Synthesis of Highly Substituted Polyenes by Palladium-Catalyzed Cross–Couplings of Sterically Encumbered Alkenyl Bromides and N-Tosylhydrazones

Article abstract of DOI:10.1002/adsc.201601155

A new method for the synthesis of polysubstituted conjugated dienes is described, through the palladium-catalyzed cross-coupling between N-tosylhydrazones and alkenyl bromides. The reaction proceeds efficiently when a combination of a highly substituted bromoalkene and a hydrazone derived from a ketone are employed, pointing to the convenience of a sterically encumbered environment. This unprecedented process allows for the stereocontrolled preparation of highly substituted dienes and polyenes. (Figure presented.).

Full text of DOI:10.1002/adsc.201601155

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DOI: 10.1002/adsc.201601155
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Synthesis of Highly Substituted Polyenes by Palladium-Catalyzed
Cross–Couplings of Sterically Encumbered Alkenyl Bromides and
N-Tosylhydrazones
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Miguel Paraja, Raquel Barroso, M. Paz Cabal, and Carlos Valdes *
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Departamento de Quımica Organica e Inorganica and Instituto Universitario de Quımica Organometalica “Enrique
Moles”, Universidad de Oviedo, c/ Julian Claverıa 8, 33006 Oviedo, Spain
Fax: (+34)985 103446
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Phone: (+34) 985 103505; e-mail: acvg@uniovi.es
Received: October 18, 2016; Revised: December 27, 2016; Published online: && &&, 0000
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18 To the memory of Prof. Jose Barluenga (deceased September 7, 2016)
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Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601155
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rently accepted for this cross-coupling reaction
(Scheme 1, a) involves formation of a palladium
carbene II, that undergoes migratory insertion to give
benzylpalladium complex III, followed by a fast b-
hydride elimination that releases the coupling product
and regenerates the Pd (0) species.
Abstract: A new method for the synthesis of
polysubstituted conjugated dienes is described,
through the palladium-catalyzed cross-coupling be-
tween N-tosylhydrazones and alkenyl bromides.
The reaction proceeds efficiently when a combina-
tion of a highly substituted bromoalkene and a
hydrazone derived from a ketone are employed,
pointing to the convenience of a sterically encum-
bered environment. This unprecedented process
allows for the stereocontrolled preparation of
highly substituted dienes and polyenes.
Keywords: Palladium catalysis; diene; polyene; N-
tosylhydrazone; alkenyl bromide
Introduction
43 The Palladium-catalyzed cross-couplings between sul-
44 fonylhydrazones and aryl halides[1] has been estab-
45 lished over the last decade as a highly robust method
46 for the synthesis of substituted alkenes,[2] which has
47 found wide application in organic synthesis, such as
48 the preparation of biologically active molecules,[3]
49 fluorinated alkenes,[4] and also participate in a variety
50 of cascade and auto-tandem catalyzed reactions.[5]
Scheme 1. Different reaction pathways of Pd-catalyzed reac-
tions involving migratory insertion reactions on Pd-carbenes.
Influence of the hydride elimination on the reaction out-
come.
51
The reaction features an almost total compatibility
52 with all types of N-sulfonylhydrazones, including those
53 derived from functionalized,[6] and also a,b-unsatu-
54 rated ketones.[7] Regarding the structure of the organic
Notably, the application of this methodology to the
55 electrophile, the coupling reaction has been applied coupling reaction with alkenyl halides remains almost
56 not only to aryl halides and sulfonates, but also to unexplored. We reported several years ago some
57 benzyl[8] and allyl derivatives.[9] The mechanism cur- limited examples on the couplings of certain alkenyl
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halides with arylaldehyde tosylhydrazones, which led of bulkier ligands such as t-BuXphos did not provide
to 1,3-dienes through a non-conventional catalytic any improvement in the outcome of the coupling
cycle that involved a formal d-hydride elimination reactions (Table 1, entry 14).
step (Scheme 1, d).[7] On the other hand, Van
Vranken, in the context of the study of the elegant
Table 1. Optimization of the reaction conditions for the
three-components carbenylative aminations of alkenyl
cross-coupling between bromoalkenes 1 and N-tosylhydra-
iodides,[5g,10] showed that the h3-allylpalladium inter-
zone 2a.[a]
mediates V (Scheme 1) generated upon migratory
insertion of the carbene ligand on the palladium-
10 alkenyl bond on intermediate IV, do not undergo fast
11 b-hydride elimination (Scheme 1, b).
12
Instead, nucleophilic attack at the less hindered
13 site of the h3-allylpalladium complex V takes place,
14 giving rise to the product of the three-components
15 reaction (Scheme 1, c). However, in the absence of an
16 external nucleophile, the catalytic cycle is slowed
17 down and uncatalyzed decomposition of the N-
18 tosylhydrazone takes place, leading to very low yields
19 of the coupling products (Scheme 1, b). Noteworthy,
20 the cross-couplings of certain alkenyl tosylates, leading
21 to dienes have been reported in processes that
22 required the employment of an extremely bulky
23 ligand.[11]
Entry
1
Base
Ligand
Yield (%)
[b]
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1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1b
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
Cs2CO3
P(2-furyl)3
PPh3
Xphos
P(o-Tol)3
BINAP
Xantphos
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
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70
79
0
0
0
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<10
<10
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33
<10
<10
[b]
[b]
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In the context of an ongoing project in our lab, we
25 were interested on exploring the cross-couplings of N-
26 tosylhydrazones with sterically encumbered alkenyl
27 halides. In the course of this work, we discovered that,
28 unlike the previous observations with less hindered
29 alkenyl bromides, the coupling reaction proceeded
30 successfully for the synthesis of highly substituted
31 conjugated dienes. However, under the same reaction
32 conditions, monosubstituted alkenyl halides, such as a-
33 and b-bromostyrene failed to provide the coupling
34 products in synthetically useful yields. Herein we wish
35 to report our results.
7[c]
8[d]
9[e]
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K2CO3
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
t-BuXphos
[a] Reaction conditions: Bromide 1, (0.1 mmol), hydrazone 2,
(2 equiv.), Pd2(dba)3 (4 mol %), Ligand (16 mol%), base (4
equiv.), 1,4-dioxane (2 mL), 1308C, 12 h.
[b] A 3: 1 Ligand/Pd ratio was used.
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Results and Discussion
[c] Pd2(dba)3 (2 mol%) and Xphos (8 mol%).
[d] N-tosylhydrazone 2a (1.2 equiv.) and LiO-t-Bu (3.2
equiv.).
39 Thus, we initiated our study with the reaction between
40 (Z)(1-bromoethene-1,2-diyl)dibenzene 1a and cyclo-
41 hexanone tosylhydrazone 2a. Several reaction condi-
42 tions and catalytic systems were examined (Table 1) to
43 discover that the diene 3a could be best obtained
44 employing a combination of Pd2(dba)3 (4 mol%) and
45 Xphos (16 mol%) with LiO-t-Bu as the base in 1,4-
[e] Carried out at 1108C.
The optimized reaction conditions were applied to
46 dioxane as solvent at 1308C (Table 1, entry 3). Lower the coupling of alkenyl bromide 1a with a set of
47 catalyst loading (entry 7) led to the recovery of different N-tosylhydrazones 2 to establish the scope of
48 substantial amounts of the starting bromide 1a while the reaction (Scheme 2). Thus, the substituted 1,3-
49 almost no reaction product was obtained at lower dienes 3 were obtained with excellent to moderate
50 temperature (entry 9). In contrast, when the same yields for the reactions with cyclic N-tosylhydrazones
51 reaction was conducted employing a-bromostyrene derived from cyclohexanones, cyclopentanones, cyclo-
52 1b, the expected diene was obtained in a quite poor heptanone and tetralones. Also the N-tosylhydrazone
53 33% isolated yield (Table 1, entry 12). Moreover, in of 3-pentanone provided the coupling product in
54 the reaction with b-bromostyrene 1c, although the excellent yield (3f). The employment of unsymmetri-
55 expected diene could be detected by GC/MS of the cally substituted N-tosylhydrazones led to a mixture of
56 reaction crude, very low isolated yield was finally regioisomers derived from a non-selective b-hydride
57 obtained (Table 1 entry 13). Of note, the employment elimination step (3g, 3l). Finally, hydrazones derived
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from acetophenone or aliphatic aldehydes failed to
provide the expected dienes in a synthetically useful
yield, although small amounts of the dienes, together
with several unidentified products were detected by
GC/MS. These results point to the necessity of a
sterically congested environment to enable the effi-
cient coupling reaction.
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Scheme 3. [a] Structurally diverse and stereodefined dienes 6
prepared by sequential Pd-catalyzed Suzuki and N-tosylhy-
drazone cross-couplings.
[a]
Reaction conditions for the Pd-catalyzed cross-coupling:
Bromide 5, (0.1–0.3 mmol), hydrazone 2, (2 equiv.), Pd2
(dba)3 (4 mol%), Xphos (16 mol%), LiOtBu (4 equiv.), 1,4-
dioxane (2 mL), 1308C, 12 h.
The reactions presented in Schemes 2 and 3 were
restricted to the employment (Z)-alkenyl bromides.
To continue the study of the scope of the cross-
coupling, we tested the reaction with bromides 7, as
representatives of trisubstituted (E)-alkenyl bromides.
Bromides 7 could be efficiently prepared also from
the corresponding N-tosylhydrazones following a
procedure recently reported by Prabhu et al.[13] How-
ever, the reaction of 7a with N-tosylhydrazone 2a
proceeded sluggishly, leading to a mixture of various
isomeric coupling products differing in the position of
Scheme 2. [a] 1,3-Dienes prepared by Pd-catalyzed cross-
coupling between bromoalkene 1a and different tosylhydra-
zones 2.
[a]
Reaction conditions: Bromide 1a, (0.1–0.3 mmol), hydra-
zone 2, (1–2 equiv.), Pd2(dba)3 (4 mol %), Xphos (16 mol
%), LiO-t-Bu (4 equiv.), 1,4-dioxane (2 mL), 1308C, 12 h.
[b] N-tosylhydrazone 2a (1.2 equiv.) and LiO-t-Bu (3.2 equiv.).
Next, we decided to apply the coupling reaction to the double bonds, that could not be separated.
46 different trisubstituted bromoalkenes. Sterodefined Gratifyingly, when the coupling reaction was con-
47 trisubstituted bromoalkenes 5 can be efficiently pre- ducted with the tetralone derived N-tosylhydrazones
48 pared by the stereoselective cross-coupling of 1,1- 2b–d, the expected 3,3’,4,4’-tetrahydro-1,1’-binaphtha-
49 dibromoolefins with boronic acids.[12] Following the lenes 8 were obtained in good yields (Scheme 4). It is
50 Suzuki coupling, a set of trisubstituted bromoalkenes worth noting the synthetic interest of dienes 8, that
51 5 was prepared, and the cross coupling reactions with have been previously used as precursors of substituted
52 N-tosylhydrazones 2 were examined (Scheme 3).
binaphthyls, as well as dienes in [4+2] cycloadditions,
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The results presented in Scheme 3 show that the oriented to the preparation of polycyclic aromatic
54 scope of the reaction is very broad allowing for the hydrocarbons, phtalocyanines and helicenes with ap-
55 preparation of a diversity of sterically encumbered plications in materials chemistry,[14] and even in
56 dienes 6, and also the synthesis of linear-conjugated graphene functionalization.[15] Noteworthy, the meth-
57 (6j) and cross-conjugated (6k, 6l) trienes.
ods available for their synthesis are based on the
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dimerization of the corresponding tetralone, and thus, presented allows for the straightforward preparation
restricted to symmetric systems. However, our meth- of these class of poorly described polienic systems.
odology enables the selective synthesis of the non-
4
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symmetrically substituted systems in a straightforward
manner from two different tetralones through their
Experimental Section
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tosylhydrazones. As an example of the usefulness of
these dienes, reaction of 8b with N-phenylmaileimi-
de[14e] led to the unprecedented nonsymmetrically
substituted pentahelicene precursor 9 (Scheme 4).
General Experimental Procedure for the
CrossÀCoupling Reaction Between Alkenyl Bromides
1, 5 or 7 and N-Tosylhydrazones 2:
A carousel reaction tube under nitrogen atmosphere was
charged with the corresponding alkenyl bromide
(0.15 mmol), N-tosylhydrazone (1 to 2 equiv.), tris(dibenzyli-
deneacetone)dipalladium(0) (4 mol%), 2-dicyclohexylphos-
phino-2’,4’,6’-triisopropylbiphenyl (Xphos) (16 mol%), lith-
ium tert-butoxide (3-4 equiv. for 1–2 equiv. of hydrazone
respectively), and 1,4-dioxane (2.4 mL). The reaction mix-
ture was stirred at 1308C for 12 h. After cooling to room
temperature, the reaction crude was dissolved in DCM and
filtered through celite. The solvents were evaporated under
reduced pressure and the residue was purified by flash
chromatography on silica gel using hexane or a mixture of
hexane/ethyl acetate.
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Acknowledgements
´
Financial support of this work by Ministerio de Economıa y
Competitividad of Spain: Grant CTQ2013-41336-P. A FPI
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predoctoral fellowship (Ministerio de Economıa y Compet-
itividad, Spain) to MP and a FICYT predoctoral fellowship
(Principado de Asturias, Spain) to RB are gratefully acknowl-
edged.
References
[1] J. Barluenga, P. Moriel, C. Valdꢁs, F. Aznar, Angew.
Chem. Int.– Ed. 2007, 46, 5587–5590.
[2] a) J. Barluenga, C. Valdꢁs, Angew. Chem. Int. Ed. 2011,
50, 7486–7500; b) Q. Xiao, Y. Zhang, J. Wang, Acc.
Chem. Res. 2013, 46, 236–247.
[3] a) E. Brachet, A. Hamze, J.-F. Peyrat, J.-D. Brion, M.
Alami, Org. Lett. 2010, 12, 4042–4045; b) S. Messaoudi,
B. Treguier, A. Hamze, O. Provot, J.-F. Peyrat, J. R.
De Losada, J.-M. Liu, J. Bignon, J. Wdzieczak-Bakala,
S. Thoret, J. Dubois, J.-D. Brion, M. Alami, J. Med.
Chem. 2009, 52, 4538–4542; c) J. Barluenga, L. Florenti-
no, F. Aznar, C. Valdꢁs, Org. Lett. 2011, 13, 510–513;
d) T. Bzeih, T. Naret, A. Hachem, N. Jaber, A. Khalaf, J.
Bignon, J.-D. Brion, M. Alami, A. Hamze, Chem.
Commun. 2016, 52, 13027–13030; e) T. Naret, P. Retail-
leau, J. Bignon, J.-D. Brion, M. Alami, A. Hamze, Adv.
Synth. Catal. 2016, 358, 1833–1847.
[4] a) A. Jimenez-Aquino, J. A. Vega, A. A. Trabanco, C.
Valdꢁs, Adv. Synth. Catal. 2014, 356, 1079–1084; b) X.
Wang, Y. Xu, Y. Deng, Y. Zhou, J. Feng, G. Ji, Y. Zhang,
J. Wang, Chem. Eur. J. 2014, 20, 961–965.
[5] a) Y. Xia, Y. Zhang, J. Wang, ACS Catalysis 2013, 3,
2586–2598; b) J. Barluenga, N. QuiÇones, M.-P. Cabal, F.
Aznar, C. Valdꢁs, Angew. Chem. Int. Ed. 2011, 50,
2350–2353; c) R. Barroso, R. A. Valencia, M.-P. Cabal,
Scheme 4. [a] Synthesis of 3,3’,4,4’-tetrahydro-1,1’-binaphtha-
lenes 8 starting from two N-tosylhydrazones and application
in the synthesis of the non-symmetric pentahelicene precur-
sor 9.
Reaction conditions for the Pd-catalyzed cross-coupling:
Bromide 7, (0.1–0.3 mmol), hydrazone 2, (2 equiv.), Pd2
(dba)3 (4 mol%), Xphos (16 mol %), LiO-t-Bu (4 equiv.),
[a]
1,4-dioxane
(2
mL),
1308C,
12
h.
[b]
Obtained as a 3: 1 inseparable mixture with a partially
aromatized dihydrobinaphthyl.
Conclusion
48 As summary, we have described herein the Pd-
49 catalyzed cross-coupling of alkenyl bromides and N-
50 tosylhydrazones as an efficient method for the prepa-
51 ration of a wide structural variety of conjugated dienes
52 and polyenes. These results contribute to highlight the
53 versatility of the already well developed Pd-catalyzed
54 cross-couplings with N-sulfonylhydrazones by the
55 incorporation of sterically congested alkenyl bromides
56 as coupling partners. Moreover, the methodology
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C. Valdꢁs, Org. Lett. 2014, 16, 2264–2267; d) M. Paraja,
[11] P. K. Patel, J. P. Dalvadi, K. H. Chikhalia, RSC Adv.
2014, 4, 55354–55361.
[12] W. Shen, Synlett 2000, 737–739.
1
2
3
4
5
6
7
8
9
M. Carmen Perez-Aguilar, C. Valdꢁs, Chem. Commun.
2015, 51, 16241–16243; e) M. Paraja, C. Valdꢁs, Chem.
Commun. 2016, 52, 6312–6315; f) A. Khanna, C. Maung,
K. R. Johnson, T. T. Luong, D. L. Van Vranken, Org.
Lett. 2012, 14, 3233–3235; g) I. D. U. A. Premachandra,
T. A. Nguyen, C. Shen, E. S. Gutman, D. L. Van Vrank-
en, Org. Lett. 2015, 17, 5464–5467.
[13] D. P. Ojha, K. R. Prabhu, Org. Lett. 2015, 17, 18–21.
[14] a) K. Sbargoud, M. Mamada, J. Marrot, S. Tokito, A.
Yassar, M. Frigoli, Chem. Sci. 2015, 6, 3402–3409; b) J.-
D. Chen, H.-Y. Lu, C.-F. Chen, Chem. Eur. J. 2010, 16,
11843–11846; c) T. Sooksimuang, B. K. Mandal, J. Org.
Chem. 2003, 68, 652–655; d) B. K. Mandal, T. Sooksi-
muang, C.-H. Lee, R. Wang, J. Porphyrins Phthalocya-
nines 2006, 10, 140–146; e) L. Minuti, A. Taticchi, A.
Marrocchi, E. Gacs-Baitz, Tetrahedron 1997, 53, 6873–
6878; f) X.-J. Li, M. Li, H.-Y. Lu, C.-F. Chen, Org.
Biomol. Chem. 2015, 13, 7628–763; g) Y. Shen, H.-Y. Lu,
C.-F. Chen, Angew. Chem. Int. Ed. 2014, 53, 4648.
[15] J. Li, M. Li, L.-L. Zhou, S.-Y. Lang, H.-Y. Lu, D. Wang,
C.-F. Chen, L.-J. Wan, J. Am. Chem. Soc. 2016, 138,
7448–7451.
[6] a) J. Barluenga, M. Escribano, P. Moriel, F. Aznar, C.
Valdꢁs, Chem.-Eur. J. 2009, 15, 13291–13294. b) J.
Barluenga, M. Tomꢂs-Gamasa, F. Aznar, C. Valdꢁs,
Chem.-Eur. J. 2010, 16, 12801–12803.
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38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
[7] J. Barluenga, M. Tomꢂs-Gamasa, F. Aznar, C. Valdꢁs,
Adv. Synth. Catal. 2010, 352, 3235–3240.
[8] Q. Xiao, J. Ma, Y. Yang, Y. Zhang, J. Wang, Org Lett
2009, 11, 4732–4735.
[9] K. Wang, S. Chen, H. Zhang, S. Xu, F. Ye, Y. Zhang, J.
Wang, Org. Biomol. Chem. 2016, 14, 3809–3820.
[10] E. S. Gutman, V. Arredondo, D. L. Van Vranken, Org.
Lett. 2014, 16, 5498–5501.
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Synthesis of Highly Substituted Polyenes by Palladium-
Catalyzed Cross–Couplings of Sterically Encumbered
Alkenyl Bromides and N-Tosylhydrazones
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