Pd(II)-catalyzed highly regio-and stereoselective assembly of C-C double bonds: An efficient method for the synthesis of 2,4-dihalo-1,3,5-trienes from alkynols

Article abstract of DOI:10.1021/ol302730x

A highly efficient method for the synthesis of 2,4-dihalo-1,3,5-trienes from alkynols was developed. This chemistry allows access to multiple conjugated double bonds in a single step with high stereoselectivity.

Full text of DOI:10.1021/ol302730x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd(II)-Catalyzed Highly Regio- and
Stereoselective Assembly of CꢀC Double
Bonds: An Efficient Method for the Synthesis
of 2,4-Dihalo-1,3,5-trienes from Alkynols
Huanfeng Jiang,* Yang Gao, Wanqing Wu, and Yubing Huang
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, PR China
jianghf@scut.edu.cn
Received October 2, 2012
ABSTRACT
A highly efficient method for the synthesis of 2,4-dihalo-1,3,5-trienes from alkynols was developed. This chemistry allows access to multiple
conjugated double bonds in a single step with high stereoselectivity.
The development of mild and efficient methods for the
synthesis of complex molecular skeletons is the central
focus of modern organic chemistry.1 1,3,5-Trienes and
polyenes with their conjugated double bonds are known
to be valuable synthons that have widespread application
in biological chemistry, natural product synthesis and
material science.2 Consequently, the stereoselective synthe-
sis of conjugated polyenes has attracted great attention,
and a number of methods have been reported,3 most of
which are based on two types of reactions: (1) transition-
metal-catalyzed cross-couplings involving Heck, Suzuki,
Hiyama, Stille and Negishi reactions,4 and (2) condensa-
tion reactions such as Wittig and HornerꢀWadsworthꢀ
Emmons (HWE) olefinations.5 Very recently, Larock et al.
utilized the vinylpalladium species to react with internal
alkynes to build polyene structures (Scheme 1A).6 Mean-
while, Nagorny’s group constructed polyenes through
bifunctional olefin sequential condensations with alde-
hydes under basic conditions (Scheme 1B).7 Despite these
achievements in this fascinating research area, the further
development of efficient and practical procedures to
(1) (a) Trost, B. M. Science 1983, 219, 245. (b) Trost, B. M. Science
1991, 254, 1471. (c) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
(d) Shenvi, R. A.; O’ Malley, D. P.; Baran, P. S. Acc. Chem. Res. 2009,
42, 530. (e) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (e) Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215.
€
(2) (a) Burghart, J.; Bruckner, R. Angew. Chem., Int. Ed. 2008, 47,
(4) Examples for transition-metal-catalyzed cross-couplings in the
synthesis of polyenes: (a) Zhang, X.; Larock, R. C. Org. Lett. 2003, 5,
2993. (b) Lipshutz, B. H.; Lindsley, C. J. Am. Chem. Soc. 1997, 119,
4555. (c) Babudri, F.; Naso, F. J. Org. Chem. 1997, 62, 3291. (d) Huang,
J. M.; Zhou, L.; Jiang, H. F. Angew. Chem. 2006, 118, 1979. (d) Angew.
Chem., Int. Ed. 2006, 45, 1945. (e) Chatterjee, T.; Dey, R.; Ranu, B. C.
New J. Chem. 2011, 35, 1103. (f) Burke, M. D.; Gillis, E. P. J. Am. Chem.
Soc. 2007, 129, 6716. (g) Lee, S. K.; Gray, K. C.; Paek, J. S.; Burke, M. D.
J. Am. Chem. Soc. 2008, 130, 466.
(5) Examples for Wittig and HWE reactions in the synthesis of
alkenes: (a) Gottschling, S. E.; Krasik, P.; Levin, D. Org. Process Res.
Dev. 2006, 10, 1296. (b) Wang, G.; Huang, Z.; Negishi, E. Org. Lett.
2008, 10, 3223.
7664. (b) Lu, C. K.; Chou, H. N.; Lee, C. K.; Lee, T. H. Org. Lett. 2005,
7, 3893. (c) Ishida, K.; Lincke, T.; Hertweck, C. Angew. Chem., Int. Ed.
2012, 51, 5470. (d) Davis, R.; Kumar, N. S. S.; Abraham, S.; Suresh,
C. H.; Rath, N. P.; Tamaoki, N.; Das, S. J. Phys. Chem. C 2008, 112,
2137. (e) Sonoda, Y.; Goto, M.; Tsuzuki, S.; Tamaoki, N. J. Phys. Chem.
A 2007, 111, 13441. (f) Sonoda, Y.; Goto, M.; Tsuzuki, S.; Tamaoki, N.
J. Phys. Chem. A 2006, 110, 13379. (g) Abraham, S.; Mallia, V. A.;
Ratheesh, V.; Tamaoki, N.; Das, S. J. Am. Chem. Soc. 2006, 128, 7692.
(h) Lightfoot, A. P.; Twiddle, S. J. R.; Whiting, A. Org. Biomol. Chem.
2005, 3, 3167. (i) Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc.
2005, 127, 8004.
(3) For recent reviews of polyene synthesis, refer to: (a) Sobotka, H.;
Bloch, E. Chem. Rev. 1944, 34, 435. (b) Thirsk, C.; Whiting, A. J. Chem.
Soc., Perkin Trans. 1 2002, 999. (c) Krasnaya, Zh. A.; Tatikolov, A. S.
Russ. Chem. Bull., Int. Ed. 2003, 52, 1641. (d) Babudri, F.; Farinola,
G. M.; Naso, F. J. Mater. Chem. 2004, 14, 11.
(6) (a) Zhang, X.; Larock, R. C. Org. Lett. 2003, 5, 2993. (b) Zhou,
C. X.; Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5, 1579.
(7) Cichowicz, N. R.; Nagorny, P. Org. Lett. 2012, 14, 1058.
r
10.1021/ol302730x
XXXX American Chemical Society

construct a 1,3,5-triene structure that minimizes the use of
special reagents, cost, time and steps remains highly desir-
able. Herein, we disclose a highly efficient method to con-
struct diverse 2,4-dihalo-1,3,5-trienes from propargylic
alcohols, providing quick access to multiple conjugated double
bonds with high selectivity in a single step (Scheme 1C). The
vinyl halogen moiety in the triene products can be easily
fuctionalized, thus making it a valuable synthon.8
As pioneered by Meyer, Schuster and Rupe,9 pro-
pargylic alcohols are versatile synthetic reagents in syn-
thetic organic chemistry. Apart from MeyerꢀSchuster and
Rupe rearrangement,10 many other elegant reactions have
utilization of propargylic alcohols as a practical and
versatile alkenylation reagent,14 in this work, we focus on
the possibility of constructing multisubstituted polyenes
using these readily available starting materials.
Our initial efforts were made to evaluate the palladium
catalysts for the nucleopalladation of 2-methylbut-3-yn-
2-ol (1a) to synthesize (E)-3,6-dibromo-2,7-dimethylocta-
2,4,6-triene (3a) with LiBr as the additive. As shown in
Table 1, Pd(II)-catalysts including Pd2(dba)3 and PdCl2
could afford the desired products, and Pd(OAc)2 proved
to be optimal (entries 1ꢀ3). The solvent was found to
have a dramatic impact on the efficiency of the reaction
(entries 3ꢀ8). Notably, HOAc was identified as the most
suitable medium for the formation of 3a (entry 3). Among
the various additives examined, LiBr gave the best result
(entry 3, 9, 10). Plus, the optimal reaction temperature
appeared to be 60 °C. Higher or lower reaction tempera-
tures just led to a decrease in the yield. However, there was
a significant increase in the yield when prolonging the
reaction time to 8 h, and the desired product was obtained
in 96% GC yield. The presence of phosphine ligands
inhibited this chemical process (entries 11ꢀ12). Thus, 1a
(0.5 mmol), Pd(OAc)2 (5 mol %), LiBr (1 mmol), and
HOAc (2 mL) as solvent at 60 °C were chosen as the
optimized conditions.
Scheme 1. Strategies for the Synthesis of Trienes
Under these optimized reaction conditions, the reaction
was applied to a range of substrates. A wide variety of tert-
propargylic alcohols successfully afforded the correspond-
ing 2,4-dibromo-1,3,5-triene derivatives (Scheme 2).
This transformation proceeded smoothly with high stereo-
selectivity and afforded the single E-type configuration
been developed.11 For instance, the SN20 displacement of
propargylic compounds with organometallic reagents (Au,
Rh, Zr, etc.) is one of the most commonly used methods to
prepare allenes.12 In analogy to this method, we have
reported a palladium-catalyzed method to prepare allenes
from propargylic alcohols,13 in which the allenes were
presumed to be generated directly through β-OH elimina-
tion. As part of our ongoing research program on the
Table 1. Optimization of Reaction Conditions for the Synthesis
of (E)-3,6-Dibromo-2,7-dimethy-locta-2,4,6,-triene from 1aa
entry
[Pd]
PdCl2
additive
solvent
yieldb (%)
1
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
CuBr2
NH4Br
LiBr
LiBr
HOAc
HOAc
HOAc
Toluene
CH3CN
DMF
85
(8) (a) Kitamura, T.; Kobayashi, S.; Taniguchi, H. J. Am. Chem. Soc.
1986, 108, 2641. (b) Kabir, M. S.; Lorenz, M.; Cook, J. M. J. Org. Chem.
2010, 75, 3626. (c) Cohen, T.; Poeth, T. J. Am. Chem. Soc. 1972, 94, 4363.
(d) Chopa, A. B.; Dorn, V. B.; Badajoz, M. A.; Lockhart, M. T. J. Org.
Chem. 2004, 69, 3801.
(9) (a) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819. (b) Rupe,
H.; Glenz, K. Justus Liebigs Ann. Chem. 1924, 436, 195.
(10) (a) Rupe, H.; Kambli, E. Helv. Chim. Acta 1926, 9, 672.
(b) Rupe, H.; Kambli, E. Justus Liebigs Ann. Chem. 1927, 459, 215.
(c) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 431.
(11) (a) Ikeda, M.; Miyake, Y.; Nishibayashi, Y. Organometallics
2012, 31, 3810. (b) Hu, S. H.; Hager, L. P. J. Am. Chem. Soc. 1999, 121,
872. (c) Tian, G. Q.; Kaiser, T.; Yang, J. Org. Lett. 2010, 12, 288.
(d) Yuki, M.; Miyake, Y.; Nishibayashi, Y. Organometallics 2010, 29,
5994. (e) Inada, Y.; Nishibayashi, Y.; Hidai, M.; Uemura, S. J. Am.
Chem. Soc. 2002, 124, 15172.
(12) (a) Huang, W.; Shen, Q. S.; Wang, J. L.; Zhou, X. G. J. Org.
Chem. 2008, 73, 1586. (b) Marshall, J. A.; Wolf, M. A. J. Org. Chem.
1996, 61, 3238. (c) Riveiros, R.; Rodrıguez, D.; Sestelo, J. P.; Sarandeses,
´
L. A. Org. Lett. 2006, 8, 1403. (d) Zhu, Y. X.; Yin, G. W.; Hong, D.; Lu,
P.; Wang, Y. G. Org. Lett. 2011, 13, 1024. (e) Pu, X. T.; Ready, J. M.
J. Am. Chem. Soc. 2008, 130, 10874.
(13) Jiang, H. F.; Liu, X. H.; Zhou, L. Chem.;Eur. J. 2008, 14,
11305.
2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
80
3
96 (93)
37
4
5
trace
n.d.
n.d.
15
6
7
DMSO
Dioxane
HOAc
HOAc
HOAc
HOAc
8
9
79
10
11c
12d
12
56
18
a Reaction conditions: unless otherwise noted, all reactions were
performed with 1a (0.5 mmol), Pd-catalyst (5 mol %), LiBr (1 mmol) in
indicated solvent (2 mL) at 60 °C for 8 h. b Determined by GC using
dodecane as the internal standard. Data in parentheses are the yield of
isolated product. n.d. = not detected. c Phosphorus ligand dimethylbis-
diphenylphosphinoxanthene (10 mol %) was added. d Phosphorus
ligand 2-di-tert-butylphosphino-20,40,60-triisopropylbiphenyl (10 mol %)
was added, and 3-bromo-3-methylbut-1-yne was the main product.
B
Org. Lett., Vol. XX, No. XX, XXXX

products in moderate to excellent yields for those alkynols
substituted with the same groups (R1 = R2). For example,
the reaction of 2-methylbut-3-yn-2-ol (1a) or 3-ethylpent-
1-yn-3-ol (1b) led to the corresponding products 3a and 3b
in 93 and 92% isolated yields, respectively. Notably,
cycloalkane substituted alkynols 1d, 1e could also be
transformed to the desired products 3d, 3e. In the cases
where R1 and R2 were different, the reaction could still
proceed in high isolated yields, but only the formation of
the central double bond was stereospecific. Interestingly,
when one of the substituents is an aromatic group, the
reaction afforded a single regioisomer (all E-type con-
figuration) with a slight decrease in yield. The stereochem-
istry of 3l and 3nwasdetermined by1H NMR and NOESY
spectra.15 Moreover, this transformation was compatible
with alkynols that contained Cl- and Br-substituted aryl
rings, which could be used for further transformations.
The electronic effects of the substituents on the phenyl
were also tested. A series of para-substituted 2-phenylbut-
3-yn-2-ols, including some with electron-donating groups
(ꢀOMe,ꢀMe) and some with electron-withdrawing groups
(ꢀF, ꢀCl, ꢀBr), were converted into the corresponding
trienes, and the alkynols bearing electron-donating groups
afforded lower yields since acetophenone became the main
products (3lꢀp).
Scheme 2. Pd(II)-Catalyzed Synthesis of
2,4-Dibromo-1,3,5-triene Derivatives from Alkynolsa
Importantly, unsymmetrically substituted trienes could
also be constructed using this general and efficient method.
It is particularly worthy that these unsymmetrical products
also showed high stereoselectivity. Further, the aromatic
groups of these unsymmetric products (3qꢀv) are specifi-
cally in the trans position of the bromine atoms. The
stereochemistry of 3v was further confirmed by 1H NMR
and NOESY spectra.15
To our delight, this method could be successfully applied
to the synthesis of 2,4-dichloro-1,3,5-trienes when switch-
ing the additive from LiBr to CuCl2 2H2O. Both the alkyl-
and aryl-subsituted alkynols could be transferred to the
desired trienes in good isolated yields (75ꢀ85%) with high
stereoselectivity (Scheme 3).
a The reactions were carried out at 60 °C, using alkynols (0.5 mmol),
LiBr (1 mmol), Pd(OAc)2 (5 mol %) in HOAc (2 mL) for 8 h. Yields refer
to the isolated yields. bAlkyl-substitute alkynol (0.25 mmol) and aryl-
substituted alkynol (0.5 mmol) were used. The ratios of isomers (3fꢀ3i)
were listed in the Supporting Information, and the Z/E ratios of 3tꢀ3v
were determined by GC or NMR.
3
To investigate the synthetic utility of the products, we
further studied the Sonogashira coupling16 of dihalo-1,3,5-
triene compounds with terminal alkynes. Treatment of
3a with phenylacetylene afforded 88% yield of the target
product 6, which may be a useful intermediate in opto-
electronic materials.17 The X-ray crystallographic analysis
of 6 further confirmed the E-configuration of the triene
products.15
Scheme 3. Formation of 2,4-Dichloro-1,3,5-trienes Derivatives
Control experiments demonstrated that no reaction
occurred in the absence of Pd(II)-catalyst, and the acidic
condition created by acetic acid could promote this pro-
cess. Next, two deuterated experiments were carried out
(16) (a) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46,
834. (b) Hundertmark, T.; Littke, A. F.; Buchwald, S. L. Org. Lett. 2000,
ꢀ
2, 1729. (c) Novak, Z.; Nemes, P.; Kotschy, A. Org. Lett. 2004, 6, 4917.
(17) (a) Christensen, R. L.; Hultzsch, K. C. J. Phys. Chem. A 2004,
108, 8229. (b) Locknar, S. A.; Peteanu, L. A.; Shuai, Z. G. J. Phys. Chem.
A 1999, 103, 2197. (c) Christensen, R. L.; Frank, H. A. J. Phys. Chem. A
2008, 112, 12629.
(14) Jiang, H. F.; Qiao, C. L.; Liu, W. B. Chem.;Eur. J. 2010, 16,
10968.
(15) See the Supporting Information for details.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Control Experiments
Scheme 5. Possible Reaction Mechanism
to distinguish the hydrogen position of the terminal
alkyne. As depicted in Scheme 4, deuterium product 7 was
obtained exclusively in 89% isolated yield, and the deuter-
ium atom (98% examined by 1H NMR spectroscopy) was
still present. However, when deuterated acetic acid was
used as the solvent, there was no deuterium in the prod-
uct. Furthermore, when ꢀOH was protected by ꢀOAc,
the desired product could not be detected in the reac-
tion system under the standard conditions, indicat-
ing that ꢀOH played an important role in the success of
the transformation.
On the basis of the above results, a plausible mechanism
involving trans-halopalladation and coordinative inser-
tion is proposed, as shown in Scheme 5. The first step
involves π-coordination of the carbonꢀcarbon triple bond
of 1 to the Pd(II) species followed by trans-halopallada-
tion to afford vinylpalladium intermediate II.18 In this
process, the chelation of the hydroxyl group to the Pd(II)
center improves the stereo- and regioselectivities of trans-
halopalladation.19 Then, the carbonꢀcarbon multiple
bond of alkynols coordinative insertion into carbonꢀ
palladium bond in the vinylpalladium intermediate occurs
to yield the diene III, which will undergo β-OH elimination
to give the allene intermediate IV with the aid of HOAc.12
Finally, nucleophilic attack of bromide ion to the allene
moiety of IV generates the desired 1,3,5-triene products.20
In conclusion, we have developed a general and efficient
method for the synthesis of dihalosubstituted-1,3,5-triene
derivatives from alkynols in a one-pot manner. The high
regio- and stereoselectivity and tolerance for a range of
functional groups as well as the mild reaction condi-
tions and good to excellent yields make the present proto-
col very attractive. The reaction scope, detailed mechan-
ism, and synthetic applications are under investigation in
our laboratory, and the results will be reported in due
course.
Acknowledgment. The authors thank the National Nat-
ural Science Foundation of China (21172076 and 20932002),
the National Basic Research Program of China (973 Pro-
gram) (2011CB808600), Guangdong Natural Science Foun-
dation (10351064101000000), China Postdoctoral Science
Foundation (2011M501318) and the Fundamental Research
Funds for the Central Universities (2012ZP0011) for finan-
cial support.
(18) (a) Huang, L. B.; Wang, Q.; Liu, X. H.; Jiang, H. F. Angew.
Chem., Int. Ed. 2012, 51, 5696. (b) Zhou, F.; Han, X. L.; Lu, X. Y. J. Org.
Chem. 2011, 76, 1491. (c) Ma, S.; Lu, X. J. Org. Chem. 1991, 56, 5120.
(d) Ma, S.; Zhu, G.; Lu, X. J. Org. Chem. 1993, 58, 3692. (e) Ji, J.; Zhang,
C.; Lu, X. J. Org. Chem. 1995, 60, 1160.
(19) (a) Pan, D.; Jiao, N. Angew. Chem., Int. Ed. 2008, 47, 4729.
(b) Bernocchi, E.; Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1992, 33, 3073. (c) Kang, S. K.; Lee, H. W.; Jang, S. B.;
Kim, T. H.; Pyun, S. J. J. Org. Chem. 1996, 61, 2604.
(20) (a) Ma, S. M; Hao, X. S.; Huang, X. Org. Lett. 2003, 5, 1217.
(b) Ma, S. M.; Wu, B.; Shi, Z. J. J. Org. Chem. 2004, 69, 1429. (c) Ma,
S. M.; Wei, Q.; Wang, H. M. Org. Lett. 2000, 2, 3893. (d) Ma, S. M.; Xie,
H. X. Org. Lett. 2000, 2, 3801.
Supporting Information Available. Typical experimen-
tal procedure, crystal data (CIF), and characterization for
all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX