 g, 99%)
as a colorless oil. Anal. Calcd for C18H34OSi: C, 73.40; H,
11.64. Found: C, 73.56; H, 11.96. IR: νmax (cm-1) (film) 1666
(CdC). 1H NMR (300 MHz) δ (ppm): 4.63 (1H, broad s, H-1),
2.1-1.0 (18 H, m), 0.87 (6H, m, H-9 and H-13), 0.19 (9H, s,
Si-Me3). 13C NMR (75 MHz) δ (ppm): 148.3 (C-2), 113.6 (C-
1), 39.7, 34.3, 33.8, 32.5, 27.0, 26.3, 24.1, 23.2, 22.6, 22.1, 14.3,
0.54 (Si-CH3).
compd
tR (min)
Rf
Rea ction s of 1:2:w Cu I/Bu Li/(S)-2-Meth oxybu ta n e Mix-
tu r es. All reactions were performed using the General
Method for Organometallic Reactions. GC internal standards
were not added as in all reactions the 1,4-addition product was
the major component (>90%).
n-C12
5
1,2-
1,4-
2.0
2.9
5.1
4.3
1.35
0.99
0.95
Rea ction w ith 5. (S)-2-Methoxybutane (523 µL, 4 ME), 5
(0.146 g, 1.0 mmol), and chiral HPLC analysis gave racemic
1,4-addition product (48.3:51.7) (tR 24, 25 min).
Rea ction w ith 6. (S)-2-Methoxybutane (523 µL, 4 ME), 6
(150 µL, 1.0 mmol), and chiral GC analysis gave racemic 1,4-
addition product (50.2:49.8) (90 °C/95 min, 5 °C min-1 f 150
°C, tR 103.2, 103.5 min).
n-Tetradecane (n-C14) (260 µL, 1.0 mmol) was used as the
GC internal standard for reactions with 6. The GC column
was programmed 90 f 130 °C, 7.5 °C min-1
. Under these
conditions the retention times (tR) and response factors (Rf)
for 6, 1,2-8 and 1,4-addition29 products were
Rea ction w ith 1. (S)-2-Methoxybutane (654 µL, 5 ME) and
1 (310 µL, 2.0 mmol) were reacted as described for the
preparation of cis-8a-butyl-3,4,4a,5,6,7,8,8a-octahydro-4a-
methyl-2-((trimethylsilyl)oxy)naphthalene. Chiral GC analysis
showed racemic recovered 1 (49.9:50.1) (150 °C, tR 20.9 (R) and
21.2 (S) min), and silyl enol ether (49.2:50.8) (110 °C/30 min,
0.5 °C min-1 f 145 °C, tR 99.4, 100.4 min).
compd
tR (min)
Rf
n-C14
6
1,2-
1,4-
4.9
1.6
2.0-3.8
4.6
1.70
1.25
1.17
The results are given in Table 1.
(S)-(+)-2-Bu ta n ol. 2-Butanol was resolved with brucine
Ack n ow led gm en t. C.L.K. thanks the Research
Committee of the New Zealand Universities Grants
Committee for a postgraduate scholarship. The chiral
HPLC column was kindly loaned by Dr N. M. Davies,
School of Pharmacy, University of Otago.
via the hydrogen phthalate ester according to published
procedures30,31 in a 34.5% yield, [R]22 ) +13.1° (neat) (lit.30
D
[R]27 ) +13.5° (neat), 97% ee). The ee was also determined
D
(27) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita,
T.; Hatanaka, Y.; Yokoyama, M. J . Org. Chem. 1984, 49, 3904-3912.
(28) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.; Maru-
yama, K. J . Org. Chem. 1982, 47, 119-126.
(29) Lipshutz, B. H.; Ellsworth, E. L.; Siahaan, T. J . J . Am. Chem.
Soc. 1989, 111, 1351-1358.
(30) Pickard, R. H.; Kenyon, J . J . Chem Soc. 1911, 99, 45-72.
(31) Ingersoll, A. W. Org. React. 1944, 2, 376-414. Kantor, S. W.;
Hauser, C. R. J . Am. Chem. Soc. 1953, 75, 1744.
Su p p or tin g In for m a tion Ava ila ble: Ee determination of
(S)-(+)-2-butanol (1 page). This material is 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.
J O970831W