Synthesis of 1,3-disubstituted cyclohexenes from dienylethers: Via sequential hydrozirconation/deoxygenative cyclisation

Article abstract of DOI:10.1039/c8ob02925c

Access to 1,3-disubstituted cyclohexenes from zirconocenes containing a latent electrophilic allylic fragment is described. Requiring a specific conformation, 6-endo-trig cyclisation is based on the TMSOTf-mediated generation of a stabilized carbocation.

Full text of DOI:10.1039/c8ob02925c

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Synthesis of 1,3-disubstituted cyclohexenes from
dienylethers via sequential hydrozirconation/
deoxygenative cyclisation†
Cite this: DOI: 10.1039/c8ob02925c
Received 23rd November 2018,
Accepted 22nd December 2018
Amandine Payet, Benjamin Blondeau, Jean-Bernard Behr
Jean-Luc Vasse
and
DOI: 10.1039/c8ob02925c
*
rsc.li/obc
Access to 1,3-disubstituted cyclohexenes from zirconocenes con-
taining
Requiring a specific conformation, 6-endo-trig cyclisation is based to 1,3-disubstituted cyclohexenes using soft11 and hard nucleo-
Additionally, transition-metal-mediated allylic additions
a
latent electrophilic allylic fragment is described. applied to cyclic substrates9,10 can also be successfully applied
on the TMSOTf-mediated generation of a stabilized carbocation.
philes.12 Ultimately,
a regioselective transition metal-free
version, involving the association of Grignard reagents with
cyclic allylic phosphorothioate esters, was achieved.13
Although structurally simple, 1,3-disubstituted cyclohexenes
remain synthetically useful precursors for accessing functiona-
lized molecules owing to the plethora of methods dedicated to
CvC double bound transformations. While the ring-closure
metathesis appears as an obvious approach to access 1,3-di-
substituted cyclohexenes,1 the preparation of the relevant
diene is not always trivial. As a consequence, most alternative
methods rely on the functionalization of carbocyclic skeletons.
In contrast, strategies based on the construction of the
cyclic skeleton are less exploited, and are restricted to malonic
entities as the internal nucleophilic entity in palladium-cata-
lyzed allylic substitution.14 In this context, a methodology
based on the intramolecular allylic coupling with a formally
hard organometallic counter-part would provide a complemen-
tary approach to the existing ones.
Among them,
a regioselective allylic C–H activation,
Generating an electrophilic fragment within the structure
of an organometallic species constitutes an attractive approach
for the synthesis of carbocyclic skeletons. Lewis acid-mediated
activation of zirconocenes bearing a latent electrophilic frag-
ment has previously been reported, allowing the preparation
of cyclopropanes,15 pyrrolidines,16 cyclopentylamines17 and
cyclopentanes.18 Recently, we described the synthesis of vinyl-
cyclopentanes from 7-methoxy-1,5-dienes via a sequential
hydrozirconation/TMSOTf-mediated activation of the allylic
ether.19 Occurring through a 5-exo-trig mode, the ring-closure
proceeds in a highly diastereoselective manner when R′ = Me
and R″ = H (Scheme 1). Noticeably, the cyclization may be
disrupted by steric congestions (R″ = Ph, Scheme 1) resulting
in a different evolution of the zirconocene. In this case, the
migration of a Ph group to the allylic fragment was observed
instead, along with the loss of a molecule of ethylene.20
combining organic and photoredox catalysis, which may be
applied to 1-arylcyclohexenes, was recently reported.2
Typically, methods based on the generation of electrophilic
cyclohexenyl fragments from allylic alcohols are predominant.
Thus, by using silyl enol ethers,3 allylsilanes4 or ketoesters5 as
nucleophilic partners, 1,3-disubstituted cyclohexenes can be
efficiently prepared. In Friedel–Crafts couplings, both allylic
alcohols6 and acetates7 were used.
Transition metal-catalyzed reactions also turn out to be
attractive tools for providing 1,3-disubstituted cyclohexenes.
Thus, an enantioselective approach from enones, combining
two consecutive transition metal-catalyzed reactions, was
described.8 The first reaction involves a tandem copper-cata-
lyzed addition of dialkylzincs in the presence of phosphorami-
dite/trapping with Tf2O, and the second, the palladium-cata-
lyzed cross coupling of the resulting vinyltriflates.
Interestingly, this strategy can also be simplified to a single
step procedure.
Institut de Chimie Moléculaire de Reims, CNRS (UMR 7312) and Université de Reims
Champagne Ardenne, 51687 Reims Cedex 2, France.
E-mail: jean-luc.vasse@univ-reims.fr
†Electronic supplementary information (ESI) available: Experimental details,
NMR data of all new compounds. See DOI: 10.1039/c8ob02925c
Scheme 1 Sequential activation of dienes.
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Table 1 Stereoselective access to E-olefins from 4-methoxybutyl-
zirconocenes
Entry
R
1 dr
2 yielda (%)
E : Zb
Fig. 1 Plausible compared evolution of zirconocenes I and II.
1
2
3
4
5
6
7
8
9
Ph
1a 99 : 1
1b 99 : 1
1c 99 : 1
1d 96 : 4
1e 99 : 1
1a 80 : 20
1f 84 : 16
1g 77 : 23
1h 62 : 38
2a (76)
2b (73)
NRc
>20 : 1
>20 : 1
—
—
—
>20 : 1
>20 : 1
>20 : 1
—
4-MeO-C6H4
4-Br-C6H4
2-Furyl
CH(Et)2
Ph
2-MeO-C6H4
2-Thiophenyl
3-Br-C6H4
Degradation
In the case of 4-methoxybutylzirconocene I (Fig. 1), we
anticipated that a similar scenario may occur, instead of the
competitive cyclobutane formation, providing an olefin. In
contrast, we envisaged that vinylogous substrates II might
favorably produce cyclohexenes according to a 6-endo mode of
cyclization.
In this paper, we disclose a general method allowing
access to 1,3-disubstituted cyclohexenes through an internal
Csp3-allylation reaction.
NRc
2a (67)
2f (64)
2g (62)
NRc
a Isolated yield. b Determined by 1H NMR analysis of the crude reaction
mixture. c The unreacted zirconocene was hydrolyzed during work-up.
The study was initiated by first studying the evolution of zir-
conocenes I under Lewis acid conditions. As model substrates,
homoallylic ethers 1 were prepared by allylation of aldehydes
followed by methylation of the resulting alcohols. Compounds
1 were obtained with variable diastereoselectivities, strongly
subordinated to the allyl metal used. While a moderate
diastereoselectivity was observed from cinnamylzinc, an analo-
gous aluminum reagent21 provided a single isomer.
Thus, zirconocenes, derived from diastereomerically pure
1a–e, were generated by hydrozirconation using 1.2 equiv. of
the Schwartz reagent at rt, and subsequently treated with
TMSOTf at −50 °C. While 1a and 1b were efficiently converted
into olefins 2a and 2b, respectively (entries 1 and 2), only
hydrolysis of the corresponding zirconocenes was observed
using 1c and 1e as the substrates (entries 3 and 5) even after a
prolonged reaction time. Moreover, degradation occurred in
the case of 1d (entry 4). Interestingly, when diastereomeric
mixtures of 1a,f–g were reacted under the same conditions,
Fig. 2 Possible simplified transition states accounting for the syn selec-
tive olefination and the formation of cyclohexenes 6.
identical levels of stereoselectivity (entries 6–8) were achieved. thus making possible the formation of cyclohexenes. As model
Although the reaction is diastereospecific, these preliminary substrates, compound 3, 5 and 5′ were tested under the above
results indicate that only substrates bearing an activable conditions.
benzylic position are involved, and therefore the method
cannot be generalized to diversely substituted alkenes abstraction of ethylene upon addition of TMSOTf, providing
(Table 1). the diene 4 as the single E,E isomer. In contrast, the cyclohex-
Similarly, the zirconocene derived from 3 underwent an
Among deoxygenative processes involving alkylzirconocenes ene 6a was obtained in 69% isolated yield when 5a was used
bearing an alkoxide fragment, the synthesis of cyclopropanes as the substrate using TMSOTf as the Lewis acid. Along with
reported by Szymoniak15b was studied in-depth by Casey.22 6a, we detected the presence of cyclopropane (11% with
Using deuterium-labeled substrates, the ring-closure was respect to 6a) which is assumed to originate from the coexist-
shown to proceed via a concerted mechanism. In the present ing regioisomeric zirconocene which arises from the reversible
case, the nearly exclusive formation of the E isomer, from a hydrozirconation of 5a. BF3·OEt2 can also be used to induce
mixture of diastereoisomers, may originate from a transient cyclization, starting from both 5a and 5′a, albeit with a lower
carbocation (Fig. 2). Accordingly, substrates bearing a stabiliz- conversion (Scheme 2).
ing fragment would be more prone to favor the formation of
the olefin, which is validated by the observed results.
In order to extend the scope of the reaction, substrates
bearing diverse combinations of substituents were next tested.
The reaction appears to be general allowing the preparation
Thus, we next focused our attention towards vinylogous
substrates which are further prone to undergo an electrophilic of 1,3-disubstituted cyclohexenes with different combinations
activation, and displayed two potential sites of cyclisation, of substituents. Among them, diaryl (entries 1–5), 1-aryl-3-
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Scheme 2 Towards disubstituted cyclohexenes.
heteroaryl (entry 6), 1-aryl-3-alkyl (entries 8 and 9), and 1-alkyl-
3-aryl (entries 10 and 11) products were obtained in moderate
to good yields. Interestingly, cyclohexene 6l bearing a vinylic
unit at the 3-position can also be obtained from a substrate
containing a conjugated dienic fragment (entry 12). Finally,
the reaction conditions are compatible with the use of sub-
strates bearing a protected alcohol chain (entry 13). In the
specific case of 6g, we were not able to prepare the corres-
ponding homoallylic ether precursor with satisfactory purity.
Nevertheless, by using the trimethylsilylether in combination
with BF3·OEt2, the expected cyclohexene 6g can be prepared,
albeit in a moderate yield (entry 7) (Table 2).
To account for the formation of cyclohexenes 6, two selec-
tive steps are required. While the regioselective hydrozircona-
tion of the terminal alkene, providing the less hindered zirco-
nocene, is likely to result from steric considerations,17,23 the
origin of the selective formation of cyclohexenes from 5 may
be attributed to the adequate positioning of the R2 substituent.
This specific localization is assumed to concomitantly
(i) further enhance the carbocation generation, or more accu-
rately a π-allyl electrophilic fragment, localizing the zircono-
cene side chain perpendicularly to the π-allyl system, to mini-
mize the steric interactions, and (ii) induce a compression
Scheme 3 Synthetic applications.
angle that allows the adoption of the suitable conformation
for promoting the cyclohexene formation and preventing the
competitive olefination and cyclobutane reactions (Fig. 2).
While such a general mechanism involving a transient cationic
entity is consistent with the experimental results, an alterna-
tive concerted SN2′-like pathway cannot be ruled out at this
stage.24
To illustrate the usefulness of this series of alkenes, conven-
tional methods of alkene functionalization were applied to
prepare valuable building blocks.
Firstly, the deprotonation25 of symmetrical 6a using n-BuLi
followed by the addition of an allylbromide or acetone
afforded 1,3,3-trisubstituted cyclohexenes 7 and 8, respectively
(Scheme 3).
Secondly, compounds 6 appear as ideal substrates for
undergoing a diastereoselective dihydroxylation reaction, and
the resulting diols would constitute candidates in pinacolic
rearrangement. Thus, dihydroxylation of 6a was attempted
under standard conditions. The diol 9a was obtained as a single
isomer according to the accurate NMR spectroscopy results,
however in a low yield. Epoxidation of 6a,c using in situ gener-
ated DMDO was next investigated. 10a,c were obtained in a
highly diastereoselective manner and isolated with a satisfac-
tory yield. Subsequent treatment with TMSOTf in the presence
of DBU afforded aldehydes 11a,c with a nearly complete trans-
fer of chirality (Scheme 3).26
Table 2 Scope of the reaction
Entry R1
R2
R
LA
6 yielda (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
6a (69)
6b (48)
6c (46)
6d (62)
6e (68)
6f (66)
4-MeO-C6H4
3-MeO-C6H4
4-Br-C6H4
Ph
2-Thiophenyl
Ph
Conclusions
4-Br-C6H4 Me
Ph
2-Pyridyl
Ph
Me
In summary, a sequential hydrozirconation/TMSOTf-mediated
cyclisation, applied to 4-methoxy-1,5-dienes, providing 1,3-di-
substituted cyclohexenes is described. This method is
assumed to rely on the generation of a stabilized carbocationic
intermediate together with a crucial positioning of the substi-
tuent to promote 6-endo-cyclization over the competitive olefi-
nation reaction. Involving simple substrates, this flexible syn-
SiMe3 BF3·OEt2 6g (32)
n-C5H11
Me
Me
Me
Me
Me
Me
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
6h (46)
6i (52)
6j (48)
6k (30)
6l (56)
6m (72)
9
iPr
Ph
10
11
12
13
Ph
Ph
iPr
Me
Ph
Ph-CHvCH
TBSO-CH2-CH2 Ph
a Isolated yield.
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thetic method provides access to diversely substituted 1,3-di-
substituted cyclohexenes, and may potentially be applied to a
larger range of substrates, including naphthalenic and quinoli-
nic fragments, which constitute valuable building blocks.
Particularly, carbocycles containing an all carbonated quatern-
ary center can be targeted. Complementary experimental work
is required to elucidate the exact mechanism of the reaction
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The University of Reims Champagne Ardenne for financial
support and Carine Machado and Anthony Robert
(ICMR-UMR 7312) for technical assistance are gratefully
acknowledged.
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