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

Article abstract of DOI:10.1055/s-0031-1290116

Oxidation of alkenyl organocuprates formed from alkenyl halides allows the formation of highly substituted symmetrical 1,3-dienes. Cuprates formed from organolithiums and Grignard reagents can be tolerated and the reaction proceeds with retention of alkenyl geometry. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1290116

298
LETTER
Synthesis of Highly Substituted Symmetrical 1,3-Dienes via Organocuprate
Oxidation
H
ighly Substit
a
uted Sym
m
r
etrical
1
a
,3-Dienes h. J. Aves,a Kieron M. G. O’Connell,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 29 November 2011
The protected alcohols were chosen as examples of al-
kenes bearing alkyl groups, with the alkenyl halides ar-
ranged in both E- and a-configurations. The synthesis of
these compounds was achieved in one or two steps from
commercially available species. Commercially available
alkenyl bromide was protected as the TBDPS ether in
quantitative yield to give 1. E-Alkenyl iodide 2 was syn-
thesised from 3-butyn-1-ol; again the alcohol was protect-
ed as the TBDPS ether in quantitative yield before the
compound was treated with Snieckus reagent14 to give the
boronic acid and subjected to basic conditions and iodine
to furnish the desired E-iodoalkene in 43% yield. Z-
Iodoalkene 3 was synthesised in 62% yield via a Wittig
reaction from the corresponding aldehyde and the requi-
site iodo ylid.15
Abstract: Oxidation of alkenyl organocuprates formed from alke-
nyl halides allows the formation of highly substituted symmetrical
1,3-dienes. Cuprates formed from organolithiums and Grignard re-
agents can be tolerated and the reaction proceeds with retention of
alkenyl geometry.
Key words: cuprates, oxidation, 1,3-diene, homocoupling, alkenyl
halides
The 1,3-diene motif is an important one in synthesis espe-
cially within the context of pericyclic reactions.1 This
functional group is also important in the development of
organic materials.2 Various protocols have therefore been
developed to perform the homocoupling of alkenyl spe-
cies; including, examples mediated by Mg,3 Ni,4 Pd,5 Mn6
and Cu.7 However, these methods suffer from a number of
disadvantages such as the toxicity of the reagents or cata-
lyst, the expense of the catalyst, the need to screen ligands
and, most importantly, the possibility of geometrical
scrambling occurring during coupling. This lack of stereo-
selectivity can also be a problem in Wittig reactions and
other olefination reactions.8
Br
Br
TBDPSCl, imidazole
HO
TBDPSO
CH2Cl2, r.t.
100%
1
(i) TBDPSCl, imidazole, CH2Cl2, r.t.
(ii) i-PP2BH, THF, 0 °C
HO
TBDPSO
Organocuprates are easily oxidised due to their high lying
HOMO,9 and this has been exploited previously in the
synthesis of both C–C and C–N bonds.10 Alkenyl cuprate
oxidation should allow stereoselective coupling and the
organocuprate structure holds apart sterically hindered
ligands due to the 180° C–Cu bond angle and long (1.9 Å)
C–Cu bond length.11 We therefore reasoned that this
methodology would provide an efficient synthesis of
highly substituted 1,3-dienes. Since we had previously de-
veloped the novel, water-soluble oxidant 5 during the
course of our work on aryl organocuprate oxidation,12 we
sought to apply its use to this system as it allowed for easy
workup of reaction mixtures13 without concomitant halo-
genation or oxygenation side reactions.
I
(iii) H2O, H2CO; (iv) NaOH; (v) I2
43%
2
+
–
PPh3
MeO
MeO
MeO
MeO
MeO
MeO
I
O
I
THF, –20 °C
62%
3
Scheme 1 Synthesis of alkenyl halides
Initial studies of the organocuprate oxidation centred on
the homocoupling of a-bromostyrene; pleasingly the 1,3-
diene product 4 was obtained in 86% yield upon oxidation
of the lithio-organocuprate with oxidant 5 (Table 1, entry
1). The use of THF as a solvent was found to be necessary,
as replacement with diethyl ether led to a large decrease in
yield16 and the appearance of large amounts of debromi-
nated starting material.
A number of non-volatile alkenyl halides with varying
alkene substitution patterns and degrees of steric hin-
drance were desired to test our procedure. A number of
these compounds were available commercially; however,
three compounds were prepared in house: protected alco-
hols 1 and 2 and Z-iodostyrenyl compound 3 (Scheme 1).
With these conditions in hand, the homocoupling of a
range of alkenyl halides was then attempted. Gratifyingly,
other alkenyl halides could be homocoupled following the
SYNLETT 2012, 23, 298–300
Advanced online publication: 22.12.2011
x
x.
x
x.
2
0
1
1
DOI: 10.1055/s-0031-1290116; Art ID: D72811ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Highly Substituted Symmetrical 1,3-Dienes
299
Table 1 Synthesis of Symmetrical 1,3-Dienes17
The reaction was also not limited to the use of lithiocu-
prates, as exemplified by the homocoupling of 3 via the
cuprate formed from the corresponding Grignard reagent.
A low temperature, functional group tolerant I/Mg ex-
change was performed on 3 following the procedure of
Knochel and co-workers.20 The resulting Grignard re-
agent was then transmetalated to the magnesiocuprate in
good yield and upon oxidation gave a 63% yield of dimer-
ic species 10 (Table 1, entry 6).
R3
(i) t-BuLi, –78 °C to r.t.
(ii) CuBr•SMe2, –78 °C
R3
R2
R1
R1
X
R1
(iii) 5, THF, –78 °C to r.t.
R2
R2
R3
O
O2N
N
N
Me
5
NO2
In conclusion, we have developed an efficient, stereo-
selective method for the synthesis of highly substituted
1,3-dienes from alkenyl halides using alkenyl cuprate ox-
idation. This discovery is a useful extension of our exist-
ing biaryl coupling methodology. As the use of mild
metalation methods is possible, the reaction should be ap-
plicable to substrates possessing relatively sensitive func-
tionality. Studies are ongoing within our laboratories to
apply this method to the synthesis of natural products and
in diversity-oriented synthesis.21
Entry
1
X
Product
Yield (%)
86
Ph
Br
Br
Ph
4
OTBDPS
OTBDPS
2
3
62
40
6
TBDPSO
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
I
OTBDPS
Acknowledgment
7
Ph
Ph
Ph
The authors thank AstraZeneca and UCB Celltech, the EU, EPSRC,
BBSRC, MRC, Wellcome Trust and the Frances and Augustus
Newman Foundation for funding.
Ph
4
5
Br
Br
79
57
Ph
Ph
8
References and Notes
(1) For applications in natural product synthesis, see:
(a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. Angew. Chem. Int. Ed. 2002, 41,
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D.-M. Synth. Met. 2001, 117, 227.
9
MeO
OMe
OMe
6
I
63a
MeO
MeO
(3) (a) Krasovskiy, A.; Tishkov, A.; del Amo, V.; Mayr, H.;
Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 5010.
(b) Sudan Maji, M.; Pfeifer, T.; Studer, A. Angew. Chem.
Int. Ed. 2008, 47, 9547.
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J. Am. Chem. Soc. 1972, 94, 9234. (b) Takagi, K.; Mimura,
H.; Inokawa, S. Bull. Chem. Soc. Jpn. 1984, 57, 3517.
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(5) For recent examples, see: (a) Alcaraz, L.; Taylor, R. J. K.
Synlett 1997, 791. (b) Eddarir, S.; Rolando, C. J. Fluorine
Chem. 2004, 125, 377. (c) Xu, J. J.; Burton, D. J. J. Fluorine
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OMe
10
a Reaction conditions: (i) i-PrMgCl·LiCl (1.1 equiv), THF, –40 °C;
(ii) CuBr·SMe2 (0.5 equiv), THF, –40 °C; (iii) oxidant 5 (1 equiv),
THF, –40 °C to r.t.
same procedure: via metalation with t-BuLi, transmetala-
tion to copper and oxidation (Table 1).17
The reaction was found to tolerate both alkenyl iodides
and bromides and the full complement of alkene geome-
tries. Protected alcohols 1 and 2 both successfully under-
went the transformation to give 6 and 7, in 62% and 40%
yields, respectively (Table 1, entries 2 and 3).18,19 Fully
substituted hexa-phenyl 1,3-diene 8 was also formed in
good yield (79%; Table 1, entry 4), demonstrating the
utility of this methodology even when using highly hin-
dered substrates.
(7) For the coupling of alkenyl stannanes see, for example:
(a) Piers, E.; McEachern, E. J.; Romero, M. A.; Gladstone,
© Thieme Stuttgart · New York
Synlett 2012, 23, 298–300

300
S. J. Aves et al.
LETTER
P. L. Can. J. Chem. 1997, 75, 694. (b) Itoh, T.; Emoto, S.;
Kondo, M.; Ohara, H.; Tanaka, H.; Torii, S. Electrochim.
Acta 1997, 42, 2133. For alkenyl silanes, see:
(c) Nishihara, Y.; Ikegashira, K.; Toriyama, F.; Mori, A.;
Hiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 985. (d) Itami,
K.; Ushiogi, Y.; Nokami, T.; Ohashi, Y.; Yoshida, J. I. Org.
Lett. 2004, 6, 3695.
equiv) in THF (2 mL) at –78 °C and was stirred for 30 min.
A solution of oxidant 5 (1 equiv) in THF (4 mL) was then
added and the solution was stirred at –78 °C for 30 min and
at r.t. for 1 h. The resultant solution was filtered through a
plug of silica eluting with PE–Et2O (1:1) and the solvent was
removed in vacuo. The residue was purified by flash column
chromatography.
(8) Vedejs, E.; Fang, H. W. J. Org. Chem. 1984, 49, 210.
(9) Mori, S.; Hirai, A.; Nakamura, M.; Nakamura, E.
Tetrahedron 2000, 56, 2805.
(18) Selected data for compound 7: clear oil; Rf 0.13 (PE–CH2Cl2,
5:1). IR (CDCl3): 2930, 2857, 1427, 1105, 1088, 986, 692
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.67–7.70 (m, 8 H),
7.36–7.43 (m, 12 H), 6.03 (m, 2 H), 5.57 (m, 2 H), 3.71 (t,
J = 6.8 Hz, 4 H), 2.34 (app q, J = 6.8 Hz, 4 H), 1.07 (s, 18
H). 13C NMR (125 MHz, CDCl3): d = 135.6 (CH), 134.0 (C),
132.2 (CH), 129.5 (CH), 128.8 (CH), 127.6 (CH), 63.7
(CH2), 36.0 (CH2), 26.8 (Me), 19.2 (C). HRMS (ESI):
m/z [M + Na]+ calcd for C40H50O2Si2Na: 641.3242; found:
641.3250.
(19) Selected data for compound 6: white amorphous solid;
Rf 0.08 (PE–EtOAc, 10:1). IR (CDCl3): 3063, 2927, 2861,
1464, 1426, 1390, 1363, 1103, 1037, 735, 757 cm–1. 1H
NMR (500 MHz, CDCl3): d = 7.65–7.67 (m, 8 H), 7.37–7.45
(m, 12 H), 6.08 (m, 2 H), 5.81 (d, J = 2.5 Hz, 2 H), 3.56 (t,
J = 6.8 Hz, 4 H), 2.49 (app t, J = 6.8 Hz, 4 H), 1.21 (s, 18 H).
13C NMR (125 MHz, CDCl3): d = 143.0 (C), 136.1 (CH),
134.2 (C), 131.6 (CH2), 129.1 (CH), 127.6 (CH), 61.3 (CH2),
40.0 (CH2), 28.6 (Me), 18.4 (C). HRMS (ESI): m/z [M + Na
+ 2 H]+ calcd for C40H52O2Si2Na: 643.3398; found:
643.3396.
(10) For recent 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.
(11) 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.
(12) (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.
(13) Oxidant-derived by-products can be easily removed by
passage through a plug of silica gel or an aqueous acid wash.
(14) Kalinin, A. V.; Scherer, S.; Snieckus, V. Angew. Chem. Int.
Ed. 2003, 42, 3399.
(20) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6,
4215.
(21) For recent reviews on DOS, see: (a) Galloway, W. R. J. D.;
Isidro-Llobet, A.; Spring, D. R. Nat. Commun. 2010, 1, 801.
(b) Schreiber, S. L. Nature (London) 2009, 457, 153.
(c) Nielsen, E.; Schreiber, S. L. Angew. Chem. Int. Ed. 2008,
47, 48. (d) Galloway, W. R. J. D.; Bender, A.; Welch, M.;
Spring, D. R. Chem. Commun. 2009, 2446. (e) Cordier, C.;
Morton, D.; Murrison, S.; Nelson, A.; O’Leary-Steele, C.
Nat. Prod. Rep. 2008, 25, 719. (f) Dow, M.; Fisher, M.;
James, T.; Marchetti, F.; Nelson, A. Org. Biomol. Chem.
2012, in press; DOI: 10.1039/C1OB06098H.
(15) Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35,
2827.
(16) In Et2O the yield dropped to ca. 5%.
(17) Typical Procedure for Alkenyl Halide Homocoupling:
Alkenyl halide (1 equiv) was dissolved in THF (4 mL) and
the mixture was cooled to –78 °C. t-Butyllithium (1.7 M in
pentane, 2 equiv) was added dropwise and the solution was
stirred at –78 °C for 30 min, and then allowed to warm to r.t.
over 10 min. The resultant solution was transferred via
cannula onto a precooled suspension of CuBr·SMe2 (0.5
Synlett 2012, 23, 298–300
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