Reaction of two different α-allenols in a heterocyclization/cross- coupling sequence: Convenient access to functionalized buta-1,3-dienyl dihydrofurans

Article abstract of DOI:10.1002/anie.200601055

(Chemical Equation Presented) In a single step a highly functionalized buta-1,3-dienyl-substituted 2,5-dihydrofuran unit can be formed from two different α-allenol derivatives through a novel heterocyclization/cross- coupling sequence (see scheme). The re

Full text of DOI:10.1002/anie.200601055

Angewandte
Chemie
Cross-Coupling Reactions
DOI: 10.1002/anie.200601055
Reaction of Two Different a-Allenols in a
Heterocyclization/Cross-Coupling Sequence:
Convenient Access to Functionalized
Buta-1,3-dienyl Dihydrofurans**
Benito Alcaide,* Pedro Almendros,* and
Teresa Martínez del Campo
In memory of Marcial Moreno-Maæas
Dihydrofurans are an important class of oxygenated hetero-
cycles that have attracted much interest because of the
biological activity of naturally occurring representatives. They
[*] Prof. Dr. B. Alcaide, Dipl.-Chem. T. Martínez del Campo
Departamento de Química Orgµnica I
Universidad Complutense de Madrid
Facultad de Química, 28040-Madrid (Spain)
Fax: (+34)91-394-4103
E-mail: alcaideb@quim.ucm.es
Dr. P. Almendros
Instituto de Química Orgµnica General
Consejo Superior de Investigaciones Científicas
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax: (+34)91-564-4853
E-mail: iqoa392@iqog.csic.es
[**] Support for this work by the DGI-MCYT (Project BQU2003-07793-
C02-01) is gratefully acknowledged. T.M.C. thanks the MEC for a
predoctoral grant. We thank Rocio Carrascosa for her help in the
preparation of some materials.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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are also useful building blocks in organic synthesis.[1] Allenes,
Table 1: Indium-mediated Barbier-type carbonyl allenylation of
aldehydes 1.
once a rarity, have become established as an extremely useful
functional group in modern synthetic organic chemistry.[2] In
particular, the transition-metal-catalyzed cyclization of func-
tionalized allenes that contain a nucleophilic center has
attracted much attention.[3] However, the cross-coupling of
two different allenes has scarcely been mentioned; only Ma
and co-workers have described reactions of this type in recent
reports on the coupling of 2,3-allenoic acids with 2,3-allenols
or 1,2-allenyl ketones.[4] In continuation of our research in
heterocyclic and allene chemistry,[5] we report herein an
efficient cross-coupling reaction between two different a-
allenol derivatives to give functionalized dihydrofurans in a
single step.
The precursors for dihydrofuran formation, a-allenols 2a–
j, were readily prepared in good overall yield from the
appropriate carbaldehyde 1a–i (Table 1) through a regiose-
lective indium-mediated Barbier-type carbonyl-allenylation
reaction in an aqueous medium.[6] When the indium-mediated
allenylation of enantiomerically pure aldehydes 1 did not take
place with complete diastereoselectivity, the diastereomeric
a-allenols 2 and anti-2 could be separated readily by gravity
flow chromatography.[7,8]
Some a-allenols 2 were protected as the corresponding
acetates or p-nitrobenzoate 3a–c by using standard proce-
dures. Initial studies evaluated the effectiveness of different
a-allenol derivatives and catalysts. Aromatic a-allenols were
selected as initial test substrates. Our early efforts focused on
the reaction between a-allenol 2d and a-allenol 2b protected
as its acetate 3a (Ar= p-MeC6H4). The use of AuCl3 resulted
in a complex mixture of unidentified products. Fortunately,
palladium catalysts such as Pd(OAc)2 and PdCl2 in the
absence of an oxidant effectively promoted this new hetero-
cyclization/cross-coupling sequence in solvents such as MeCN
and DMF at ambient temperature (Scheme 1, Table 2). It was
Entry
1
R1CHO
R2
Product
Yield [%][a]
99
Me
1a
(Æ)-2a
2
3
Me
Me
66
97
1b
1c
(Æ)-2b
(Æ)-2c
4
5
6
Me
Me
Me
77
96
58
1d
1e
(Æ)-2d
(Æ)-2e
1 f
(Æ)-2 f
7
Me
Me
Ph
67
70
74
68
(À)-1g
(+)-1h
(À)-1i
(À)-1i
(À)-2g
(+)-2h
(+)-2i
(+)-2j
8
Scheme 1. Synthesis of the 2,3,4-trisubstituted 2,5-dihydrofuran 4a
through palladium(II)-catalyzed heterocyclization/cross-coupling of a-
allenol derivatives 2d and 3a. PMP=4-MeOC6H4.
9
discovered that the treatment of a-allenol 2d with PdCl2
(5 mol%) in DMF (0.2m) led to the desired cyclization
adduct 4a in an impressive 90% yield when the protected a-
allenol 3a was used as the coupling partner (Table 2, entry 4).
No homodimerization products were detected. Furthermore,
the domino cyclization reaction is totally regioselective, with
exclusive formation of the five-membered oxacycle. The free
a-allenol component undergoes heterocyclization to give a
2,5-dihydrofuran, and the protected a-allenol cross-coupling
partner becomes attached to the C4 carbon atom of the
oxacycle as a substituted buta-1,3-diene functionality.
10
Me
[a] Yield of the pure, isolated product with correct analytical and spectral
data. Bn=benzyl, PMP=4-MeOC6H4.
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Table 2: Reaction of a-allenol derivatives 2d and 3a under different
conditions: palladium(II)-catalyzed heterocyclization/cross-coupling.[a]
Entry
Catalyst[a]
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
AuCl3
CH2Cl2
DMF
MeCN
DMF
24
24
48
4
[c]
10
[c]
90
55
Pd(OAc)2
Pd(OAc)2
PdCl2
PdCl2
MeCN
9
[a] All reactions were conducted with5 mol% of the catalyst. [b] Yield of
the pure, isolated product with correct analytical and spectral data. The
disappearance of the starting material 2d was observed in all cases. [c] A
complex mixture of unidentified products was obtained. DMF=N,N-
dimethylformamide.
To further probe the scope of this transformation, we
tested the tolerance of the PdII-catalyzed heterocyclization/
cross-coupling to structural alterations to both the a-allenol
and protected a-allenol moieties. As expected, g-allenols
were found to be completely unreactive under these con-
ditions. It was possible to couple chemoselectively the
protected a-allenol 3a with compound 2e, which contains
both a- and g-allenol functionalities. None of the coupled g-
allenol was obtained, but instead the product 4b was formed
exclusively by selective coupling to the a-allenol moiety
(Scheme 2). Next, we decided to use heteroaromatic a-allenol
derivatives as the reactants (Scheme 2). Buta-1,3-dienyl
dihydrofuran 4c was obtained in a reasonable yield from 2 f
and 3a.
Satisfied with the above results, we set out to evaluate the
cross-coupling process for substrates that contain stereocen-
ters. Thus, a series of aliphatic enantiomerically pure a-allenol
derivatives were tested (Scheme 2). The a-allenols 2g–j were
converted smoothly into the desired functionalized optically
active dihydrofuran derivatives 4d–g. These results indicate
that stereochemical integrity is conserved at the carbinol
carbon atom of the allenol as well as at the distal stereocen-
ters in the course of the allene–allene cross-coupling process.
The sterically more encumbered phenyl-substituted allenol
derivative 2i readily underwent the cyclization/coupling
sequence under identical conditions. Remarkably, the heter-
ocyclization/cross-coupling reaction between the 2-azetidi-
none-tethered allenol 2j and the 1,3-dioxolane-tethered
protected allenol 3c gave the b-lactam–dihydrofuran hybrid
4g in 59% yield. Thus, it was shown that the heterocycliza-
tion/cross-coupling of two different a-allenol derivatives can
be considered in the planning of a complex synthetic route.
In this study, the assignment of the configuration of the
newly formed 1,3-diene moiety of dihydrofurans 4 was a
crucial problem, which we thought we might solve conven-
iently by means of X-ray crystallography. However, the
reluctance of most of these compounds to form suitable
crystals for X-ray analysis prompted us to consider an
alternative method. We focused our attention on NMR
spectroscopic methods for the determination of the geometry
of substituted alkenes. Indeed, qualitative homonuclear NOE
difference spectra allowed us to assign the E configuration as
depicted in Schemes 1 and 2.
Scheme 2. Synthesis of 2,3,4-trisubstituted 2,5-dihydrofurans 4b–g through
palladium(II)-catalyzed heterocyclization/cross-coupling of a-allenol derivatives
2 and 3. Reagents and conditions: a) PdCl2 (5 mol%), DMF, RT; 4b: 6 h(at
08C); 4c: 2.5 h; 4d: 4 h ;4e: 4 h ;4 f: 4 h(at 0 8C); 4g: 5 h . Ar=p-tolyl,
PMP=4-MeOC6H4, PNP=4-NO2C6H4.
reaction between a-allenols and protected allenols. A possi-
ble catalytic cycle is shown in Scheme 3. Regioselective
palladium(II)-mediated intramolecular oxypalladation of the
free allenol component 2 generates a palladadihydrofuran
intermediate 5, which then undergoes a cross-coupling
reaction with the protected allenol partner 3. The coupling
of vinyl palladium(II) intermediates 5 with protected allenols
3 to give species 6 takes place regioselectively at the central
allene carbon atom of 3. Finally, trans-b-deacyloxypalladation
generates a buta-1,3-dienyl dihydrofuran 4 in a highly
stereoselective manner with exclusive formation of the
E isomer and concomitant regeneration of the palladium(II)
species.
In conclusion, we have developed a mild, palladium(II)-
catalyzed heterocyclization/cross-coupling reaction to form
2,3,4-trifunctionalized 2,5-dihydrofurans from two different
a-allenols that is applicable to compounds with a wide range
of substitution patterns. As our studies indicate high levels of
regioselectivity as well as the possibility of using optically
The formation of buta-1,3-dienyl dihydrofurans 4 can be
rationalized through a novel heterocyclization/cross-coupling
Angew. Chem. Int. Ed. 2006, 45, 4501 –4504
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Communications
[1] For selected reviews, see: a) T. G. Kilroy, T. P. OꢀSullivan, P. J.
Guiry, Eur. J. Org. Chem. 2005, 4929; b) X.-L. Hou, Z. Yang, K.-S.
Yeung, H. N. C. Wong in Progress in Heterocyclic Chemistry,
Vol. 17 (Eds.: G. W. Gribble, J. A. Joule), Elsevier, Oxford, 2005,
pp. 142– 171; c) X.-L. Hou, Z. Yang, K.-S. Yeung, H. N. C. Wong
in Progress in Heterocyclic Chemistry, Vol. 16 (Eds.: G. W.
Gribble, J. A. Joule), Elsevier, Oxford, 2004, pp. 156 – 197;
d) The Chemistry of Heterocycles: Structure, Reactions, Syntheses,
and Applications (Eds.: T. Eicher, J. S. Hauptmann), Wiley-VCH,
Weinheim, 2003; e) B. M. Fraga, Nat. Prod. Rep. 1992, 9, 217;
f) A. T. Merrit, S. V. Ley, Nat. Prod. Rep. 1992, 9, 2 43; g) K.
Nakanishi, Natural Products Chemistry, Kodansha Academic,
New York, 1974; h) A. I. Meyers, Heterocycles in Organic Syn-
thesis, Wiley, New York, 1974; i) F. M. Dean in Advances in
Heterocyclic Chemistry, Vol. 30 (Ed.: A. R. Katritzky), Academic,
New York, 1982, pp. 167 – 238; j) H. Heaney, J. S. Ahn in
Comprehensive Heterocyclic Chemistry II, Vol. 2 (Ed.: C. W.
Bird), Elsevier, 1995, chap. 2.06, pp. 297 – 350.
[2] For general and comprehensive reviews, see: a) S. Ma, Chem. Rev.
2005, 105, 2829; b) Modern Allene Chemistry (Eds.: N. Krause,
A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004; c) R. Zimmer,
C. U. Dinesh, E. Nandanan, F. A. Khan, Chem. Rev. 2000, 100,
3067.
Scheme 3. Mechanistic explanation for the PdII-catalyzed heterocycliza-
tion/cross-coupling of a-allenols and protected a-allenols.
[3] For selected reviews, see: a) A. Hoffmann-Röder, N. Krause, Org.
Biomol. Chem. 2005, 3, 387; b) S. Ma, Acc. Chem. Res. 2003, 36,
701; c) R. W. Bates, V. Satcharoen, Chem. Soc. Rev. 2002, 31, 12 ;
d) A. S. K. Hashmi, Angew. Chem. 2000, 112, 3737; Angew. Chem.
Int. Ed. 2000, 39, 3590.
[4] a) S. Ma, Z. Gu, J. Am. Chem. Soc. 2005, 127, 6182; b) S. Ma, Z.
Gu, Z. Yu, J. Org. Chem. 2005, 70, 6291; c) S. Ma, Z. Yu, Chem.
Eur. J. 2004, 10, 2078; d) S. Ma, Z. Yu, Angew. Chem. 2002, 114,
1853; Angew. Chem. Int. Ed. 2002, 41, 1775.
active substrates, this is a potentially attractive method for
organic synthesis. Current work is aimed at exploring the
scope of the reaction with respect to both a-allenols and
protected a-allenols, and identifying applications in complex-
molecule synthesis.
Experimental Section
[5] a) B. Alcaide, P. Almendros, C. Aragoncillo, M. C. Redondo,
M. R. Torres, Chem. Eur. J. 2006, 12, 1539; b) B. Alcaide, P.
Almendros, J. M. Alonso, Chem. Eur. J. 2006, 12, 2 874; c) B.
Alcaide, P. Almendros, R. Rodríguez-Acebes, J. Org. Chem. 2006,
71, 2346 – 2351; d) B. Alcaide, P. Almendros, R. Rodríguez-
Acebes, Chem. Eur. J. 2005, 11, 5708; e) B. Alcaide, P. Almendros,
G. Cabrero, M. P. Ruiz, Org. Lett. 2005, 7, 3981; f) B. Alcaide, P.
Almendros, R. Rodríguez-Acebes, J. Org. Chem. 2005, 70, 2713.
[6] a) B. Alcaide, P. Almendros, C. Aragoncillo, M. C. Redondo, Eur.
J. Org. Chem. 2005, 98; b) B. Alcaide, P. Almendros, C.
Aragoncillo, Chem. Eur. J. 2002, 8, 1719; c) M. B. Isaac, T.-H.
Chan, J. Chem. Soc. Chem. Commun. 1995, 1003; the a-allenol
(À)-2g had been prepared previously as a mixture of regio- and
diastereoisomers by stannane chemistry: d) A. McCluskey, I. W.
Muderawan, Muntari, D. J. Young, J. Org. Chem. 2001, 66, 7811.
[7] Complete diastereoselectivity was observed in all cases except for
the reaction of the aldehyde (+)-1h.
[8] The configuration at the carbinol stereogenic center of the
enantiomerically pure a-allenols 2g–j was established by com-
parison of the 1H NMR chemical shifts of the corresponding
acetylmandelates according to the method developed by Trost
and co-workers: a) B. M. Trost, J. L. Belletire, S. Godleski, P. G.
McDougal, J. M. Balkovec, J. J. Baldwin, M. E. Christy, G. S.
Ponticello, S. L. Varga, J. P. Springer, J. Org. Chem. 1986, 51, 2370;
b) K. M. Sureshan, T. Miyasou, S. Miyamori, Y. Watanabe,
Tetrahedron: Asymmetry 2004, 15, 3357; for a review, see:
c) J. M. Seco, E. Quiꢁoꢂ, R. Riguera, Chem. Rev. 2004, 104, 17.
General procedure: PdCl2 (0.005 mmol) was added to a stirred
solution of an a-allenol 2 (0.10 mmol) and the appropriate protected
a-allenol 3 (0.30 mmol) in N,N-dimethylformamide (1.0 mL). The
reaction mixture was stirred under an argon atmosphere until the
starting material had disappeared (monitored by TLC). Water
(0.5 mL) was then added, and the reaction mixture was extracted
with ethyl acetate (3 ” 4 mL). The organic phase was washed with
water (2” 2mL), dried (MgSO ), and concentrated under reduced
4
pressure. Chromatography of the residue with mixtures of hexanes
and ethyl acetate as the eluent gave analytically pure 2,3,4-trisub-
stituted 2,5-dihydrofurans 4. (+)-4e: Prepared from (+)-2h (55 mg,
0.19 mmol); chromatographic purification of the crude product
(hexanes/ethyl acetate 20:1) gave (+)-4e (64 mg, 75%) as a colorless
oil; [a]D = + 45.5 (c = 2.1, CHCl3); 1H NMR (300 MHz, CDCl3,
258C): d = 7.48 (d, J = 9.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.97 (d,
J = 8.0 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 6.17 (br s, 1H), 5.28–5.30 (m,
1H), 5.21 (d, J = 1.2Hz, 1H), 4.72(d, J = 5.6 Hz, 1H), 4.67–4.69 (m,
2H), 4.58 (d, J = 1.2Hz, 1H), 4.55–4.57 (m, 1H), 3.67 (s, 3H), 3.65 (s,
3H), 2.33 (d, J = 0.7 Hz, 3H), 1.84 (d, J = 1.2Hz, 3H), 1.66–1.68 ppm
(m, 3H); 13C NMR (75 MHz, CDCl3, 2 58C): d = 164.9, 156.3, 144.2,
136.2, 135.9, 134.9, 134.5, 133.5, 130.4, 129.3, 129.1, 128.6, 118.9, 114.2,
114.1, 86.9, 82.7, 77.6, 61.7, 59.4, 55.3, 21.1, 15.1, 12.0 ppm; IR
(CHCl3): n˜ = 1742cm À1; MS (ESI): m/z (%): 446 (100) [M+H]+, 445
(11) [M]+; elemental analysis calcd (%) for C28H31NO4 (445.5): C
75.48, H 7.01, N 3.14; found: C 75.72, H 7.06, N 3.10.
Received: March 16, 2006
Published online: June 7, 2006
Keywords: allenes · cross-coupling · domino reactions ·
.
heterocycles · palladium
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