Gold-catalysed tuning of reactivity in allenes: 9-endo hydroarylation versus formal 5-exo hydroalkylation

Article abstract of DOI:10.1039/c2cc37872h

The divergent gold-catalysed reactivity (C_sp²-H versus C_sp³-H) of aryloxy-tethered allenes has been uncovered.

Full text of DOI:10.1039/c2cc37872h

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Gold-catalysed tuning of reactivity in allenes: 9-endo
hydroarylation versus formal 5-exo hydroalkylation†
Cite this: Chem. Commun., 2013,
49, 1282
Benito Alcaide,*a Pedro Almendros,*b Sara Cembell´ın,a Teresa Mart´ınez del Campoa
Received 30th October 2012,
Accepted 19th December 2012
c
´
and Israel Fernandez
DOI: 10.1039/c2cc37872h
www.rsc.org/chemcomm
The divergent gold-catalysed reactivity (Csp
2
–H versus Csp –H) of
3
aryloxy-tethered allenes has been uncovered.
The preparation of medium-sized ring polycycles through selective
C–H bond activation is a big challenge. In this regard, the gold-
catalysed intramolecular hydroarylation of allenes1 may be a possible
solution to produce eight- or nine-membered carbocycles,
although this achievement has not yet been accomplished.
We present here an unprecedented Au-catalyzed 9-endo
carbocyclization of aryl allenes as a powerful synthetic tool to
obtain novel nine-membered annulated b-lactam derivatives.2
In addition, it is shown that the outcome of the reaction (9-endo
hydroarylation versus formal 5-exo hydroalkylation) can be
modulated by the allene tether.
To explore the reactivity of (aryl)allene-tethered 2-azetidinones 1
towards hydroarylation, we selected acetate 1a as a model substrate.
As a first try, we were happy to notice that although the reaction of
derivative 1a afforded dienol ester 2a as a major component (34%
isolated yield), the intramolecular hydroarylation adduct 3a was also
isolated as a minor component (13%) (Scheme 1). Thus, in order to
prevent the [3,3]-sigmatropic rearrangement involving the acetate
group,3 the hydroxy functionality was protected in the form of
methyl ether. Fortunately, treatment of allene 1b with [(Ph3P)AuNTf2]
in 1,2-dichloroethane at room temperature gave full conversion;
benzo[b]oxonine 3b being isolated in 51% yield in a totally selective
fashion (Scheme 1).4 Clearly, applying microwave irradiation and
using deactivated silica gel during purification resulted in an
increased 72% yield for adduct 3b. Similar figures were observed
Scheme 1 Controlled intramolecular gold-catalysed hydroarylation of
allenyl-tethered arenes 1a–h. (i) 5 mol% [(Ph3P)AuNTf2], DCE, mwave, 110 1C
(RT for 1a). Ac = COMe. Tf = triflyl. DCE = 1,2-dichloroethane.
for tricyclic products 3c–h without harming the sensitive b-lactam
ring (Scheme 1). Remarkably, this rare 9-endo carbocyclization
reaction was the only operative cyclization mode.
We also decided to undertake a study of the potential use of more
diverse substrates in this novel allene hydroarylation mode. Thus,
(aryloxy)allenyl-tethered sugars 4a–e were studied by using the
optimum reaction conditions obtained for (aryloxy)allenyl-tethered
2-azetidinones 1b–h. Remarkably, we found a divergent reactivity
compared with the transformation found with allenes 1; instead of
the expected hydroarylation adducts, tricycles 5 arising from a rare
5-exo hydroalkylation were obtained (Scheme 2). Notably, the direct
and selective functionalization of an otherwise inactive Csp3–H bond
has been achieved.5 Besides, regioselectivity can be completely
a
´
´
Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Quımica Organica,
´
Unidad Asociada al CSIC, Facultad de Quımica, Universidad Complutense de
Madrid, 28040-Madrid, Spain. E-mail: alcaideb@quim.ucm.es;
Fax: +34 91-3944103
b
c
´
´
Instituto de Quımica Organica General, IQOG, CSIC, Juan de la Cierva 3,
28006-Madrid, Spain. E-mail: Palmendros@iqog.csic.es; Fax: +34 91-5644853
´
´
´
Departamento de Quımica Organica, Facultad de Quımica, Universidad
Complutense de Madrid, 28040-Madrid, Spain
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data for new compounds, and copies of NMR spectra. See
DOI: 10.1039/c2cc37872h
Scheme 2 Controlled intramolecular formal 5-exo hydroalkylation reaction of
allenyl-tethered arenes 4a–e under gold-catalysed conditions.
c
1282 Chem. Commun., 2013, 49, 1282--1284
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gold salt to the distal allenic double bond. Next, chemo- and
regioselective 9-endo carboauration forms species 6. Attack
from the activated 2-position of the arene occurs as a result
of the stability of the intermediate oxonium cation type 6. Loss
of proton generates neutral species 7, which followed by
protonolysis of the carbon–gold bond afforded fused nine-
membered cycles 3 with concurrent regeneration of the gold
catalyst (Scheme 3).
Density functional theory (DFT) calculations have been
carried out to gain more insight into the reaction mechanism
of the abovediscussed gold-catalysed 9-endo hydroarylation
reaction. The corresponding computed reaction profile of the
model allenyl-b-lactam reactant 1M with [(Me3P)AuNTf2] as
catalyst is illustrated in Fig. 1, which shows the corresponding
free energies in CH2Cl2 solution (PCM-M06/def2-SVP//
PCM-B3LYP/def2-SVP level). Our calculations suggest that the
Scheme 3 Mechanistic explanation for the gold-catalysed hydroarylation of
allenyl-tethered oxyarenes 1.
+
reaction starts with the exergonic coordination of the AuPMe3
catalyst to the distal double bond of the allenic moiety of 1M
reversed by using the sugar derivative, thus favouring the cyclization (DG298 = À9.4 kcal molÀ1). Then, the 9-endo carbocyclization
of the aryloxy ether group toward the central allene carbon over the reaction to produce the nine-membered ring tricyclic inter-
cyclization towards the terminal allene carbon. The reaction of mediate 2M occurs through the transition state TS1. This
allenes 4 did take place with complete stereoselectivity, representing saddle point is associated with the nucleophilic addition of
a selective method to afford fused cyclopentenes 5 bearing a the activated ortho-carbon atom to the electrophilic gold
quaternary stereocenter.6 Complete conversion was observed by complex. Although the activation barrier of this model reaction
TLC and 1H NMR analysis of the crude reaction mixtures of allenols is relatively high (DGa,298 = 29.9 kcal molÀ1),7 this process is
4, and no side-products from isomerisation or polymerisation kinetically and thermodynamically favoured over the corresponding
reactions were detected. Unfortunately, some decomposition carbocyclization reactions leading to 7- or 8-membered ring
was observed on sensitive tricycles 5 during purification by flash intermediates.8 This result is in agreement with the exclusive
chromatography, which may be responsible for the moderate formation of nine-membered ring tricyclic compounds 3, as
isolated yields.
experimentally observed. Intermediate 2M is then transformed
A possible pathway for the gold-catalysed achievement of into the neutral complex 4M via the initially formed complex
À
tricycles 3 from allenyl-tethered arenes 1 may initially involve 3M (where the NTf2 anion is weakly bonded to 2M) through
the formation of a complex 1–Au(L) through coordination of the transition state TS2. The latter saddle point is associated with
Fig. 1 Computed reaction profile for the reaction of allenyl-b-lactam 1M and [(PMe3)AuNTf2] catalyst.11
c
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In conclusion, the divergent gold-catalysed reactivity (Csp2–H
versus Csp3–H) of aryloxy-tethered allenes has been studied. We
report herein an efficient gold-catalysed 9-endo carbocyclization
to fused tricyclic b-lactams from easily accessible aryl allene
substrates under mild conditions. In salient contrast to the
reaction of (aryloxy)allenyl-tethered 2-azetidinones, the allenyl
sugar derivatives provided the 5-exo hydroalkylation adducts as
the sole products. The reactions were found to proceed with
complete control of product regio- and chemoselectivity.
Support for this work from the MICINN [CTQ2009-09318,
CTQ2010-20714-C02-01,
and
Consolider-Ingenio
2010
(CSD2007-00006)], and CAM (Projects S2009/PPQ-1752 and
S2009/PPQ-1634) is gratefully acknowledged. S.C. thanks
´
Comunidad Autonoma de Madrid and Fondo Social Europeo
Scheme 4 Mechanistic explanation for the gold-catalyzed formal 5-exo hydro-
alkylation of allenyl-tethered oxyarenes 4.
´
for a predoctoral contract. I.F. is a Ramon y Cajal fellow.
Notes and references
À
the easy and exergonic proton abstraction in 2M by the NTf2
anion (DGa,298 = 1.4 kcal molÀ1 and DG298 = À16.9 kcal molÀ1
,
1 For a review, see: (a) N. Krause and C. Winter, Chem. Rev., 2011,
111, 1994. For available reports, see: (b) W. Kong, C. Fu and S. Ma,
Chem.–Eur. J., 2011, 17, 13134; (c) B. Alcaide, P. Almendros,
from 3M). The addition of the readily formed NHTf2 to 4M
forms complex 5M, which evolves into complex 6M via TS3
(associated with the protonolysis reaction of the carbon–gold
´
´
J. M. Alonso, M. T. Quiros and P. Gadzinski, Adv. Synth. Catal.,
2011, 353, 1871; (d) R. M. Zeldin and F. D. Toste, Chem. Sci., 2011,
´
2, 1706; (e) J. Barluenga, M. Piedrafita, A. Ballesteros, A. L. Suarez-
bond). The latter process is also highly exergonic (DG298
=
´
Sobrino and J. M. Gonzalez, Chem.–Eur. J., 2010, 16, 11827;
À19.4 kcal molÀ1) and proceeds with a very low activation
barrier (DGa,298 = 0.9 kcal molÀ1).9,10 Thus, it can be concluded
that the initial 9-endo carbocyclization reaction constitutes the
bottle-neck of the process in view of the corresponding ender-
gonicity and relatively high activation barrier. Finally, the
( f ) W. Kong, C. Fu and S. Ma, Eur. J. Org. Chem., 2010, 6545;
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73, 2439; ( j) C. Park and P. H. Lee, Org. Lett., 2008, 10, 3359;
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2 b-Lactams are not only the most commonly prescribed antibacterial
agents, but also exhibit some other biological activities.
3 A. K. Buzas, F. M. Istrate and F. Gagosz, Org. Lett., 2007, 9, 985.
4 A screening of different gold complexes was undertaken. AuCl3,
AuCl, and [(PPh3)AuOTf] all failed to catalyse this reaction. The
cyclizations of allene 1b using [IPrAuSbF6] or [IPrAuBF4] catalysts
did not lead to complete consumption of starting 1b, providing
adduct 3b in very low yield. Change in the nature of the phosphine
in the gold pre-catalyst has little effect on the reaction, because
replacing [(Ph3P)AuNTf2] by [P(tBu)2(o-biphenyl)AuNTf2] did not
show any appreciable difference.
+
reaction ends up with the release of the AuPMe3 catalyst,
which is coordinated to the endocyclic CQC double bond of
6M, to produce the final tricyclic species 7M.
A mechanistic rationale for the gold-catalysed conversion of
allenyl-tethered sugars 4 into fused cyclopentenes 5 is more
intricate. It is worth noting that the cyclization affords adducts
5 from an allene umpolung hydrofunctionalization instead of
that from the usually preferred conventional hydrofunctionaliza-
tion. The pathway proposed in Scheme 4 looks valid for the
formation of tricycles of type 5. It could be presumed that the
initially formed gold complex 4–Au(L), through coordination of
the gold salt to the distal allenic double bond, undergoes a 1,6-
hydride shift (rare transfer of hydride versus normal nucleophilic
group attack), giving rise to the oxonium species 8. Intra-
molecular trapping of the oxonium group by the alkenylgold
moiety in intermediates 8 generates cationic species 9, through
formal 5-exo hydroalkylation. Finally, demetalation yields fused
cyclopentenes 5 and regenerates the gold catalyst (Scheme 4).
Preliminary DFT calculations on the model (aryloxy)allenyl-
tethered sugar species 8M (see Fig. S3 in the ESI†) indicate that
the direct 1,6-hydride shift from the distal double bond-coordi-
nated complex 8M–Au occurs with a relatively high activation
barrier (DGa,298 = 37.7 kcal molÀ1, that is 25.2 kcal molÀ1 above
5 For a 1,5-hydride shift from benzyl ethers and tetrahydrofurans onto
allenes, see: B. Bolte and F. Gagosz, J. Am. Chem. Soc., 2011,
133, 7696.
6 Biologically active heliconols having the 2H-cyclopenta[b]furan core
of fused compounds 5 have been isolated from natural sources.
7 The barrier energy is reduced to 25.8 kcal molÀ1 when the more
+
realistic AuPPh3 catalyst is used (see Fig. S1 in the ESI†).
8 See Fig. S2 in the ESI†.
9 In sharp contrast, the corresponding proton abstraction and
protonolysis reactions in the 7-membered ring formation process
proceed with much higher activation barriers (DGa,298 = 16.9 and
37.1 kcal molÀ1). This makes the 7-membered ring formation a
non-competitive transformation. See Fig. S2 in the ESI†.
10 The easiness of the protonolysis reaction is in contrast to related
processes whose computed activation barriers are much higher.
´
See: (a) B. Alcaide, P. Almendros, T. Martınez del Campo and
+
´
I. Fernandez, Chem. Commun., 2011, 47, 9054; (b) B. Alcaide,
the separate reactants 8M and AuPMe3 ). This step is followed by
´
P. Almendros, T. Martınez del Campo, E. Soriano and J. L. Marco-
the highly exergonic C–C bond forming reaction (i.e. oxonium
Contelles, Chem.–Eur. J., 2009, 15, 1909.
trapping) via TS5 with an activation barrier of 26.1 kcal molÀ1
.
11 Plain values indicate the relative free energies (DG, at 298 K) at the
PCM(CH2Cl2)-M06/def2-SVP//PCM(CH2Cl2)-B3LYP/def2-SVP level,
whereas values in parentheses are computed at the PCM(CH2Cl2)-
B3LYP/def2-SVP level. Bond distances of the transition states are
given in angstroms.
Further DFT calculations involving the NTf2-mediated 1,6-hydride
shift and more realistic species leading to a process more compatible
with a reaction at room temperature are currently underway.
c
1284 Chem. Commun., 2013, 49, 1282--1284
This journal is The Royal Society of Chemistry 2013