Pd-catalyzed borylative cyclisation of 1,7-enynes

Article abstract of DOI:10.1039/c2cc34468h

Reaction of a variety of 1,7-enynes with bis(pinacolato) diboron catalysed by Pd bis(trifluoroacetate) affords homoallylic and allylic boronates containing a six membered carbo- or heterocycle, by formation of C-C and C-B bonds

Full text of DOI:10.1039/c2cc34468h

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COMMUNICATION
Pd-catalyzed borylative cyclisation of 1,7-enyneswz
´
´
Virtudes Pardo-Rodrıguez, Elena Bunuel, Daniel Collado-Sanz and Diego J. Cardenas*
Received 21st June 2012, Accepted 16th August 2012
DOI: 10.1039/c2cc34468h
Reaction of a variety of 1,7-enynes with bis(pinacolato) diboron
catalysed by Pd bis(trifluoroacetate) affords homoallylic and
allylic boronates containing a six membered carbo- or hetero-
cycle, by formation of C–C and C–B bonds
Enynes are versatile starting compounds for the metal-catalysed
formation of carbocycles. Depending mainly on the catalyst, a wide
variety of structures can be accessed. The reactivity of 1,6-enynes
has been extensively studied during the last few years. In contrast,
systematic studies on 1,7-enynes are not as abundant.1 Cyclisation
of 1,7-enynes can afford 5,2 6, 7,3 and even 84 membered carbo-
cycles. Reactions can be catalysed by complexes of several metals
such as Pd,5 Pt,6 Au,7 Ru,8 Co,9 Ga,10 In,11 Ti,12 etc. In addition to
the cycloisomerisation,13 skeletal rearrangement,14 and metathesis,15
cascade reactions involving additional reagents can be powerful
tools for the construction of complex molecules. Thus, 1,7-enynes
have been described in processes involving alkoxycyclisation,16
reaction with carbonyl compounds,17 oxidation,18 Pauson–Khand
type reactions,19 and carboxylation,20 among others. We are
especially interested in reactions in which the cyclisation is accom-
panied by the introduction of a main group element, in order to
prepare carbon nucleophiles suitable for further functionalisation.
In this respect, cyclisation of 1,7-enynes with concomitant
silylation,21 or borylstannylation,22 has been reported.
Some years ago, we described a Pd-catalyzed borylative cyclisa-
tion of 1,6-enynes for the preparation of cyclopentane-derived
homoallylic boronates in good yields, smooth conditions, and in
the presence of functional groups, since there is no need to use
highly nucleophilic and basic Li or Mg nucleophiles.23 Cascade
borylative polycyclisation of different enediynes,24 and borylative
cyclisation of enallenes and allenynes25 allow the preparation of
alkyl and allylboronates as well.
This reaction leads to the formation of six-membered rings,
and can be considered as a formal 1,8-hydroboration with
concomitant cyclisation. Borylation takes place at the terminal
alkene carbon of the starting enyne. The alkylboronate is
prone to be used in subsequent transformations, what confers
this reaction a high potential from a synthetic point of view.
For this reason, we tried to find optimized conditions. An
extensive study varying Pd catalysts, added ligands, solvents,
reaction time and temperature led us to develop this reaction
and to explore its scope. Interestingly, Pd(TFA)2 resulted to
be much more convenient compared with Pd(OAc)2, and
provided products in moderate to high yields. In general,
reactions take place at higher temperature compared to
1,6-enynes, although they can be performed even at room
temperature in some cases. Addition of different phosphines
for the reaction of 1b resulted in hydroboration of the alkyne
in low yield.26 As it can be seen in Table 1, the expected cyclic
homoallylic boronates have been isolated for substrates con-
taining a homopropargylic chain (1a–1i).
In general, internal alkynes afford higher reactions yields
(entries 2, 4, 5, 11, 14 and 16) compared with terminal ones, and
homoallylic boronates containing exclusively E alkenes are formed,
as determined by NOESY experiments. Configuration of the
double bond was confirmed in the crystal structure of compounds
2i and 4g (see ESIz for details). Substrates containing terminal
alkenes, on the other hand, provide better results. The absence of
substituents containing hydrogen atoms susceptible of being elimi-
nated in the intermediate complexes is probably the reason for this
behaviour. Thus, for substituted alkenes on the distal carbon
(entries 6 and 7), more complex crude reaction mixtures, containing
non-borylated cyclic products, were obtained. For homoallylic
alkenes, sulfones afford better results compared with malonate
derivatives, probably due to the lower coordinating ability of the
former, as we will discuss below. Interestingly, the tether group has
an influence on the reaction outcome when homoallylic substrates
(3a–h) are subjected to the reaction conditions. Thus, sulfone
derivatives 3f–g experience again the regioselective formation of
the expected cyclic boronates (4f–g). In contrast, malonate and
tosylamide derivatives (3a–e) showed the formation of mixtures of
In this communication, we report the first borylative cycli-
sation of 1,7-enynes, which has remained elusive for years.
Initial experiments under the optimised conditions for 1,6-
enynes afforded the desired products in low yields.
´
Departamento de Quımica Organica, Facultad de Ciencias,
Universidad Autonoma de Madrid, Campus de Cantoblanco, 28049-
´
´
Madrid, Spain. E-mail: diego.cardenas@uam.es;
Fax: +34 914973966; Tel: +34 914974358
w Dedicated to the memory of our friend and colleague Dr G.
Christian Claessens, who regretfully passed away last June 2012.
z Electronic supplementary information (ESI) available: Experimental
procedures, data and computational details. CCDC 888322 and
888323. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc34468h
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10517–10519 10517

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Table 1 Pd-catalyzed borylative cyclisation of 1,7-enynes (reaction
conditions: B2(pin)2 (1.05 equiv.), Pd(TFA)2 5 mol%, MeOH (1 equiv.),
toluene, [substrate] = 0.2 M, reaction times to completion are shown)
Fig. 1 Proposed reaction pathway for the borylative cyclisation.
The hydride evolves by insertion of the alkyne into the Pd–H bond,
which would account for the observed alkene configuration.
Alternatively, intermediate B could be formed by oxidative cyclo-
metalation of the enyne to give A, followed by protonolysis of the
alkenyl–Pd bond. Transmetalation reaction with B2(pin)2, which
could be assisted by methoxide released upon Pd–H formation,
and subsequent reductive elimination lead to the final product.
b-Hydrogen elimination involving the side chain R0 in inter-
mediate D is in accord with the lower yields observed in some
cases. Elimination of the hydrogen of methyne groups is not
observed for intermediates with X = CH2.
Formation of derivatives 5 can be explained by b-elimination
of H from intermediates of type F to give G (Fig. 2). Subsequent
hydrometalation from G with the opposite regioselectivity
would afford allyl complex H. In the absence of added ligands,
Z3-allyl complexes I are probably formed. Again, transmetala-
tion with the diboron reagent followed by reductive elimination
would give rise to the final product.
We tried to get insight into the reasons for the different
behaviour observed for substrates containing a homoallylic
chain with malonate as tether. In these cases, b-hydrogen
elimination seems to take place easily, in contrast to those
substrates containing a homopropargyl chain, and/or sulfone
as a connecting group between both unsaturated moieties. We
hypothesised that the different coordinating ability of malonate
and sulfone, and the relative position to Pd in intermediates B
could be the reason. DFT calculations have been used to
determine the relative energies of intermediates formed by
a
c
b
10 mol% of Pd(TFA)2. Yield from the 1H NMR spectrum.
d
Non-borylated cyclic compounds were also formed. 1.05 equiv.
of B2(pin)2 and 5 mol% of Pd(TFA)2 were additionally added after
e
22.5 h. When 5 mol% of Pd(TFA)2 was used, conversion was 92%
and the product was isolated in 74% yield.
two different isomers (4 and 5) in a 3 : 1 to 9 : 1 ratio depending on
the substrate. Compounds 5 are again cyclic boronates, and in this
case the boryl group binds to the alkyne terminal carbon of the
starting enyne, and the newly formed C–C double bond is
endocyclic. Lower temperature favours the formation of derivatives
4a–e, but conversion is not complete. Although isomers could not
be separated by column chromatography, GC-MS analysis allowed
us to obtain separate mass spectra. For the formation of
compounds 2 and 4, we propose the pathway outlined in Fig. 1.
The reaction probably starts by reduction of precatalyst to Pd(0)
and formation of a Pd hydride by protonation with the alcohol.
Fig. 2 A feasible reaction pathway for the formation of compounds 5.
c
10518 Chem. Commun., 2012, 48, 10517–10519
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MECD for a FPU fellowship to D. C.-S., and the Centro de
Computacion Cientıfica-UAM for computation time.
´ ´
Notes and references
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Fig. 3 Intermediate Pd complexes studied by DFT calculations.
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cyclisation in which either the new alkene or the substituent
group (sulfone or malonate) coordinates to Pd (Fig. 3, see ESIz
for details). After alkene carbometalation, intermediates J are
expected to be formed. Ligand exchange processes should be
associative, involving external ligand attack. Assuming fast
ligand exchange, activation energies are not relevant.
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for sulfones, whereas malonate groups in either two possible
positions are able to displace the alkene to give complexes K or
L. Once the alkene is dissociated, a free vacant site necessary
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process and therefore are stable enough and afford a single
isomer. On the other hand, intermediates K (from homo-
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Oxidation can be performed on the reaction crude without
previous isolation of boronates. Thus, the following sequence
afforded the expected mixture of alcohols 7 and 8 in the same
ratio observed for the borylative cyclisation (Fig. 5).
23 J. Marco-Martı
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nez, V. Lopez-Carrillo, E. Bunuel, R. Simancas
´ ´
´
´
´
In conclusion, we have developed a general borylative cyclisation
of 1,7-enynes to homoallylic and allylic boronates containing
six-membered ring under smooth conditions compatible with the
presence of functional groups. The products can be further
functionalised and constitute useful synthetic intermediates.
We thank the MICINN (CTQ2010-15927) and the CAM
(AVANCAT PPQ-1634 and a fellowship to V. P.-R.), the
´
´
´
´
´
´
guez, J. Marco-Martınez, E. Bunuel and
´
´
26 A similar behaviour was found in the study of the stannylative
cyclisation of enynes: M. Lautens and J. Mancuso, Org. Lett.,
2000, 2, 671.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10517–10519 10519