Cooperative Iodide Pd(0)-Catalysed Coupling of Alkoxyallenes and N-Tosylhydrazones: A Selective Synthesis of Conjugated and Skipped Dienes

Article abstract of DOI:10.1002/chem.201800765

Palladium(0)-catalysed hydro-alkylation or -alkenylation of alkoxyallenes with N-tosylhydrazones gives direct access to conjugated and skipped 1-alkoxydienes with high efficiency and excellent functional-group compatibility. The reaction is proposed to in

Full text of DOI:10.1002/chem.201800765

A Journal of
Accepted Article
Title: Cooperative Iodide Pd(0) Catalysed Coupling of Alkoxyallenes
and N-Tosylhydrazones: a Selective Synthesis of Conjugated and
Skipped Dienes
Authors: Stefano Parisotto, Lorenzo Palagi, Cristina Prandi, and
Annamaria Deagostino
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10.1002/chem.201800765
Chemistry - A European Journal
Cooperative Iodide • Pd(0) Catalysed Coupling of Alkoxyallenes
and N-Tosylhydrazones: a Selective Synthesis of Conjugated and
Skipped Dienes
Stefano Parisotto, Lorenzo Palagi, Cristina Prandi and Annamaria Deagostino*[a]
The efficient and stereoselective synthesis of dienes remains a
major challenge in organic chemistry. Both 1,3-(conjugated) and
1,4-(skipped) dienes are ubiquitous structure units existing in
natural products such as polyenic macrolides,[1] macrolactames,[2]
alkaloids[3] and functional materials.[4] Moreover, they are key
intermediates in organic synthesis given their structural and
reaction properties.[5] As far as skipped dienes are concerned, the
Pd(0) promoted allylic vinylation, both stoichiometric[6] and
catalytic,[7] represents one of the most applied synthetic
approaches.[8] More recently Ir,[9] Ni[8a, 10], Ti[11] and Cu[12] have
been also exploited. Examples of the enantioselective
introduction of a stereogenic centre adjacent to double bonds
have been reported.[13] Another effective method is the
functionalisation of 1,3 dienes catalysed by Co[14] or Pd again.[15]
In the same way, the stereodefined construction of functionalised
conjugated dienes represents
a
major goal in organic
synthesis,[4a, 5a, 5b, 16] and many efforts have been devoted in the
past decades exploiting metal catalysed couplings of alkynes or
allenes and suitable alkenes[17] or 1,4 elimination processes.[18]
Nevertheless, great attention is still paid to their preparation.[17a-c]
Domino allylic alkylation/4π-electrocyclic ring opening,[1c, 19] ring
closing metathesis,[20] allene-Claisen rearrangement[21] and Pd
catalysed coupling of allenes and boronic derivatives[17d] were
lately reported. In our laboratory we have been studying 1,2-
alkoxydiene reactivity in Heck reactions and α-arylated-α,β-enals
(Scheme 1),[22] dihydrobenzofurans and indolidines[23] have been
prepared in a cascade domino process. Alkoxyallenes ease of
synthesis and exceptional reactivity make them unusual and
versatile building blocks.[24] Recently, interesting Pd catalysed
functionalisation of alkoxyallenes have been developed.[25] In our
procedures allenes were prepared via the isomerisation of
internal alkynes promoted by n-butyllithium, not compatible with
electrophilic moieties. In this context terminal allenes represent an
appealing alternative, since mild isomerisation conditions are
required on propynol ethers.[26] For this reason, we envisaged N-
tosylhydrazones as ideal nucleophilic partners in a Pd(0)
catalysed reaction, due the requirement for an additional carbon
atom to assembly a butadiene. Our hypothesis was supported by
Scheme 1 Pd(0) catalysed reactions of alkoxyallenes, diazo compounds and
allenes previously reported and the synthesis of skipped and conjugated dienes
by reaction of alkoxyallenes and N-tosylhydrazones.
With the goal in mind of testing alkoxyallene reactivity in a three
component coupling with tosylhydrazones and aryl halides, we
set up a reaction with iodobenzene, alkoxyallene 1a and
benzophenone tosylhydrazone 2a. Unfortunately, due to the
alkoxy group influence on the allene electronic properties, it was
not possible to promote a multicomponent process and the
desired 1-alkoxy-1,3-diene 6a was afforded in low yield together
with many side products virtually impossible to separate.
Nevertheless, one of those side products was easily isolated and
characterised. Surprisingly the alkoxydiene 3a was recovered,
which was clearly the product of a coupling between alcoxyallene
1a and tosylhydrazone 2a competing with the planned three
component reaction (scheme 2). Diene 3a came from the allene
hydroalkylation and was formed in a total E stereoselective
fashion, as confirmed by NMR-NOESY (see ESI).
a
publication describing the synthesis of highly arylated
butadienes by a three component coupling between aryl iodides,
tosylhydrazones or diazo esters and propadienyl arenes (Scheme
1).[27] N-tosylhydrazone role in Pd(0) cross couplings is well
established[28] especially thanks to the pioneering work of
Barluenga and Valdés[29] and Wang.[27, 30] Examples of dienes
obtained via Pd(0) catalysed reactions of N-tosylhydrazones have
been reported.[31]
Scheme 2 Pd(0) catalysed coupling of alkoxyallene 1a and benzophenone N-
tosylhydrazone 2a.
Encouraged by the initial result, we searched for the optimal
conditions. First, iodobenzene was excluded, but surprisingly only
traces of diene 3a were recovered. We hypothesised that the aryl
iodide might be needed to sustain the catalytic cycle, which was
confirmed by the yield increasing with catalytic loading of PhI (5%
mol, see ESI for complete screening). Triethylamine is essential
as well since other tertiary amines, like DIPEA, are completely
inefficient. Moreover, a 10:1 ratio with THF is ideal (see ESI).
Following up, the remaining conditions were optimised, results
are summarised in Table 1.
[a]
S., Parisotto, L. Palagi, prof. C. Prandi, dr. A. Deagostino
Department of Chemistry
University of Torino
Via Giuria, 7, 10125
E-mail: annamaria.deagostino@unito.it,
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/chem.201800765
Chemistry - A European Journal
Table 1. Optimisation of Pd(0) catalysed coupling of alkoxyallene 1a and
benzophenone N-tosylhydrazone 2a.a
PPh3 (15% mol). b Determined on isolated product. c Reaction scaled up to 5
mmol. d E/Z ratio determined by 1H NMR on the crude.
Entry Iodide 2a (eq),
Base (eq)
Catalyst
Yield
[%]b
49c
41c
0c
Both electron withdrawing (entries 4-11) and -donating (entries 1-
3, 12) groups are tolerated on the phenyl ring. Better results are
obtained with the formers, with 3,3’-NO2 as exception.
Asymmetric N-tosylhydrazones afforded dienes 3h-l (entries 8-
12) in excellent yields. The reaction can also be performed on
differently substituted allenes, with benzyl group giving a purer
crude (entry 13). A tenfold scale-up successfully afforded 1.12 g
of diene 3a in a single batch.
Lately, we extended the substrate scope to arylalkyl-N-
tosylhydrazones 4a-p. The experimental conditions applied to
diaryl-N-tosylhydrazones 2a-l were not optimal, so we looked for
better ones, focusing our attention on temperature and allene
protecting group. The coupling was sensitive to the former, with a
higher temperature (90°C) as the best value. On the contrary, the
allene protecting group did not have any influence, but we choose
the benzylated allene 1c for studying the coupling scope, given
benzyl group resilience compared to THP. With these derivatives
we were conscious of the possible issue with the selectivity in the
β hydrogen abstraction since the presence of two hydrides prone
to elimination. Nevertheless, we were delighted to observe a
complete regioselectivity towards skipped dienes, kinetically
favoured. With these tailored conditions, a library of 1,4-dienes
was prepared (Table 3).
1
2
3
4
5
6
7
8
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
TBAI
LiI
1.2, t-BuOLi 1.2
1.0, t-BuOLi 1.0
1.2, t-BuONa 1.2
1.2, K2CO3 1.2
1.2, t-BuOLi 2.4
1.2, t-BuOLi 1.2
1.2, t-BuOLi 1.2
1.2, t-BuOLi 1.2
1.2, t-BuOLi 1.2
1.2, t-BuOLi 1.2
1.2, t-BuOLi 1.2
1.2, t-BuOLi 1.2
1.2, t-BuOLi 1.2
1.2, t-BuOLi 1.2
1.2, t-BuOLi 1.2
Pd(OAc)2, P(o-tol)3
Pd(OAc)2, P(o-tol)3
Pd(OAc)2, P(o-tol)3
Pd(OAc)2, P(o-tol)3
Pd(OAc)2, P(o-tol)3
Pd(OAc)2
0c
tracec
0c
Pd(OAc)2,Xphos
Pd(OAc)2,DMPP
Pd(OAc)2,PPh3
PdCl2, P(o-tol)3
tracec
7c
9
80c
47c
10
11
12
13
14
15
PdCl2·(MeCN)2,P(o-tol)3 45c
Pd(OAc)2,PPh3
Pd(OAc)2,PPh3
Pd(OAc)2,PPh3
Pd(OAc)2,PPh3
39
85
37d
0e
LiI
LiI
a Reactions conditions: alkoxyallene 1a 0.5 mmol, dry THF 5 mL, Et3N 0.5 mL,
b
Iodide source (5% mol), Pd cat. (5% mol), Phosphine (15% mol), T = 75°C.
Determined on isolated product. Negligible amount of 3a’ is detected.
Reaction carried out in toluene. e Reaction carried out in acetonitrile.
c
d
The initial conditions were almost optimal, considering that THF
and t-BuOLi gave the best result. Both t-BuONa and K2CO3
(entries 3-4), which are usually effective as well, were completely
inefficient in this case. We believe that this sharp difference was
due to Li+ ability to keep the iodide counterion in solution (NaI is
slightly soluble in THF while KI is completely not soluble). An
excess of tosylhydrazone 2a respect to alkoxyallene 1a was
required (entries 1-2) but equimolar to t-BuOLi (entry 5). Different
catalysts were tested (entry 6-11) and we were pleased to
observe a huge improvement with PPh3 (entry 9).
Table 3.Pd(0) coupling of alkoxyallenes (1a-c) and N-tosylhydrazones (4a-p)
to afford 4-aryl-1-alkoxypenta-1,4-dienes(5a-u).a
Finally, we realised that PhI was only required as iodide (I-)
source. This hypothesis was actually confirmed by replacing it
with tetrabutylammonium iodide (entry 12) or lithium iodide (entry
13), with the last giving an optimal 85% yield. PhI and LiI have
similar efficacy in feeding iodide to the catalyst with the former
always affording an unavoidable amount of the diene 3a’ which
does not affect 3a yield anyway. Still, toluene and acetonitrile
were tested without any improvement (entries14 and 15). It must
be noticed that THF is rarely employed in Pd(0) couplings with N-
tosylhydrazones. Nevertheless, it is known for its ability in
stabilising electronpoor Pd(II) complexes and moreover it gives a
homogeneous solution, preventing LiI precipitation and the
consequent reaction failure. We chose the conditions reported in
entry 13 of Table 1 for studying the reaction scope. Different
benzophenones were converted in tosylhydrazones and then
coupled with terminal alkoxyallenes to generate diarylated 1-
alkoxy-1,3-dienes (3a-n) in good yield and stereoselective
manner; results are listed in Table 2.
Entry
R1
Ar
R2
Yield[%]b
E/Zc
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
2-Tol
3-Tol
4-Tol
4-MeOPh
2-BrPh
3-BrPh
4-BrPh
4-ClPh
2-CF3Ph
4-CNPh
Ph
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
5a
5b
5c
5d
5e
5f
85,
84/16
81/19
84/16
87/13
81/19
78/22
78/22
80/20
77/23
77/23
72/28
84/16
77/23
84/16
80/20
81/19
75/25
74/26
85/15
75/25
82/18
47
73,
94
52
78,
84,
60
54
70
73
72
67
55
77
94
78
80
79
75
64
5g
5h
5i
5j
5k
5l
4-Py
5m
5n
5o
5p
5q
5r
2-Thienyl
2-Naphtyl
Ph
3-BrPh
4-CNPh
Ph
THP
THP
THP
MEM
MEM
Bn
Table 2.Pd(0) coupling of alkoxyallenes (1a-c) and N-tosylhydrazones (2a-l) to
afford 4,4’-diaryl-1-alkoxybuta-1,3-dienes (3a-n).a
5s
5t
5u
4-CNPh
4-ethinylPh
a Reactions conditions: alkoxyallene 0.5 mmol, N-tosylhydrazone (1.2 eq), t-
BuOLi (1.2 eq), dry THF, 5 mL, Et3N 0.5 mL, LiI (5% mol), Pd(OAc)2 (5% mol),
PPh3 (15% mol). b Determined on isolated product. c E/Z ratio determined by 1H
NMR and GC on the crude.
Also in this case, the influence of the substituents on the aromatic
ring and of the allene protecting group was explored. Results are
in accordance with those listed in Table 2 for tosylhydrazones 2a-
l and good yields were obtained with both electron donating
(entries 1-5) and -withdrawing moieties (entries 6-11). Sterically
hindered naphtyl group is also effective (entry 15), like
Entry
R
Ar1
Ar2
Yield[%]b
E/Z (C3-C4)d
1
2
3
4
5
6
7
8
THP
THP
THP
THP
THP
THP
THP
THP
THP
THP
THP
THP
Bn
Ph
Ph
4-Tol
4-MeOPh 3c,
3a,
3b,
85
65
47
89
55
81
45
88
88
85
90
65
-
-
-
-
-
-
-
4-Tol
4-MeOPh
4-FPh
4-PhOPh
4-ClPh
3-NO2Ph
Ph
Ph
Ph
Ph
Ph
4-FPh
4-PhOPh
4-ClPh
3-NO2Ph
4-ClPh
2-ClPh
3-CF3Ph
4-CN
2-Tol
Ph
Ph
Ph
3d,
3e
3f,
3g,
3h,
3i,
3j,
3k,
3l,
propiophenone tosylhydrazone (entry 12)[32]
. The reaction
tolerates arylbromides and chlorides, differently from aryl iodides
which probably undergo oxidative addition. Electronpoor and -rich
heteroarenes (entry 13 and 14 respectively) were tested with
good outcomes. Moreover, thanks to the very short reaction time,
this coupling is compatible with acetylenes without producing any
pyrazole coming from the [3+2] dipolar cycloaddition (entry 21).[33]
Finally the reaction was extended to differently protected
alkoxyallenes (1b-c) without any remarkable changes respect to
55/45
50/50
66/33
70/30
50/50
-
9
10
11
12
13
14
15
Ph
Ph
Ph
3m, 92
MEM
THP
3n,
3a,
87
-
-
73C
a
Reaction conditions: alkoxyallene 0.5 mmol, N-tosylhydrazone (1.2 eq), t-
BuOLi (1.2 eq), dry THF, 5 mL, Et3N 0.5 mL, LiI (5% mol), Pd(OAc)2 (5% mol),
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10.1002/chem.201800765
Chemistry - A European Journal
benzyl group (entries 16-20). In all cases isomer E was
1
predominant with the E/Z ratio determined by H NMR and GC.
Acknowledgements
We thank prof. Alessandro Barge for his help with NMR
elaboration. This work was supported by MIUR.
Traces of the regioisomer deriving from the carbene α-addition
were in some cases detected (see ESI). A plausible mechanism
is depicted in Scheme 3.
Keywords: Tosylhydrazones • Alkoxyallenes • Palladium •
Iodide • Dienes
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Scheme 3 Mechanism proposal
The key step of the overall process is the generation of the allyl
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t-butanol a yield increase up to 45% was noticed. Finally, the
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tosylhydrazone 2a(D) with alcoxyallene 1a showed the formation
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of D-labelled diene 3a(D), where
a
little amount of
deuteropalladation of sp C of allene 1a is observed. Actually, a
mixture of dienes 3a and 3a(D) was observed in the 1H NMR (see
scheme 1 and figure 2 in ESI), with a high ratio 3a/3a(D) which
suggests that more than one proton source is present in the
reaction milieu. At the beginning it is only the tosylhydrazone
2a(D), which explains D-incorporation in the product. Then the
catalytic cycle itself might sustain the reaction, via an active role
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