Synthesis of highly substituted symmetrical 1,3-dienes via tandem carbocupration and organocuprate oxidation

Article abstract of DOI:10.1055/s-0030-1259024

A 'one-pot' tandem carbocupration/organocuprate oxidation allows the formation of highly substituted symmetrical 1,3-dienes from alkynyl esters and alkyl organolithium or Grignard reagents with three C-C bonds being formed in one step. Georg Thieme Verlag

Full text of DOI:10.1055/s-0030-1259024

LETTER
2839
Synthesis of Highly Substituted Symmetrical 1,3-Dienes via Tandem
Carbocupration and Organocuprate Oxidation
Tandem
C
arbo
a
cupration
a
r
nd Orga
a
nocuprate
Oh
xidation J. Aves,a Kurt G. Pike,b David R. Spring*a
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336362; E-mail: spring@ch.cam.ac.uk
b
AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK
Received 2 September 2010
Retrosynthetically it can be envisaged that 1,3-diene 1 can
be formed as a result of oxidative homo-coupling of alke-
nyl cuprate 2 which is in turn formed by the carbocupra-
tion of alkynyl ester 3 by organocuprate 4 (Scheme 2). If
isomerisation of the alkenyl cuprate is minimised then
geometrically pure 1,3-dienes will result. This tandem re-
action would allow the formation of three C–C bonds in
one step and the desired 1,4-substituted motif to be effi-
ciently built up from simple starting materials, unlike oth-
er routes to this class of compound which require the
synthesis and isolation of dimethyl bromomethylfuma-
rate.2b–2d Isolated reports of tandem carbocupration/oxida-
tion of alkynyl esters in the literature5,6 highlighted that
this was a viable approach to the desired 1,3-diene system
and that a study to find more general conditions could
prove worthwhile. The disconnection outlined in
Scheme 2 is conceptually similar to that of the oxidation
of lithium enolates to form 1,4-dicarbonyl compounds7
but at a different oxidation level. This latter class of reac-
tion has been exploited recently by Baran and co-workers
in the total synthesis of several complex natural products.8
Abstract: A ‘one-pot’ tandem carbocupration/organocuprate oxi-
dation allows the formation of highly substituted symmetrical 1,3-
dienes from alkynyl esters and alkyl organolithium or Grignard re-
agents with three C–C bonds being formed in one step.
Key words: cuprates, oxidation, carbocupration, 1,3-diene, tandem
reaction
The substituted 2,3-bis(alkylidene)succinate motif (1) is a
versatile building block in organic chemistry, able to un-
dergo a range of reactions including Diels–Alder and
Michael additions.1 It is however difficult to access rapid-
ly, especially in a geometrically pure form with 1,4-sub-
stitution.2
During the course of our work on organocuprate
oxidation3,4 we demonstrated that aryl and alkenyl orga-
nocuprates could be generated from the corresponding ha-
lides and oxidatively coupled under the influence of
dinitroarene oxidant 5. As in our work on directed lithia-
tion and oxidation3b we reasoned that the use of organoha-
lides could be avoided if another copper-mediated process
were used to form the alkenyl cuprate for oxidation: a car-
bocupration reaction (Scheme 1). This in conjunction
with oxidation of the resulting organocuprate would allow
molecular complexity to be rapidly built up in a ‘one-pot’
tandem reaction that would allow access to the desired
2,3-bis(alkylidene)succinate motif.
R1
O
O
CuM
OR2
R2O
R2O
2
O
2
R1
1
R1
previously:
CO2R2
R12CuM
+
alkenyl
halide
formation
3
4
metalation
Scheme 2 Retrosynthetic route to the 1,4-substituted 2,3-bis(alkyli-
dene)succinate motif (M = Li or MgCl)
R
R
M
R
X
transmetalation
R
this work:
The geometrical purity of 1 is of vital importance. This re-
quires complete selectivity in the carbocupration and cou-
pling steps. An analysis of the literature suggested that
these aspects can be managed by careful choice of reac-
tion conditions.
R2CuM
CuM
carbocupration
2
Scheme 1 Comparison of methods of formation of alkenyl cuprate
species (X = I, Br, M = Li, Mg, Zn etc.)
The carbocupration of an alkynyl ester with a Gilman re-
agent was first carried out by Corey,5 closely followed by
others.9 It was found that the ratio of syn to anti addition
products across the alkyne was both solvent and tempera-
ture dependent, with ethereal solvents and low tempera-
tures giving the best selectivity. The mechanism of
addition was later elucidated by Ullenius and co-
SYNLETT 2010, No. 19, pp 2839–2842
Advanced online publication: 03.11.2010
DOI: 10.1055/s-0030-1259024; Art ID: D23810ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

2840
S. J. Aves et al.
LETTER
workers10 via 13C NMR studies, where these workers dis- tenuates the basicity of the initial alkyl organocuprate thus
covered that the production of the anti addition product avoiding a competing deprotonation of the acetylinic pro-
was as a result of isomerisation of the alkenyl cuprate ton in ethyl propiolate. This competing reaction (verses
through an allenolate-type structure. This isomerisation carbocupration) is not an available pathway in the case of
did not take place in THF or if lithium salts were excluded internal alkynes. The lack of solution structure studies on
from the cuprate in Et2O.
magnesiocuprates in the literature makes it difficult to as-
certain what effect changing the counterion has on reac-
tivity here. However, it has been noted that changing the
cations present in organocuprate clusters alters the reac-
tivity of the complex,14 which could go some way to ex-
plaining this difference in reactivity.
Previous studies11 on the oxidation of alkenyl cuprates
produced via carbocupration of substituted acetylenes
showed that the homocoupling of the ligands on copper
was completely stereoselective, retaining the geometry of
the intermediate cuprate.
This information was used to guide the initial optimisation
studies which focused upon the formation of 8a,b via the
carbocupration of alkynyl esters 7a,b with the organocu-
prates 6a–c. We initially examined the conditions of
Marino, which utilised a heterocuprate reagent to perform
the carbocupration and bromine as the oxidant.6 This
however gave a complex reaction mixture (Table 1, entry
1). We therefore employed a homocuprate in the carbocu-
pration step and also our previously developed dinitroare-
ne oxidant 5 (Figure 1),3a which had been successful in
oxidising aryl organocuprates and allowed for easy work-
up of reaction mixtures.12 THF was used as solvent and
the low reaction temperature was retained as these were
thought to be the most favourable conditions for the for-
mation of the desired product (see above). Since different
types of oxidant can cause reactions other than
homocoupling11b of the intermediate cuprate it was pleas-
ing to find that oxidant 5 gave the desired 1,3-diene prod-
uct (Table 1, entry 2). In addition, both ligands were
transferred from the alkyl organocuprate to the alkyne
which is not always the case in carbocupration reactions.13
This is advantageous as it is less wasteful if more complex
cuprates resulting from advanced reaction intermediates
are used. In these studies minor amounts (ca. 10%) of
product resulting from anti addition in the carbocupration
step were observed; these could be removed in purifica-
tion by flash column chromatography.
Table 1 Optimisation of Reaction Conditions
i) R3
CO2R4, –78 °C
CO2R4
R1
R3
R1
7a: R3 = H, R4 = Et
7b: R3 = Ph, R4 = Me
R1R2CuM
ii) oxidant, –78 °C to r.t.
solvent
R3
R4O2C
6a: R1 = n-Bu, R2 = n-hexynyl
M = Li
6b: R1 = R2 = n-Bu
M = Li
6c: R1 = R2 = n-Bu
M = MgCl
.
8a,b
Entry Cuprate Alkynyl ester Oxidant Solvent Yield 8 (%)
1
2
3
4
5
6a
6b
6c
6b
6c
7a
7a
7a
7b
7b
Br2
5
Et2O
THF
THF
THF
THF
0
55a
85
47
10
5
5
5
a Protonated carbocupration adduct was also isolated in 23% yield.
With optimised conditions for the ‘one-pot’ process in
hand, reactions with a range of substitution patterns on
both the alkyne and the organocuprate were examined in
order to explore the scope of the methodology (Table 2).
A slight excess of organocuprate was used in order to push
the reaction to completion, as unreacted alkynyl ester had
been observed in some of the initial reactions. The appro-
priate alkyl organometallic reagent was selected accord-
ing to the substitution pattern of the alkyne in order to
maximise yields.
O
O2N
N
N
Me
NO2
5
Figure 1 The structure of dinitroarene oxidant 5
The tandem carbocupration/oxidation reaction proceeded
in 22–85% yield, allowing the formation of three C–C
bonds in one pot. Use of an excess of alkyl cuprate had the
desired effect of increasing the yield in the case of sub-
strate 8b (Table 2, entry 2). Since these molecules are tet-
ra- and hexa-substituted 1,3-dienes they are necessarily
very sterically hindered, and so the fact that they can be
formed even with use of the less reactive Me2CuLi shows
the utility of this strategy. It is postulated that the 180° C–
Cu–C bond angle and long (1.9 Å) C–Cu bond length15
enable the formation of these systems as steric clashing
between the ligands on copper is minimised during the
It was also observed that the metal counterion present
from the organometallic reagent used to form the initial
cuprate 6 affected the outcome of the reaction, with use of
a magnesiocuprate giving the best results for the reaction
of ethyl propiolate (Table 1, entry 3). However, for the in-
ternal alkyne methyl phenylpropiolate, it was the lithiocu-
prate (Table 1, entry 4) that gave the best results as
reactions with the magnesiocuprate did not go to comple-
tion and oxidation appeared less facile (Table 1, entry 5).
The reason for this selectivity is not immediately clear,
but it is possible that the more Lewis acidic magnesium at-
Synlett 2010, No. 19, 2839–2842 © Thieme Stuttgart · New York

LETTER
Tandem Carbocupration and Organocuprate Oxidation
2841
course of the reaction. Again, the dienes were formed with
high geometrical selectivity and with syn addition prod-
ucts predominating; the minor amount of undesired iso-
mer being removed by column chromatography.
Acknowledgment
We thank the BBSRC and AstraZeneca for funding (DTA and
CASE award to S.J.A.).
References and Notes
Table 2 Synthesis of Symmetrical 1,3-Dienes
i) 0.5 equiv CuBr⋅SMe2, –78 °C
CO2R4
R3
(1) (a) Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y.
Tetrahedron Lett. 1987, 28, 6671. (b) Tarnchompoo, B.;
Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron Lett.
1987, 28, 6675. (c) Kotera, M.; Lehn, J.-M.; Vigneron, J.-P.
Tetrahedron 1995, 51, 1953.
R3
CO2R4,
ii) 0.95 equiv
–78 °C
R1
7a–c
R1
R1M
iii) 5, –78 °C to r.t., THF
R3
R4O2C
9
(2) For recent examples of the synthesis of 2,3-
bis(alkylidene)succinate compounds, see: (a) Kiji, J.;
Okano, T.; Fujii, E.; Tsuji, J. Synthesis 1997, 869. (b) Béji,
F.; Lebreton, J.; Villiéras, J.; Amri, H. Tetrahedron 2001,
57, 9959. (c) Béji, F.; Lebreton, J.; Villiéras, J.; Amri, H.
Synth. Commun. 2002, 32, 3273. (d) Patel, R. M.; Argade,
N. P. J. Org. Chem. 2007, 72, 4900.
(3) (a) Surry, D. S.; Su, X.; Fox, D. J.; Franckevicius, V.;
Macdonald, S. J. F.; Spring, D. R. Angew. Chem. Int. Ed.
2005, 44, 1870. (b) Surry, D. S.; Fox, D. J.; Macdonald, S. J.
F.; Spring, D. R. Chem. Commun. 2005, 2589. (c) Su, X.;
Fox, D. J.; Blackwell, D. T.; Tanaka, K.; Spring, D. R.
Chem. Commun. 2006, 3883. (d) Su, X.; Surry, D. S.;
Spandl, R. J.; Spring, D. R. Org. Lett. 2008, 10, 2593.
(e) Su, X.; Thomas, G. L.; Galloway, W. R. J. D.; Surry,
D. S.; Spandl, R. J.; Spring, D. R. Synthesis 2009, 3880.
(4) For reviews, see: (a) Surry, D. S.; Spring, D. R. Chem. Soc.
Rev. 2006, 35, 218. (b) Aves, S. J.; Spring, D. R. In The
Chemistry of Organocopper Compounds; Rappoport, Z.;
Marek, I., Eds.; Wiley: Chichester, 2009, 585.
8a–f
Entry Organometallic 9 Alkynyl Product
Yield
(%)
ester
H
CO2Et
n-Bu
1
2
n-BuMgCl
n-BuLi
7a
7b
85
n-Bu
EtO2C
H
8a
Ph
CO2Me
n-Bu
53
64
22a
47
38
n-Bu
MeO2C
Ph
8b
CO2Et
n-Bu
3
4
5
6
n-BuLi
i-PrMgCl
MeLi
7c
7a
7b
7c
n-Bu
EtO2C
8c
(5) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc.
H
CO2Et
1969, 91, 1851.
(6) Marino, J. P.; Linderman, R. J. J. Org. Chem. 1983, 48,
4621.
(7) Ito, Y.; Konoike, T.; Harada, T.; Saegusa, T. J. Am. Chem.
Soc. 1977, 99, 1487.
i-Pr
i-Pr
EtO2C
H
8d
Ph
(8) For examples of carbonyl enolate couplings, see: (a) Baran,
P. S.; Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D.
Angew. Chem. Int. Ed. 2005, 44, 606. (b) Baran, P. S.;
DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083.
(9) (a) Siddall, J. B.; Biskup, M.; Fried, J. H. J. Am. Chem. Soc.
1969, 91, 1853. (b) Klein, J.; Turkel, R. M. J. Am. Chem.
Soc. 1969, 91, 6186.
(10) Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold, A.; Krause,
N. Chem. Eur. J. 1998, 4, 2051.
(11) (a) Normant, J. F.; Cahiez, G.; Chuit, C.; Villieras, J.
J. Organomet. Chem. 1974, 77, 269. (b) For a different
oxidation pathway following carbocupration, see: Zhang,
D. H.; Ready, J. M. Org. Lett. 2005, 7, 5681.
CO2Me
MeO2C
Ph
8e
CO2Et
MeLi
EtO2C
8f
a Competing Cu acetylide formation observed leading to lower yields.
(12) Oxidant-derived by-products can easily be removed by an
acidic wash during workup or by filtration through a pad of
silica gel.
(13) Taylor, R. J. K. In Organocopper Reagents: A Practical
Approach; Taylor, R. J. K., Ed.; Oxford University Press:
Oxford, 1994, 13.
(14) Lipshutz, B. H. In Organometallics in Synthesis: A Manual;
Schlosser, M., Ed.; Wiley: Chichester, 2002, 2nd ed., 665.
(15) van Koten, G.; James, S. L.; Jastrzebski, J. T. B. H. In
Comprehensive Organometallic Chemistry II, Vol. 3; Abel,
E. W.; Stone, F. G. A.; Wilkinson, G.; Wardell, J. L., Eds.;
Pergamon: Oxford, 1995, 57.
(16) General Procedure for Tandem Carbocupration/
Oxidation Reaction: A solution of the requisite
organometallic reagent (2.10 mmol) was added to a
suspension of CuBr·SMe2 (216 mg, 1.05 mmol) in THF
In conclusion, we have developed a ‘one-pot’ tandem car-
bocupration/oxidation of alkynyl esters to allow rapid ac-
cess to highly substituted symmetrical 1,3-dienes of the
2,3-bis(alkylidene)succinate class.16 The reaction allows
three C–C bonds to be formed in one step, with good syn
selectivity in carbocupration, and a range of substitution
patterns is also tolerated. As molecular complexity can be
quickly built up from simple starting materials to yield a
versatile synthetic intermediate we envisage that this
methodology will prove useful in a wide synthetic context
with applications in both target- and diversity-oriented
synthesis.17
Synlett 2010, No. 19, 2839–2842 © Thieme Stuttgart · New York

2842
S. J. Aves et al.
LETTER
m/z [M + Na]+ calcd for C20H34O4Na: 361.2349; found:
(4 mL) at –78 °C and stirred for 30 min. Alkyne (2.00 mmol)
was added dropwise and the reaction was stirred for 3 h at
–78 °C. A solution of oxidant 5 (589 mg, 2.00 mmol) in THF
(4 mL) was added, the reaction was allowed to stir at –78 °C
for 30 min and then allowed to warm to r.t. over 1 h. The
resulting solution was filtered through a plug of silica,
eluting with either PE–Et2O (1:1) or i-hexane–Et2O (1:1)
and the solvent was removed in vacuo. The residue was
purified by flash column chromatography.
(2E,3E)-Diethyl 2,3-dipentylidenesuccinate (8a):
colourless oil; Rf 0.25 (PE–EtOAc, 10:1). IR (Neat): 2957,
2932, 2871, 1712 (C=O), 1631 (C=C), 1464, 1363, 1231,
1206 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.01 (t, 2 H,
J = 7.6 Hz), 4.16 (q, 4 H, J = 7.1 Hz), 2.02 (app q, 4 H, J =
7.2 Hz), 1.36–1.46 (m, 4 H), 1.26–1.36 (m, 4 H), 1.24 (t, 6
H, J = 7.1 Hz), 0.90 (t, 6 H, J = 7.2 Hz). 13C NMR (125 MHz,
CDCl3): d = 166.5 (C), 146.3 (CH), 127.6 (C), 60.5 (CH2),
30.3 (CH2), 29.3 (CH2), 22.4 (CH2), 14.2 (Me), 13.8 (Me).
HRMS (ESI): m/z [M + H]+ calcd for C18H31O4: 311.2217;
found: 311.2217.
361.2348.
(2E,3E)-Diethyl 2,3-bis(2-methylpropylidene)succinate
(8d): yellow oil; Rf 0.28 (PE–EtOAc, 10:1). IR (CDCl3):
2963, 2872, 1712 (C=O), 1231, 1038, 731 cm–1. 1H NMR
(400 MHz, CDCl3): d = 6.77 (d, 2 H, J = 10.7 Hz), 4.15 (q,
4 H, J = 7.1 Hz), 2.35 (m, 2 H), 1.22 (t, 6 H, J = 7.1 Hz), 0.96
(m, 12 H). 13C NMR (125 MHz, CDCl3): d = 166.6 (C),
151.9 (CH), 125.2 (C), 60.6 (CH2), 29.0 (CH), 21.4 (Me),
14.2 (Me). HRMS (ESI): m/z [M + Na]+ calcd for
C16H26O4Na: 305.1723; found: 305.1708.
(2Z,3Z)-Dimethyl 2,3-bis(1-phenylethylidene)succinate
(8e): white amorphous solid; Rf 0.04 (PE–EtOAc, 10:1). IR
(CDCl3): 2950, 1712 (C=O), 1433, 1221, 1199, 1043, 907,
720, 699 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.15–7.29
(m, 10 H), 3.37 (s, 6 H), 2.10 (s, 6 H). 13C NMR (125 MHz,
CDCl3): d = 167.6 (C), 149.8 (C), 142.5 (C), 128.0 (CH),
127.5 (CH), 127.1 (C), 126.5 (CH), 51.4 (Me), 23.0 (Me).
HRMS (ESI): m/z [M + H]+ calcd for C22H23O4: 351.1596;
found: 351.1601.
(2Z,3Z)-Dimethyl 2,3-bis(1-phenylpentylidene)succinate
(8b): colourless crystals; mp 60–64 °C (i-hexane–EtOAc);
Rf 0.13 (PE–EtOAc, 10:1). IR (CDCl3): 2957, 2871, 1717
(C=O), 1429, 1305, 1219, 1166, 1022 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.28–7.39 (m, 6 H), 7.18–7.23 (m, 4 H),
3.45 (s, 6 H), 2.53 (m, 4 H), 1.18–1.32 (m, 8 H), 0.83 (t, 6 H,
J = 6.7 Hz). 13C NMR (125 MHz, CDCl3): d = 168.0 (C),
154.0 (C), 141.2 (C), 128.0 (CH), 127.3 (CH), 127.1 (CH),
126.5 (C), 51.5 (Me), 36.1 (CH2), 29.1 (CH2), 22.9 (CH2),
13.9 (Me). HRMS (ESI): m/z [M + Na]+ calcd for
Diethyl 2,3-di(propan-2-ylidene)succinate(8f): colourless
oil; Rf 0.31 (PE–EtOAc, 10:1). IR (CDCl3): 2982, 2911,
1709 (C=O), 1625 (C=C), 1444, 1220, 1076 cm–1. 1H NMR
(400 MHz, CDCl3): d = 4.12 (q, 4 H, J = 7.1 Hz), 2.16 (s,
6 H), 1.72 (s, 6 H), 1.22 (t, 6 H, J = 7.1 Hz). 13C NMR (125
MHz, CDCl3): d = 167.4 (C), 149.1 (C), 125.7 (C), 59.9
(CH2), 23.7 (Me), 22.1 (Me), 14.2 (Me). LCMS (ES+):
m/z = 255 [M + H]+. Spectroscopic data were consistent with
the literature values.18
(17) For recent reviews on DOS, see: (a) Schreiber, S. L. Nature
(London) 2009, 457, 153. (b) Galloway, W. R. J. D.; Spring,
D. R. Expert Opin. Drug Discovery 2009, 4, 467.
(c) Nielsen, E.; Schreiber, S. L. Angew. Chem. Int. Ed. 2008,
47, 48. (d) Spandl, R.; Bender, A.; Spring, D. R. Org.
Biomol. Chem. 2008, 6, 1149. (e) Spandl, R.; Diaz-Gavilan,
M.; O’Connell, K. M. G.; Thomas, G. L.; Spring, D. R.
Chem. Rec. 2008, 8, 129.
C28H34O4Na: 457.2349; found: 457.2368.
(2E,3E)-Diethyl 2,3-di(hexan-2-ylidene)succinate (8c):
colourless oil; Rf 0.37 (PE–EtOAc, 10:1). IR (CDCl3): 2957,
2927, 2867, 1709 (C=O), 1613 (C=C), 1459, 1206, 1092,
1039 cm–1. 1H NMR (400 MHz, CDCl3): d = 4.11 (q, 4 H,
J = 7.1 Hz), 2.13 (s, 6 H), 2.04 (br s, 4 H), 1.32–1.40 (m, 4
H), 1.22–1.29 (m, 4 H), 1.21 (t, 6 H, J = 7.1 Hz), 0.86 (t, 6
H, J = 7.3 Hz). 13C NMR (125 MHz, CDCl3): d = 167.6 (C),
152.7 (C), 125.2 (C), 59.8 (CH2), 37.0 (CH2), 29.1 (CH2),
22.8 (CH2), 19.7 (Me), 14.2 (Me), 13.9 (Me). HRMS (ESI):
(18) Maercker, A.; van de Flierdt, J.; Girreser, U. Tetrahedron
2000, 56, 3373.
Synlett 2010, No. 19, 2839–2842 © Thieme Stuttgart · New York