Effect of additives on the stereochemical integrity and reactivity of α-alkoxycarbonyl alkenylcopper intermediates. Optimal conditions for the synthesis of isomerically pure tetrasubstituted alkenes

Article abstract of DOI:10.1021/jo034465u

A systematic study on the effect of additives on the isomerizability of 1-alkoxycarbonyl alkenylcopper(I) intermediates revealed that the lithium chelator 12-crown-4 is significantly more efficient than HMPA at retarding isomerization. On the other hand, 12-crown-4 alone is unable to promote effective coupling with alkyl halides. The combination of 12-crown-4 and a reduced amount of HMPA, however, led to an improved procedure for the preparation of useful, isomerically pure tetrasubstituted alkenes such as allylation reagents and skipped dienes.

Full text of DOI:10.1021/jo034465u

SCHEME 1. F or m a tion of Tr i- a n d
Tetr a su bstitu ted Alk en es by Ca r bocu p r a tion /
Electr op h ilic Tr a p p in g of Acetylen ic Ester s 1
Effect of Ad d itives on th e Ster eoch em ica l
In tegr ity a n d Rea ctivity of
r-Alk oxyca r bon yl Alk en ylcop p er
In ter m ed ia tes. Op tim a l Con d ition s for th e
Syn th esis of Isom er ica lly P u r e
Tetr a su bstitu ted Alk en es
Na Zhu and Dennis G. Hall*
Department of Chemistry, University of Alberta,
Edmonton, Alberta T6G 2G2, Canada
dennis.hall@ualberta.ca
Received April 12, 2003
Abstr a ct: A systematic study on the effect of additives on
the isomerizability of 1-alkoxycarbonyl alkenylcopper(I)
intermediates revealed that the lithium chelator 12-crown-4
is significantly more efficient than HMPA at retarding
isomerization. On the other hand, 12-crown-4 alone is unable
to promote effective coupling with alkyl halides. The com-
bination of 12-crown-4 and a reduced amount of HMPA,
however, led to an improved procedure for the preparation
of useful, isomerically pure tetrasubstituted alkenes such
as allylation reagents and skipped dienes.
catalyzed allylborations,7 we found that iodomethylbor-
onates were sufficiently reactive, under optimal condi-
tions with HMPA as a cosolvent, for trapping 3 with no
loss of stereochemical integrity and afford tetrasubsti-
tuted allylboronates with overall cis double functional-
ization (8 with R3 ) CH2B(OR)2 in Scheme 1). In contrast,
poor yields and selectivities were observed when THF
alone was used as solvent. These results suggest that the
HMPA stabilizes alkenylcopper intermediate 3, thereby
allowing the electrophile to trap it prior to isomerization
to 5, hence avoiding erosion of selectivity and formation
of trans-addition products 9. We became interested in
further examining the effect of additives and understand-
ing the role of HMPA in the isomerization and alkylation
of 1-alkoxycarbonyl alkenylcopper intermediates. More-
over, we were attracted by the possibility of replacing or
minimizing the required amount of carcinogenic additive
HMPA. Herein, we describe a systematic survey of
additives that led to an optimized procedure for the
formation of useful, isomerically pure tetrasubstituted
alkenes, as well as providing new insight on the crucial
effect of HMPA and other molecules on the stability and
reactivity of 1-alkoxycarbonyl alkenylcopper intermedi-
ates.
Stereocontrol in the formation of tri- and tetrasubsti-
tuted alkenes remains a challenging problem in organic
synthesis.1 In this respect, the conjugate addition of
organocopper reagents to acetylenic esters followed by a
cis-selective, low-temperature protic quench is one of the
most efficient methods to access isomerically pure, trisub-
stituted R,â-unsaturated esters (6 in Scheme 1).2,3 Un-
fortunately, unless very potent alkyl halides (R3X) are
employed as electrophiles,4 no efficient extensions of this
chemistry are available for the construction of tetrasub-
stituted alkenes (8) in high overall cis-addition selectivity.
The alkylation step is hampered by the low reactivity of
the 1-alkoxycarbonyl alkenylcopper(I) intermediate 3,
and its tendency to isomerize via a copper allenolate (4)
at higher temperatures (typically above -30 °C) (Scheme
1).5
In the course of our studies on the preparation of
tetrasubstituted allylboronates6 for use in Lewis acid-
Excess lithium was long known to have a deleterious
effect on the stereochemical integrity of intermediate 3,
leading to the mechanistic hypothesis that the “free”
lithium from R2CuLi‚LiX promotes the isomerization
process through a lithium allenolate.8 As proposed by
Krause and co-workers, the superior ability of polar
solvents (e.g., THF over Et2O) at retarding the isomer-
ization of 3 is due to their more efficient coordination of
the free lithium cation.5 This is supported by experiments
where lithium was excluded through use of salt-free
R2CuLi.9 A priori, our previous observations6 on the
* To whom correspondence should be addressed. Fax: 780-492-8231.
Phone: 780-492-3141.
(1) For recent approaches, see: (a) Marino, J . P.; Nguyen, H. N. J .
Org. Chem. 2002, 67, 6291-6296. (b) Thadani, A. N.; Rawal, V. H.
Org. Lett. 2002, 4, 4317-4320. (c) Zhou, C.; Emrich, D. E.; Larock, R.
C. Org. Lett. 2003, 5, 1579-1582 and references cited therein.
(2) (a) Corey, E. J .; Katzenellenbogen, J . A. J . Am. Chem. Soc. 1969,
91, 1851-1852. (b) Siddall, J . B.; Biskup, M.; Fried, J . H. J . Am. Chem.
Soc. 1969, 91, 1853-1854.
(3) For reviews on synthetic applications of organocuprates, see: (a)
Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631. (b)
Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186-
204.
(4) For example, see: Hall, D. G.; Chapdelaine, D.; Pre´ville, P.;
Deslongchamps, P. Synlett 1994, 660-663.
(5) Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold, A.; Krause, N.
Chem. Eur. J . 1998, 4, 2051-2058 and references cited therein.
(6) Kennedy, J . W. J .; Hall, D. G. J . Am. Chem. Soc. 2002, 124, 898-
899.
(7) Kennedy, J . W. J .; Hall, D. G. J . Am. Chem. Soc. 2002, 124,
11586-11587.
(8) Klein, J .; Levene, R. J . Chem. Soc., Perkin Trans. 2 1973, 1971-
1978.
10.1021/jo034465u CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/28/2003
6066
J . Org. Chem. 2003, 68, 6066-6069

TABLE 1. Effect of Ad d itives on th e Ster eoch em ica l
In tegr ity of r-Alk oxyca r bon yl Alk en ylcop p er
In ter m ed ia tes (see Sch em e 1)a
TABLE 2. Op tim iza tion of Ad d itive Stoich iom etr y in
th e Selective F or m a tion of Tetr a su bstitu ted
Allylbor on a te 8a a
ratio of
yieldb
(%)
ratio of
entry
additive
none
HMPA
HMPA
HMPA
HMPA
DMPU
DMEU
DMSO
P(OEt)3
PPh3
P(t-Bu)3
tmeda
Dabco
sparteine
pyridine
bipyridine
Bu4NCN
Bu4NI
18-crown-6
15-crown-5
12-crown-4
12-crown-4
equivalenceb
6a :7a c
12-crown-4
(equiv)
HMPA
(equiv)
entry
8a :9a c
1
2
3
4
5
6
7
8
9
1:1
9:1
4:1
2.5:1
2:1
1:2
1:2
1:2
1:2
1:2
2.5:1
1:1
1.5:1
6:1
1:2
1:2
1:2
1:2
2.5:1
4:1
9:1
9
6
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
2
3
4
5
6
7
0
1
1
2
2
2
1
9
9
1
1
0
2
2
70
70
37
53
20
50
66
>19:1
19:1
9:1
19:1
19:1
>19:1
>19:1
a
Reactions were conducted with Me2CuBr-LiBr prepared from
MeLi and CuBr-SMe2 and 3 equiv of ICH2BPin as described in
the text and Supporting Information (typical scale: 1 mmol).
1
11
12
13
14
15
16
17
18
19
20
21
22
b
Yields based on the mass of isolated products after flash
chromatography purification. Entries 3-5 are accompanied by
variable amounts of trisubstituted alkene from the protic quench,
indicative of incomplete alkylation. c Estimated by integration of
representative 1H NMR signals.
isomer 7a as the major product.10 In comparison, while
the use of 9 equiv of HMPA gave little isomerization, with
a 9:1 ratio of isomers 6a and 7a , a rather modest 2:1 ratio
was observed in the presence of only 2 equiv (entries
2-5). Yet, of over 15 additives surveyed, few fared as well
as HMPA. The strong lithium chelator 12-crown-4 (en-
tries 21 and 22), however, was significantly more efficient
than HMPA at retarding alkenylcopper isomerization
when both were compared under similar conditions (2
equiv).
4:1
a
Reactions were conducted with Me2CuBr-LiBr prepared from
MeLi and CuBr-SMe2 as described in the text and Supporting
b
Information (typical scale: 1 mmol). With respect to the starting
alkynoate 1a . c Estimated by integration of representative 1H
NMR signals on crude reaction product isolated after a protic
quench.
beneficial effect of HMPA at promoting stereoselective
alkylation may thus be explained by its ability to
sequester lithium and retard the isomerization process
long enough to allow cis-addition intermediate 3 to react
completely with the electrophile. Alternatively, HMPA
may favor higher reaction yield and selectivity by ac-
celerating the alkylation step without necessarily stabi-
lizing intermediate 3. We envisaged that a systematic
study comparing different additives known to coordinate
lithium cations may help clarify the putative role of
HMPA in this reaction. By using pentynoic ester 1a as a
model substrate with Me2CuLi‚LiBr, the effect of a large
number of additives on the isomerizability of 3 was
investigated (Table 1).
Next we set out to seek optimal conditions, using
different relative stoichiometries of 12-crown-4 and HMPA,
to alkylate intermediates 3 and provide tetrasubstituted
alkenes in high isomeric purity. Given our interest in the
resulting allylboronates,6,7 we chose to use the electro-
phile iodomethylboron pinacolate as a model to fine-tune
the use of additives in the reaction procedure (Table 2).
The ratio of cis- and trans-addition isomers 8a and 9a
1
was measured by H NMR on purified product obtained
after 2 h of reaction. As previously demonstrated,6 as
much as 9 equiv of HMPA are required to obtain 8a in
high cis-addition selectivity (entry 1). The data shown
in Table 2 indicate that 12-crown-4, when used alone, is
unable to provide high yields of alkylated product (entry
5). This observation is not surprising given the known
retarding effect of crown ethers in SN2 reactions with
organocuprates.11 Although the results of entries 2-4
show that the use of HMPA effectively leads to higher
yields of allylboronate product, we ought to minimize the
required amount of this carcinogenic additive. To obtain
8a in acceptable yield and high isomeric purity, a
satisfactory compromise was found in the combined use
of 12-crown-4 (1 equiv) and HMPA (2 equiv) (entry 7).
For each entry, the additive (2 equiv) was added at -78
°C after the conjugate addition step. The temperature
was then allowed to warm to 0 °C in the course of 2 h.
At this point, an aqueous quench was carried out and
the ratio of the respective Z- and E-trisubstituted isomers
1
6a and 7a was measured by H NMR on a sample of the
crude reaction product. Under these conditions, control
runs in the absence of any additive provided a 1:1 ratio
of isomers (entry 1). Similarly, a large number of addi-
tives were ineffective, and even led to the trans-addition
(10) The reason for the predominance of 7a in these cases is
unknown.
(11) Ouannes, C.; Dressaire, G.; Langlois, Y. Tetrahedron Lett. 1977,
815-818.
(9) (a) Krause, N. Tetrahedron Lett. 1989, 30, 5219-5222. (b)
Nilsson, K.; Andersson, T.; Ullenius, C. J . Organomet. Chem. 1997,
545-546, 591-595.
J . Org. Chem, Vol. 68, No. 15, 2003 6067

TABLE 3. Eva lu a tion of Differ en t Electr op h iles for th e
Syn th esis of Tetr a su bstitu ted Alk en es 8a
From the results of Table 1, it is clear that 12-crown-4
is highly efficient at stabilizing and retarding the isomer-
ization of 1-alkoxycarbonyl alkenylcopper intermediates
3. This behavior is in agreement with the hypothesis
associating the stereochemical integrity of 3 with the
lithium-coordination ability of the solvent or the additive.
Of the three crown-ethers of Table 1, 12-crown-4 is indeed
the most efficient lithium coordinator of this series.12 On
the other hand, the results of Table 2 suggest that 12-
crown-4 does not provide any advantage in the coupling
step with carbon-based electrophiles to make tetrasub-
stituted alkenes. Whereas HMPA is not as efficient for
stabilizing intermediate 3 (as much as 9 equiv are
required to match the efficiency of 2 equiv of 12-crown-
4), it does appear to play a highly beneficial role in the
alkylation step.13 The exact mechanism of carbon-carbon
bond coupling involving intermediates of type 3 is not
known.14 One of the more likely possibilities is that of
halide displacement by copper to give a copper(III)
intermediate, followed by reductive elimination with
concomitant formation of the coupling product.15 Presum-
ably, HMPA can facilitate the coupling of 3 to the
electrophile by stabilizing the transient, high-energy
copper(III) intermediate of type R3(alkenyl)CuR2.16 Un-
like 12-crown-4, the dual role of HMPA in this reaction
may thus be assigned to its ability to coordinate with both
lithium and copper. The combined use of these two
additives (1 equiv of 12-crown-4 and 2 equiv of HMPA)
makes efficient use of their respective abilities, and leads
to a significant decrease in the amount of HMPA previ-
ously required in this reaction.
To test the generality of the optimized procedure, other
alkyl halide electrophiles were evaluated toward access-
ing useful tetrasubstituted alkenes in high isomeric
purity (Table 3). Other allylation reagents such as 8b and
8c were isolated respectively in good and modest yield
with excellent cis-addition selectivity (entries 1 and 2).
Furthermore, allylic bromides were found to react ef-
ficiently, providing skipped dienes such as 8e-g (entries
4-6). The hindered di-s-butyl cuprate was equally effec-
tive (entry 7), and other useful alkynoate esters can be
used, as shown by the formation of alkene 8i containing
a masked formyl group (entry 8). Among other alkyl
halides, methyl iodide and butyl iodide gave a low yield
of product. Other types of cuprates such as the cyano-
cuprates were not tested due to precedents documenting
their inferior ability at preserving the stereochemical
integrity of the resulting alkenylcopper intermediate.5
alkynoate cuprate
electrophile
(R3X)
yieldc
entry
(R1)
(R2)
productb (%)
1
2
3
4
5
6
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
ICH2SnBu3
ICH2SiMe3
BrCH2Ph
BrCH2CHdCH2
BrCH2C(Br)dCH2
BrCH2CHdCMe2
8b
8c
8d
8e
8f
8g
8h
8i
80
30
40
76
57
78
72
85
7d Et
s-Bu BrCH2CHdCH2
8e TBDPSOCH2 Me
BrCH2CHdCH2
a
For entries 1-6 and 8, reactions were conducted with
Me2CuBr-LiBr prepared from MeLi and CuBr-SMe2 and 3 equiv
of electrophile (4 equiv for entries 3-5) as described in the text
b
and the Supporting Information (typical scale: 1 mmol). Cis-
addition isomer with over 19:1 selectivity estimated by integration
of representative 1H NMR signals. Entries 2 and 3 were ac-
companied by variable amounts of trisubstituted alkene from the
protic quench, indicative of incomplete alkylation. c Yields based
on the mass of isolated products after flash chromatography
d
purification. The di-s-butyl cuprate was formed from s-BuLi as
described in the Supporting Information. e The methyl ester was
employed.
In summary, a systematic study of additives revealed
that 12-crown-4 is most effective at protecting the ster-
eochemical integrity of 1-alkoxycarbonyl alkenylcopper-
(I) intermediates (3) originating from the conjugate
addition of R2CuLi‚LiX onto acetylenic esters. Yet, as 12-
crown-4 was found inept at increasing the reactivity of
intermediates 3, a small amount of HMPA is required to
promote the alkylation step. With a judicious combination
of these two additives (12-crown-4 and HMPA), however,
it is possible to overcome the inherent isomerization
tendency and low reactivity of 1-alkoxycarbonyl alkenyl-
copper(I) intermediates. By using an optimized procedure
that successfully reduces the amount of HMPA previously
required in this reaction, isomerically pure tetrasubsti-
tuted alkenes were synthesized in high isomeric purity
from different alkynoate esters, cuprates, and electro-
philes. These compounds are difficult to access by other
means, and applications of the allylating reagents and
skipped dienes thus formed will be reported in due
course.
(12) Kimura, K.; Shono, T. In Cation Binding by Macrocycles;
Complexation of Cationic Species by Crown Ethers; , Inoue Y.; Gokel,
G. W., Eds.; Marcel Dekker Inc.: New York, 1990; Chapter 10, pp 429-
463.
(13) Piers and co-workers have previously reported on the use of
HMPA as cosolvent in the alkylation of the more configurationally
stable 2-trimethylstannyl 1-dimethylaminocarbonyl alkenylcuprate
intermediates from acetylenic amides: Piers, E.; Chong, J . M.; Keay,
B. A. Tetrahedron Lett. 1985, 26, 6265-6268.
(14) For a review on the mechanism and structure of organocopper
reagents, see: Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. 2000,
39, 3750-3771.
(15) (a) Dorigo, A. E.; Wanner, J .; Schleyer, P. v. R. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 476-478. (b) Snyder, J . P. J . Am. Chem. Soc.
1995, 117, 11025-11026. (c) Nakamura, E.; Mori, S.; Morokuma, K.
J . Am. Chem. Soc. 1998, 120, 8273-8274. (d) Mori, S.; Nakamura, E.;
Morokuma, K. J . Am. Chem. Soc. 2000, 122, 7294-7307.
(16) This suggestion may be likened to the known effect of HMPA
ligation at altering the oxidation potential of Sm(II): Shabangi, M.;
Kuhlman, M. L.; Flowers, R. A., II Org. Lett. 1999, 1, 2133-2135.
Exp er im en ta l Section
Gen er a l P r oced u r e for Com p ou n d s 8b -i (Ta ble 3). A
slurry of CuBr‚Me2S (0.208 g, 1.010 mmol) in dry THF (12 mL)
at 0 °C under N2 was treated with MeLi (1.40 M in Et2O, 1.40
mL, 2.00 mmol). When a clear and colorless solution formed,
the flask was placed in an acetone/CO2 bath (-78 °C) and ethyl
2-pentynoate (140 µL, 1.00 mmol) was added dropwise. The
resulting light yellow mixture was stirred at -78 °C for 1 h and
then treated sequentially with 12-crown-4 (161 µL, 1.00 mmol),
HMPA (346 µL, 2.00 mmol), and the electrophile (3 or 4 mmol,
see Table 3). The mixture was allowed to warm at 0 °C for 2 to
3 h. The reaction was quenched with NH4Cl(aq) (5 mL) and the
layers were separated. The aqueous layer was extracted with
ether (3 × 10 mL). The combined organic layers were washed
6068 J . Org. Chem., Vol. 68, No. 15, 2003

with water (5 × 10 mL) and brine (10 mL), dried (anhydrous
Na2SO4), and evaporated to give the crude product as an oil.
The crude product was purified by flash chromatography on
silica gel (Et2O/hexanes) to give a colorless oil. The ratio of cis-
and trans-addition isomers 8 and 9 was measured on the crude
reaction mixture according to the height and integration of
signals from the allylic protons.
authors thank Dr. J ason Kennedy for helpful discus-
sions.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details, representative model procedures for the prepara-
tion of 8a and other tetrasubstituted alkenes, characterization
1
data (MS and NMR) and copies of H and 13C NMR spectra
for all compounds of Table 3 (8b-i). This material is available
Ack n ow led gm en t. This work was funded by the
Natural Sciences and Engineering Research Council
(NSERC) of Canada and the University of Alberta. The
free of charge via the Internet at http://pubs.acs.org.
J O034465U
J . Org. Chem, Vol. 68, No. 15, 2003 6069