Gold(I)-catalyzed intermolecular cycloaddition of allenamides with α,β-unsaturated hydrazones: Efficient access to highly substituted cyclobutanes

Article abstract of DOI:10.1021/ol503121q

α,β-Unsaturated N,N-dialkyl hydrazones undergo a mild [2 + 2] cycloaddition to allenamides when treated with a suitable gold catalyst. The method, which represents the first application of N,N-dialkyl hydrazones in gold catalysis, is compatible with a wide variety of substituents at the alkenyl moiety of the hydrazone component, proceeds with excellent levels of regio- and diastereoselectivity, and provides densely substituted cyclobutanes with good to excellent yields.

Full text of DOI:10.1021/ol503121q

Letter
pubs.acs.org/OrgLett
Gold(I)-Catalyzed Intermolecular Cycloaddition of Allenamides with
α,β-Unsaturated Hydrazones: Efficient Access to Highly Substituted
Cyclobutanes
Paloma Bernal-Albert,† Helio Faustino,† Ana Gimeno,§ Gregorio Asensio,§ Jose L. Mascarenas,*,†
́
́
̃
and Fernando Lopez*,†,‡
́
†Centro Singular de Investigacion
Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain
‡Instituto de Química Organ
ica General CSIC, Juan de la Cierva 3, 28006, Madrid, Spain
§Departamento de Química Organ
́
ica, Universidad de Valencia, Avda. Vicent Andres Estelles s/n, 46100-Burjassot, Valencia, Spain
́ ́ ́
en Química Bioloxica e Materiais Moleculares (CIQUS) and Departamento de Química Organica,
́
́
́
S
* Supporting Information
ABSTRACT: α,β-Unsaturated N,N-dialkyl hydrazones under-
go a mild [2 + 2] cycloaddition to allenamides when treated
with a suitable gold catalyst. The method, which represents the
first application of N,N-dialkyl hydrazones in gold catalysis, is
compatible with a wide variety of substituents at the alkenyl
moiety of the hydrazone component, proceeds with excellent
levels of regio- and diastereoselectivity, and provides densely
substituted cyclobutanes with good to excellent yields.
these methods, their success is associated with the use of
styrenes, enol ethers, or enamides as reaction partners, which
restricts the type of substituents (R1/R2) that can be
incorporated in the resulting cyclobutanes, as well as access to
cyclobutanes with quaternary stereocenters.6
yclobutanes not only constitute the basic structural motif of
Ca wide range of biologically active products but, owing to
their inherent strain energy, are also highly valuable synthetic
building blocks.1,2 The most common strategies to assemble
cyclobutanes are based on [2 + 2] cycloadditions of unsaturated
precursors, reactions which are typically carried out under
photochemical conditions,3 although in some cases they can also
be promoted by Lewis acids.4 Alternatively, transition metal
catalysis has recently emerged as a powerful tool for uncovering
new types of [2 + 2] annulations.5 In this context, the groups of
Considering the mechanism proposed for these cyclo-
additions,6,7 which involves the formation of intermediates I
and II, we were curious to analyze the behavior of other types of
electron-rich alkenes that could afford alternative, diversely
substituted cyclobutanes. In particular, we focused our attention
on α,β-unsaturated N,N-dialkyl hydrazones, a relatively unex-
plored class of substrates that are easily prepared from N,N-
dialkylhydrazines and enals.8 Although these species have been
typically used as azadienes in hetero-Diels−Alder cyclo-
additions,9 the electron-donor characteristics of the N,N-
dialkylamino group convert them into umpoled enals (vinyl-
ogous aza-enamines, Scheme 1, eq 2).8 Curiously, this umpolung
reactivity has been scarcely exploited10,11 and, to the best of our
knowledge, remains essentially unexplored in transition metal
catalyzed processes.12 Herein, we report that α,β-unsaturated
N,N-dialkyl hydrazones are excellent two-carbon partners in
gold-catalyzed cycloadditions with allenamides, providing for the
efficient assembly of highly substituted cyclobutanes with
excellent regio- and diastereoselectivities.13
́
Chen, Gonzalez, and ours have independently reported an
efficient approach to cyclobutanes based on the Au(I)-catalyzed
intermolecular [2 + 2] cycloadditions between allenamides and
electron-rich alkenes (Scheme 1, eq 1).6 Despite the relevance of
Scheme 1. Au-Catalyzed [2 + 2] Cycloadditions and
Umpolung Reactivity of Conjugate Hydrazones
We started our research by analyzing the reactivity of
allenamide 1a with the N,N-diisopropylhydrazone 2a in the
presence of several Au or Pt catalysts. As can be seen in Table 1,
Pt(II) complexes, such as PtCl2, PtBr2, or [PtCl2(C2H4)]2/P(o-
Received: October 25, 2014
Published: November 19, 2014
© 2014 American Chemical Society
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Letter
a
a
Table 1. Preliminary Screening with Pt and Au Catalysts
Table 2. Scope of the [2 + 2] Au-Catalyzed Cycloaddition
a
1a (1 equiv), 2a (2 equiv) and [M] (10%) were heated at 85 °C
(0.25 M in DCE), unless otherwise noted. The table indicates the
proportion of products as deduced from 1H NMR of the crude
b
c
mixtures. Conversions >99% after the indicated time. Carried out at
d
e
rt. Carried out with 5% catalyst. Z-3aa isolated in 99% yield.
Tol)3, promote intermolecular annulations between the
conjugated hydrazone and the allenamide to yield, after a few
hours at 85 °C, the [2 + 2] cycloadduct E-3aa, together with
minor amounts of the [3 + 2] and [4 + 2] adducts 4aa and 5aa,
respectively (Table 1, entries 1−3). On the other hand, the use of
AuCl or the gold(III) complex PicAuCl2 led exclusively to the [2
+ 2] cycloadducts 3aa, as 5:1 and 9:1 mixtures of E/Z isomers
(entries 4 and 5). Gratifyingly, cationic Au(I) complexes were
also active catalysts for the cycloaddition. Thus, while
Ph3PAuNTf2 provided the [2 + 2] adduct Z-3aa, together with
the acyclic product 6aa (7:3 ratio, entry 6), the Johnphos-based
gold(I) complex Au1 exclusively provided Z-3aa, which was
isolated after 10 min at rt, in 99% yield using just 5% of the
catalyst (entry 7). The structure and stereochemical identity of
this adduct could be further corroborated by X-ray analysis,
which confirmed the cis disposition of the Ph and Me groups and
the Z configuration of the enamide (Figure S2, Supporting
Information).
a
1a (1 equiv) was added to a mixture of 2b−k (2 equiv) and Au1
b
(5%) in DCE (0.25 M) and heated at the indicated temperature. Z/E
c
ratios determined by 1H NMR of the crude mixtures. Isolated
Noteworthy, the cyclobutanes 3aa incorporate the phenyl
substituent at the β-positon of the exo-enamide and, therefore,
can be considered as regioisomers of those obtained in the
previous annulations of allenamides and styrenes.6
d
combined yield of Z and E isomers. Carried out with 10% catalyst.
The reaction is also efficient with α,β-unsaturated hydrazones
bearing alkyl substituents at the β-position. Thus, hydrazones 2f
and 2g, with a methyl substituent, provided the corresponding [2
+ 2] adducts, 3af and 3ag, in excellent yields, as 8:2 and 6:4
mixtures of Z and E isomers, respectively (entries 6 and 7). In
consonance with the lower reactivity of the α-unsubstituted
hydrazone 2b with respect to its α-methylated analog 2a,
inducing the reaction of hydrazone 2h, derived from
crotonaldehyde, also required more drastic conditions (16 h at
85 °C and 10% of the catalyst). Using these conditions, the
expected product was obtained in 95% yield and with complete Z
selectivity (entry 8). Gratifyingly, hydrazone 2i, derived from
cyclohexene-1-carbaldehyde, also participated in the [2 + 2]
We next analyzed the scope of the process. The N,N-
diisopropyl hydrazone derived from cinnamaldehyde (2b) did
also participate in the cycloaddition, although full conversions
required heating at 55 °C and longer reaction times (Table 2,
entry 2). In any case, the corresponding cyclobutane, Z-3ab, was
isolated in good yield and with complete stereoselectivity. The
reaction tolerated electron-rich (e.g., p-OMe) or electron-poor
(e.g., p-F) substituents at the hydrazone-phenyl moiety (entries 3
and 4). On the other hand, the introduction of a phenyl group at
the α-position of the conjugate hydrazone (2e) allows the
reaction to be completed at rt in <1 h; the [2 + 2] adduct 3ae was
obtained in 95% yield (Z/E ratio = 6:4, entry 5).
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Letter
cycloaddition providing, in excellent yield and complete syn
selectivity at the ring fusion, the bicyclo[4.2.0]octane product
3ai, an attractive bicyclic scaffold quite common in many natural
products (entry 9).14 The analog hydrazone 2j, derived from
cyclopentenecarbaldehyde, did not afford the bicyclo[3.2.0]-
heptane adduct (3aj), presumably because of the higher strain
associated with the formation of this bicyclic system. Instead, the
acyclic product 6aj was isolated in 65% yield (entry 10).
Electron-withdrawing groups at the β-position of the hydrazone
are tolerated. Indeed, 2k, featuring an ethyl carboxylate at this
position, provided the [2 + 2] adduct 3ak in 83% yield (entry
11).
The current methodology is not restricted to oxazolidinone-
derived allenamides such as 1a. As can be seen in entries 8 and 9,
the N-tosyl phenyl allenamide 1b also participated in the
cycloaddition, providing the expected cycloadducts with
complete selectivity and excellent yields (95−97% yield).
The cyclobutane adducts obtained in the above cycloadditions
offer interesting potential for further manipulations (Scheme 2).
Thus, the hydrazone moiety of 3aa can be converted into a nitrile
by treatment with magnesium monoperoxiphthalate (MMPP).
Alternatively, hydrolysis and subsequent reduction allow the
hydrazone to be readily converted into the alcohol 8a in a good
overall yield. Interestingly, a catalytic dihydroxylation of the exo-
enamide of 8a afforded, with total diastereoselection, the
cyclobutane-fused γ-lactol 9a, a type of scaffold that recalls the
core of biologically relevant products.16
The annulation reaction is not restricted to N,N-diisopropyl
hydrazones. As can be seen in Table 3, N,N-dimethyl hydrazones
a
Table 3. Scope of the Hydrazone and Allenamide
Scheme 2. Preliminary Manipulation of the Cycloadducts
A plausible mechanism for the cycloaddition reaction is
proposed in Scheme 3. An initial activation of the allenamide by
the carbophilic catalyst would provide the zwitterionic
intermediate I, species that has been theoretically located in
the context of intermolecular [4 + 2] Au-catalyzed cycloadditions
between dienes and allenamides.7 Regioselective interception of
I by the nucleophilic β-carbon of the alkenylhydrazone affords
the acyclic intermediate II, which might evolve to the final
cycloadduct 3 by direct cyclization with concomitant elimination
of the catalyst.7 Alternatively, the cyclization might proceed
through the alkyl gold intermediate III, which would explain the
formation of Z/E mixtures of 3.17 The diasteroselectivity of the
reaction, to give cyclobutanes in which R1 and R2 are in a cis
disposition, is consistent with an approach of the vinyl gold
moiety of II from the opposite face to that of the R2 group. A
cyclization via rotamer II′, leading to a hypothetical trans isomer,
should be less favorable due to steric reasons. Finally, the
a
1 (1 equiv) was added to a mixture of 2 (2 equiv) and Au1 (5%) in
b
DCE (0.25 M), unless otherwise noted. Z/E ratios (determined by
1H NMR spectroscopy of the crude mixtures) are 1:0 unless otherwise
c
d
e
noted. 6aa′ (6%) was also isolated. 6af′ (21%) was also isolated. Z/
E ratio = 9.3:0.7. 6af″ (9%) was also isolated.
f
Scheme 3. Mechanistic Proposal
with aryl or alkyl substituents at the alkene (2a′−c′,f′,k′)
provided the [2 + 2] cycloadducts, although the reactions
required slightly higher reaction times and temperatures (Table
3, entries 1−5). For example, while the cycloaddition of the
diisopropyl hydrazone 2a occurred at rt in 5 min (99% yield,
Table 2, entry 1), that of its N,N-dimethyl analog 2a′, which gives
3aa′, required 3.5 h at 55 °C (76% yield, Table 3, entry 1). Small
amounts of the acyclic products of type 6 were also isolated in
some cases (entries 1 and 4).15 The SAMP-derived chiral
hydrazone 2a″ also participated in the process providing the
corresponding [2 + 2] cycloadduct in 85% yield and moderate
diastereoselectivity (dr = 7:3, entry 6). Similarly, the SAMP-
hydrazone 2f″ provided the expected adduct as a 6:4 mixture of
diastereomers. Thus, these preliminary results suggest that
further modifications in the chiral hydrazone moiety might allow
the development of asymmetric versions of the reaction.
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Letter
E.; Gonzal
́
ez, J. M. Adv. Synth. Catal. 2012, 354, 1651. (c) Faustino, H.;
formation of acyclic side products of type 6 can be explained by
assuming a hydrogen abstraction in intermediate II (i.e., R1 =
CH3) followed by protodeauration of the resulting acyclic species
IV.19 In consonance with this mechanistic proposal and the
involvement of species of type II, we have found that the
cycloaddition of Z-2b provides the same cycloadduct (Z-3ab)
that is obtained from E-2b.18
In summary, we have developed a new gold-catalyzed
cycloaddition which involves allenamides and conjugate N,N-
dialkyl hydrazones. The reaction provides densely substituted
cyclobutanes in good yields with excellent levels of regio- and
diastereoselectivity. To the best of our knowledge, this method
constitutes the first transition-metal-catalyzed process in which
this type of α,β-unsaturated hydrazones exhibits azaenamine
vinylogous reactivity. Consequently, in just three simple steps, it
is now possible to transform an enal into a highly substituted
cyclobutane that incorporates a quaternary stereocenter.
Bernal, P.; Castedo, L.; Lop
2012, 354, 1658. (d) Suarez-Pantiga, S.; Hernan
Gonzalez, J. M. Angew. Chem., Int. Ed. 2012, 51, 11552.
(7) Montserrat, S.; Faustino, H.; Lledos, A.; Mascarenas, J. L.; Lop
F.; Ujaque, G. Chem.Eur. J. 2013, 19, 15248.
(8) Lazny, R.; Nodzewska, A. Chem. Rev. 2010, 110, 1386.
́
ez, F.; Mascarenas, J. L. Adv. Synth. Catal.
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́
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dez-Díaz, C.; Rubio, E.;
́
́
́
ez,
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(9) For a review, see: (a) Behforouz, M.; Ahmadian, M. Tetrahedron
2000, 56, 5259. See also: (b) Lomberget, T.; Baragona, F.; Fenet, B.;
Barret, R. Org. Lett. 2006, 8, 3919.
(10) For examples of this umpolung reactivity using acid catalysis, see:
(a) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int. Ed.
2011, 50, 3489. (b) Hashimoto, T.; Kimura, H.; Maruoka, K. Angew.
Chem., Int. Ed. 2010, 49, 6844. (c) Sridharan, V.; Ribelles, P.; Estev
Villacampa, M.; Ramos, M. T.; Perumal, P. T.; Menen
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ez, V.;
́
dez, J. C. Chem.
Eur. J. 2012, 18, 5056. For representative stoichiometric examples, see:
(d) Kamitori, Y.; Hojo, M.; Msuda, R.; Yoshida, T.; Ohara, S.; Yamada,
K.; Yoshikawa, N. J. Org. Chem. 1988, 53, 519. (e) Hegedus, L. S.;
Sestrick, M. R.; Michaelson, E. T.; Harrington, P. J. J. Org. Chem. 1989,
54, 4141.
(11) In contrast to the α,β-unsaturated N,N-dialkyl hydrazones, the
homologues derived from formaldehyde have been widely used as
umpoled species in catalysis, see: (a) Brehme, R.; Enders, D.; Fernan
R.; Lassaletta, J. M. Eur. J. Org. Chem. 2007, 5629. (b) Crespo-Pelna, A.;
ASSOCIATED CONTENT
* Supporting Information
■
S
́
dez,
Full experimental procedures and characterization data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
́
́
Monge, D.; Martín-Zamora, E.; Alvarez, E.; Fernandez, R.; Lassaletta, J.
M. J. Am. Chem. Soc. 2012, 134, 12912.
(12) N,N-Dialkyl hydrazones are typically used as ancillary ligands in
transition metal catalysis.8 For isolated examples of their use as reactants,
AUTHOR INFORMATION
Corresponding Authors
■
́
́ ́
see: (a) Ros, A.; Lopez-Rodríguez, R.; Estepa, B.; Alvarez, E.; Fernandez,
R.; Lassaletta, J. M. J. Am. Chem. Soc. 2012, 134, 4573. (b) Pair, E.;
Monteiro, N.; Bouyssi, D.; Baudoin, O. Angew. Chem., Int. Ed. 2013, 52,
5346. (c) Prieto, A.; Jeamet, E.; Monteiro, N.; Bouyssi, D.; Baudoin, O.
Org. Lett. 2014, 16, 4770. For a report involving transition metal Lewis
*E-mail: joseluis.mascarenas@usc.es.
̃
*E-mail: fernando.lopez@csic.es.
Notes
acid catalysis, see: (d) Monge, D.; Martín-Zamora, E.; Vaz
́
quez, J.;
The authors declare no competing financial interest.
́
Alcarazo, M.; Alvarez, E.; Fernan
́
dez, R.; Lassaletta, J. M. Org. Lett. 2007,
9, 2867.
ACKNOWLEDGMENTS
■
(13) For previous Au-catalyzed annulations of allenamides, see ref 6
and: (a) Faustino, H.; Lopez, F.; Castedo, L.; Mascarenas, J. L. Chem. Sci.
2011, 2, 633. (b) Faustino, H.; Alonso, I.; Mascarenas, J. L.; Lop
This work was supported by the Spanish MINECO (SAF2013-
41943-R and FPI to P.B.A.), the ERDF, the European Research
Council (Adv. Grant No. 340055), and the Xunta de Galicia
(GRC2013-041). We thank the Orfeo-Cinqa network.
́
̃
́
ez, F.
̃
Angew. Chem., Int. Ed. 2013, 52, 6526. (c) Zhou, W.; Li, X. X.; Li, G. H.;
Wu, Y.; Chen, Z. Chem. Commun. 2013, 49, 3552. (d) Li, G. H.; Zhou,
W.; Li, X. X.; Bi, Q. W.; Wang, Z.; Zhao, Z. G.; Hu, W. X.; Chen, Z.
Chem. Commun. 2013, 49, 4770. For a recent review on allenamides,
see: (e) Lu, T.; Lu, Z. J.; Ma, Z. X.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2013, 113, 4862. For a cycloaddition leading to products related to 5aa,
see: Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629.
(14) Braun, I.; Rudroff, F.; Mihovilovic, M. D.; Bach, T. Angew. Chem.,
Int. Ed. 2006, 45, 5541 and references therein.
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