Ambiphilic allenes: Synthesis and reactivity

Article abstract of DOI:10.1039/b819613c

Ambiphilic allenes are generated by an organocatalyzed domino reaction of alkyl propiolates and aromatic 1,2-diketones; in the absence of any external chemical agent, these allenes perform a thermally-driven dimerization reaction to generate the correspon

Full text of DOI:10.1039/b819613c

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Ambiphilic allenes: synthesis and reactivityw
ab
c
d
David Tejedor,*ab Gabriela Mendez-Abt, Javier Gonzalez-Platas, Miguel A. Ramırez
´
´
´
and Fernando Garcı
´
a-Tellado*ab
Received (in Cambridge, UK) 4th November 2008, Accepted 6th February 2009
First published as an Advance Article on the web 11th March 2009
DOI: 10.1039/b819613c
Ambiphilic allenes are generated by an organocatalyzed domino
reaction of alkyl propiolates and aromatic 1,2-diketones; in the
absence of any external chemical agent, these allenes perform
a
thermally-driven dimerization reaction to generate the
corresponding fully-substituted cyclobutanes in a regio- and
highly stereoselective manner.
The search for organic molecules expressing ambiphilic
reactivity is a sought-after challenge in organic chemistry.1
Isocyanides constitute a paradigmatic example with a carbon
atom able to react with both electrophiles and nucleophiles.2
Allenes armed with an e-donating group and an e-acceptor
group at the C3-p system (1,3-relationship) are expected to
express this property at the C2 position (Fig. 1). Allene
reactivity is regulated to a large extent by the substitution
pattern adorning the C3-p system.3 In this sense, although the
individual effects of e-donating (EDG) and e-withdrawing
groups (EWG) on allene reactivity are well established
(Fig. 1),3a,4 the overall effect when they operate in a
1,3-assonant manner remains to be evaluated. With these
precedents we have initiated a research program aimed
at the synthesis and study of 1,3-bifunctional allenes as
synthetically relevant ambiphilic reactants for the development
of novel domino and multicomponent reactions. For
experimental reasons related to our previous work on the
chemistry of non-metallic conjugated acetylides,5 we selected
the allenic esters 1 as the target bifunctional allene for these
studies.6
Fig. 1 Substituent effect on allene reactivity.
We envisioned that these allenic esters could be synthesized
by a tertiary amine-catalyzed domino reaction involving
1,2-diketones and terminal conjugated acetylides (Scheme 1).
The manifold was devised on the basis of our previous studies
on the organocatalyzed generation of conjugated acetylides I
and their reactivity against different types of electrophiles.7 It
was hypothesized that the intermediate II, obtained from the
nucleophilic addition of I onto the 1,2-diketone, should suffer
Scheme 1 Tertiary amine-catalyzed domino-based manifold.
a rearrangement that would lead to the rupture of the more
labile CO–CO bond (BE E 70 kcal molꢀ1) via epoxide III.8
Interestingly, and in accordance with our previous experiences,
in the process to form the desired allene 1, intermediate IV
would be basic enough to generate more acetylide and
regenerate the nucleophile from its b-ammonium acrylate
resting state, and thus, keep the catalytic cycle going.
a
´ ´
Instituto de Productos Naturales y Agrobiologıa, CSIC, Astrofısico
´
Francisco Sanchez 3, 38206, La Laguna, Tenerife, Spain.
E-mail: dtejedor@ipna.csic.es. E-mail: fgarcia@ipna.csic.es
b
c
To test this proposal, we chose the Et3N-catalyzed reaction
of benzil (2a) and methyl propiolate (3a) as the model reaction
(Scheme 2). It was found that when a solution of both
reactants in dichloromethane was treated at 0 1C with
Et3N (10 mol%), a smooth reaction occurred affording a
major product which slowly transformed into other products.
Interestingly, this intermediate could be detected by TLC but
it could not be isolated for characterization. A more detailed
study of the reaction showed that after 10 min at 0 1C the
´
Instituto Canario de Investigacion del Cancer, Spain. www.icic.es
Servicio de Difraccion de Rayos X, Departamento de Fısica
´
´
´
´
Fundamental II, Universidad de La Laguna, Astrofısico Francisco
´
Sanchez 2, 38206, La Laguna, Tenerife, Spain
d Instituto Universitario de Bioorga´nica Antonio Gonza´lez, Universidad
´ ´
de La Laguna, Astrofısico Francisco Sanchez 2, 38206, La Laguna,
Tenerife, Spain
w Electronic supplementary information (ESI) available: Experimental
section and physical data for compounds 4–9. CCDC 704023 and
704024. For ESI and crystallographic data in CIF format see DOI:
10.1039/b819613c
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Table 1 Et3N-catalyzed reaction of 1,2-diketones 2 with alkynoates 3
Entry
2
Ar =
3
6 (dr)a
8
Rsmb
1
2
3
4
5
6
7
8
9
10
a
a
a
a
a
b
c
d
e
f
Ph
Ph
Ph
Ph
a
a
b
c
d
a
a
a
a
a
Me 54 (97 : 3)
Me 47 (97 : 3)c 21
26 10
—
Et
tBu 40 (9 : 1)
Bn 43 (97 : 3)
Me 51 (97 : 3)
48 (96 : 4)
21 13
28 23
20 22
20 13
Ph
4-Me-C6H4
4-F-C6H4
4-MeO-C6H4
3-MeO-C6H4
2 = (2-FurylCO)2
Me 55 ( Z 99) 17 14
Me 50 (97 : 3)
Me 42 (96 : 4)
Me 22 ( Z 99)
14 24
18 14
6
20
a
Trans
:
cis ratio determined by integration of representative
b
1H-NMR signals. Recovered 1,2-diketone. 100 mmol scale.
c
6 and 8 typically of 60–75%. Although relatively small
amounts of 1,2-diketone starting materials were always
recovered, use of excess propiolate did not increase the
conversion. In all of the cases, cyclobutanes 6 were obtained
as the major products with an impressive high trans-
diastereoselectivity (more interesting C2-symmetry), while
minor cyclobutenes 8 were generated as single geometric
isomers. The regioselectivity of the formal [2 + 2]-cycloaddition
is moderate and it remains practically unchanged in the ꢀ781
to 20 1C temperature range. Finally, and not less importantly
for practical purposes, the reaction could be easily scaled up to
100 mmol with a similar chemical efficiency (68% of combined
yield) (entry 2).
Scheme 2 Et3N-catalyzed reaction of benzil and methyl propiolate.
practical totality of the starting benzil had been transformed
into this new compound. Quenching the reaction at this time
with pyrrolidine afforded enamine 4 (77%) which could be
isolated and further hydrolyzed to ketone 5. Because enamine
4 is the expected addition compound on an allene such as 1aa,
we assigned this structure to the main reaction intermediate,
thus verifying the postulated cascade of events shown in
Scheme 1. This assignment was further corroborated by
running the reaction in an NMR tube using CDCl3 as solvent.
13C-NMR analysis of the reaction mixture at different times
showed that the quaternary allene peak at 210 ppm,6c
clearly visible just minutes after setting the reaction, totally
disappeared when the reaction was completed. In a separate
experiment, the reaction was allowed to progress overnight at
room temperature and under these conditions, allene 1aa was
fully transformed into the mixture of cyclobutanes 6aa–7aa
and cyclobutene 8aa (80%) (Scheme 2). Prolonged treatment
of this mixture with Et3N (1 equiv.; 24 h) generated the mixture
of cyclobutanes 6aa and cyclobutenes 8aa via quantitative
transformation of 7aa into 8aa. Structures of cyclobutane 6aa
and cyclobutene 8aa were unambiguously confirmed by X-ray
crystallographic analyses.w To the best of our knowledge, this
protocol constitutes the first example of a synthesis of allenes
involving a rearrangement of 1,2-diarylketones.
Cyclic acenaphthenequinone 2g afforded spiro-1,3-
dioxolane derivatives
9 and a small amount of 6ga
(Scheme 3).7 Observe that in this case, the CO–CO s-bond
is strong enough to inhibit the rearrangement and the
transformation is funnelled toward the 1,3-dioxolane
9
formation through an ABB0 three-component acetylide-driven
process.9 When fixing the stoichiometry to that required for
this process (2 : 1), the yield of 9 goes up to 70% (mixture of
isomers) and 6ga is not produced.
A preliminary DFT study at the B3LYP/6-31G* level
showed a HOMO–LUMO gap of 0.17030 eV for allene 1aa,
a magnitude sufficiently small to allow an ambiphilic reactivity
profile (Table 2).10 This property also explains the observed
smooth tendency for dimerization and the complete observed
regioselectivity. Table
2 highlights the activating effect
exercised by both the Ph and OBz groups allocated at C3
and the opposite effect played by the ester group at C1.
Although a widely accepted stepwise mechanism involving a
perpendicular bisallyl diradical11 would explain the observed
Cyclobutanes 6aa and 7aa constitute therefore the chemical
picture of the allene’s basal reactivity which is expressed as a
stereoselective and self-biased formal [2 + 2]-cycloaddition.
Due to the novelty and functional complexity of these
cyclobutanic products, we undertook a study of the synthetic
scope of this transformation (Table 1z). The reaction proved
to be general with regard to both the alkyl propiolate (entries
1–5) and the electronic nature of the aromatic 1,2-diketones
(entries 1, 6–10) affording a combined yield of cyclic products
Scheme 3 Acetylide-driven 1,3-dioxolane 9 formation.
Chem. Commun., 2009, 2368–2370 | 2369
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Table 2 HOMO–LUMO energies (eV) for R1R2CQCQCHR3
7.41 (tt, J = 7.4 and 1.3 Hz, 2H), 7.56 (m, 4H), 7.69 (m, 4H);13C NMR
(100 MHz, CDCl3, 25 1C): d = 51.5, 92.4, 117.8, 127.6, 128.0, 128.1,
128.2, 129.2, 129.9, 132.5, 134.8, 151.2, 163.3, 164.7; IR (HCCl3):
n~ = 3027.8, 1730.3, 1449.9, 1436.1, 1343.8, 1268.1, 1222.3, 1108.6
cmꢀ1; anal. calc. for C36H28O8: C, 73.46; H, 4.79. Found: C, 73.47; H,
4.71%; m/z (%): 588 (0.3) [M+], 362 (8.4), 162 (28), 130 (19), 105
(100), 77 (32). Cyclobutene 8aa: yellow solid, mp = 156.5–157.9 1C; 1H
NMR (400 MHz, CDCl3, 25 1C): d = 3.32 (s, 3H), 3.38 (s, 3H), 6.08 (s,
1H), 7.33–7.41 (m, 6H), 7.46–7.54 (m, 6H), 7.65 (tt, J = 7.5 and 1.3
Hz, 2H), 8.19 (m, 2H); 13C NMR (100 MHz, CDCl3, 25 1C): d = 51.0,
51.5, 110.4, 126.5, 127.5, 127.9, 128.0, 128.6, 128.77, 128.79, 129.0,
129.5, 130.1, 131.1, 133.9, 134.4, 136.5, 142.2, 149.5, 156.6, 161.5,
164.6, 165.4; IR (HCCl3): n~ = 3028.2, 2953.0, 1731.6, 1435.9, 1258.0,
1063.4 cmꢀ1; anal. calc. for C29H22O6: C, 74.67; H, 4.75. Found: C,
74.77; H, 5.00%; m/z (%): 466 (24) [M+], 330 (10), 215 (17), 106 (19),
105 (100), 77 (60).
R1
R2
R3
HOMO
LUMO
DE
H
H
H
H
H
OBz
OBz
H
H
H
CO2Me
H
CO2Me
ꢀ0.26297
ꢀ0.21846
ꢀ0.24221
ꢀ0.26746
ꢀ0.21814
ꢀ0.22733
0.02065
ꢀ0.02670
ꢀ0.05275
ꢀ0.03807
ꢀ0.04983
ꢀ0.05703
0.28362
0.19176
0.18946
0.22939
0.16831
0.17030
Ph
OBz
H
Ph
Ph
regio- and stereoselectivity, a concerted mechanism cannot be
ruled out.12
In summary, we have reported a novel and efficient
organocatalytic synthetic manifold to gain access to bifunctional
allenes 1 from readily available starting materials, under mild
reaction conditions and in very short periods of time. In the
absence of other chemical reactants, these allenes suffer a
remarkably smooth thermally-driven dimerization to form
the functionalized complex cyclobutanes 6 and cyclobutenes
8. Overall, the reaction mainly generates one C2-symmetric
cyclobutane ring featuring two quaternary aromatic esters,
1 A. K. Yudin and R. Hili, Chem.–Eur. J., 2007, 13, 6538.
2 A. Domling, Chem. Rev., 2006, 106, 17.
¨
3 (a) Modern Allene Chemistry, ed. N. Krause and A. S. E. K.
Hashmi, Wiley-VCH, Weinheim, 2004; (b) K. M. Brummond and
J. E. DeForrest, Synthesis, 2007, 795; (c) S. Ma, Chem. Rev., 2005,
105, 2829.
4 For a selected review: D. J. Pasto, Tetrahedron, 1984, 40, 2805.
5 (a) D. Tejedor, S. Lo
and F. Garcıa-Tellado, Angew. Chem., Int. Ed., 2009, DOI:
10.1002/anie.200801987; (b) D. Tejedor, D. Gonzalez-Cruz,
A. Santos-Exposito, J. J. Marrero-Tellado, P. de Armas and
F. Garcıa-Tellado, Chem.–Eur. J., 2005, 11, 3502.
pez-Tosco, F. Cruz-Acosta, G. Mendez-Abt
´ ´
´
´
two exocyclic conjugated aliphatic esters, and thus,
a
´
(Z,Z)-1,3-diene function. Interestingly, the reaction network
forms two C–O and four C–C bonds, while it breaks only two
C–C bonds. Finally, and not less important, the in situ
generation of these allenes is mild enough to be compatible
´
6 The number of reported examples in the bibliography for these
units is scarce. For selected examples, see: (a) T. Schwier,
A. W. Sromek, D. M. L. Yap, D. Chernyak and V. Gevorgyan,
J. Am. Chem. Soc., 2007, 129, 9868 and references cited therein;
(b) C. Bee and M. A. Tius, Org. Lett., 2003, 5, 1681;
(c) M. R. Sestrick, M. Miller and L. S. Hegedus, J. Am. Chem.
Soc., 1992, 114, 4079.
with
a large number of organic functionalities and it
constitutes an excellent workbench for the discovery of new
complexity generating processes. The efficient formation of
enamine 4 is a good example of this property. This issue is
being developed in our lab.
7 (a) D. Tejedor, A. Santos-Expo
Chem.–Eur. J., 2007, 13, 1201; (b) D. Gonzalez-Cruz,
D. Tejedor, P. de Armas and F. Garcıa-Tellado, Chem.–Eur. J.,
2007, 13, 4823; (c) D. Tejedor, F. Garcıa-Tellado, J. J. Marrero-
sito and F. Garcıa-Tellado,
´ ´
´
This work was supported by the Spanish Ministerio de
´
Tellado and P. de Armas, Chem.–Eur. J., 2003, 9, 3122.
8 For a precedent for this rearrangement: A. N. Pillai, C. H. Suresh,
C. H and V. Nair, Chem.–Eur. J., 2008, 14, 5851.
Educacion y Ciencia and the European Regional Development
´
Fund (CTQ2005-09074-C02-02), the Spanish MSC ISCIII
(RETICS RD06/0020/1046), CSIC (Proyecto Intramural
9 ABB’ three-component reaction is defined as a chemical process
that utilizes two different components (A and B) to give a product
which incorporates into its structure one unit of component A and
two chemo-differentiated units of component B (B and B’). For full
details and more examples of this type of multicomponent reac-
Especial 200719) and Fundacio
Investigacion del Cancer (FICI-G.I.N108/2007). The authors
thank technicians Sonia Rodriguez Dıaz and Aida Sanchez
Lopez for preparative work.
´
n Instituto Canario de
´
´
´
´
´
´
tions: D. Tejedor and F. Garcıa-Tellado, Chem. Soc. Rev., 2007,
36, 484.
Notes and references
10 (a) A. Rauk, Orbital Interaction Theory of Organic Chemistry, John
Wiley and Sons, New York, 1994, pp. 118; (b) D. Nori-Shargh,
F. Deyhimi, J. E. Boggs, J.-B. Saeed and R. Shakibazadeh, J. Phys.
Org. Chem., 2007, 20, 355.
z Representative procedure: 1,2-diketone 2a (3.00 mmol) and methyl
propiolate (3a) (3.00 mmol) are dissolved in CH2Cl2 (5 mL) and the
solution is cooled to 0 1C in an ice bath. Et3N (0.30 mmol) is added
and the reaction is allowed to react overnight without further cooling.
Et3N (3 mmol) is added and the reaction is allowed to react for one
additional day (this step simplifies the isolation of 6aa while 7aa
cis/trans transforms into 8aa. Purification of products 6aa trans/cis
and 8aa was carried out by flash column chromatography (silica gel,
n-hexane–EtOAc 80 : 20 to 60 : 40). Cyclobutane 6aa trans-isomer
(major): white solid, mp = 181.0–182.6 1C; 1H NMR (400 MHz,
CDCl3, 25 1C): d = 3.37 (s, 6H), 6.86 (s, 2H), 7.16–7.29 (m, 10H),
11 (a) For an interesting example of allene dimerization involving
stabilized bisallyl biradical intermediates see: E. V. Banide,
Y. Ortin, C. M. Seward, L. E. Harrington, H. Muller-Bunz and
¨
M. J. McGlinchey, Chem.–Eur. J., 2006, 12, 3275 and references
cited therein. For mechanistic considerations on the biradical
mechanism, see: (b) M. Christl, S. Groetsch and K. Gunter, Angew.
¨
Chem., Int. Ed., 2000, 39, 3261 and references cited therein.
12 A theoretical study of this reaction is undergoing in our group.
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This journal is The Royal Society of Chemistry 2009
2370 | Chem. Commun., 2009, 2368–2370