Chemodivergence in alkene/allene cycloetherification of enallenols: Iron versus noble metal catalysis

Article abstract of DOI:10.1002/chem.200801166

A method was proposed for chemo-differentiation between an alkene and an allene moiety using iron- or precious-metal catalysis. Chemodivergence in alkene and allene were also reported by cycloetherification of enallenols. It was observed that racemic enallenols were prepared from the 4-oxoazetidine-2- carbaldehyde through regio-controlled indium-mediated Barbier carbonyl-allenylation reactions. Prenylation and allenylation process were used to prepare an optically active non-β-lactam precursors from (R)-2,3-O-isopropylideneglyceraldehyde. The effects of different metal catalysis in the chemoselectivity of the hydroalkoxylation reaction were also observed during the study. The Lewis-acid catalyzed cyclization of unsaturated alcohol was examined in the presence of different metallic chlorides.

Full text of DOI:10.1002/chem.200801166

DOI: 10.1002/chem.200801166
Chemodivergence in Alkene/Allene Cycloetherification of Enallenols:
Iron versus Noble Metal Catalysis
Benito Alcaide,*[a] Pedro Almendros,*[b] and Teresa Martínez del Campo[a]
Dedicated to Prof. Dr. Carmen Pardo on the occasion of her 65th birthday and retirement
A resplendent age of metal catalysis has bloomed in the
last years. Particularly, gold and platinum complexes are ex-
lyzed chemodistinguishing (alkene versus allene) oxycycliza-
tion of enallenols. The results of our investigation using
iron, platinum, and gold salts form the subject of this paper.
The structures of enallenols that we synthesized and used
for chemodifferentiation are shown in Figure 1. Racemic
enallenols 1a–d were readily prepared beginning from the
appropriate 4-oxoazetidine-2-carbaldehyde via regiocontrol-
led indium-mediated Barbier-type carbonyl–allenylation re-
action in aqueous media using our previously described
methodology.[6] Optically active non-b-lactam precursors
syn-1e and anti-1e were prepared from (R)-2,3-O-isopropy-
lideneglyceraldehyde, via metal-mediated sequential preny-
lation and allenylation, followed by protecting groups ma-
nipulation (Scheme S1, see Supporting Information).
À
À
cellent catalysts for the formation of C C and C heteroa-
tom bonds.[1] Recently, iron salts have emerged as powerful
alternatives in viewof their inexpensiveness and environ-
mental friendliness.[2] On the other hand, allenes are a class
of compounds with two cumulative carbon-carbon double
bonds, which are versatile synthetic intermediates in organic
synthesis.[3] A process which involves a selective chemical re-
action, even if the structure of the substrate suggests numer-
ous possibilities for reactivity, represents an attractive strat-
egy. These substrates must have diverse reactive sites, at
which different transformations can take place. In this con-
text, carbon–heteroatom cyclization is of major interest. Al-
though many efforts have been made in these fields, to the
best of our knowledge, the chemodivergent metal-catalyzed
heterocyclization of alcohols bearing both an allene and an
alkene center has not yet been reported.[4] The selective
preparation of different oxacycles from the same enallenol
requires two appropriate catalytic systems that are capable
of chemodifferentiating between various alkene functions
and developing a dissimilar role for each partner. Otherwise,
a mixture of at least two different products is possible. As
part of a program aimed at expanding the use of metal cat-
alysis in heterocyclic and allene chemistry,[5] we focused on
finding a solution to the challenging problem of metal-cata-
Figure 1. Structures of enallenols 1a–e. PMP=4-MeOC6H4.
Initially, we planned to study the cyclization of olefinic a-
allenol 1a under different metal catalysis. In a first series of
runs, the cyclization of enallenol 1a was catalyzed by pre-
[a] Prof. Dr. B. Alcaide, Dipl.-Chem. T. Martínez del Campo
Departamento de Química Orgµnica I, Facultad de Química
Universidad Complutense de Madrid, 28040 Madrid (Spain)
Fax : (+34) 91-3944103
cious metal salts (AgNO3, [PtCl2(CH2=CH2)]2, and AuCl3)
G
to afford the allene cycloisomerization adduct 2a as the sole
isomer (Table 1, entries 1–3).[7] Further studies were de-
signed to test the effects of different metal catalysis in the
chemoselectivity of the hydroalkoxylation reaction. The pos-
sibilities of Lewis-acid catalyzed cyclization of unsaturated
alcohol 1a were first studied in the presence of different
metallic chlorides.[8] The reactivities of BiCl3, InCl3, and
HfCl4, were examined under catalytic amounts (20 mol%)
in refluxing dichloromethane. However, complete conver-
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros
Instituto de Química Orgµnica General
Consejo Superior de Investigaciones Científicas
CSIC, Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34) 91-5644853
E-mail: Palmendros@iqog.csic.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801166.
1
sion of enallenol 1a was not detected by TLC and H NMR
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COMMUNICATION
Table 1. Chemodivergent cycloetherification reaction of enallenol 1a
under modified metal-catalyzed or metal-promoted conditions.[a]
Entry Catalyst (mol%)
Conditions[a]
C
Yield
[%][b]
1
2
3
AuCl3 (5)
AgNO3 (100)
A
B
C
100:0
100:0
100:0
65
55
63
A
N
4
5
6
7
8
BiCl3 (150)
InCl3 (150)
HfCl4 (150)
FeCl3 (10)
HCl (10)
D
D
D
E
F
0:100
0:100
0:100
0:100
0:100
60
60
70
83
30
Scheme 1. Chemodivergent metal-catalyzed preparation of dihydrofurans
2 and tetrahydrofurans 3. i) 5 mol% AuCl3, CH2Cl2, RT, 2b: 1 h; 2c:
[a] Reaction conditions. A: 5 mol% AuCl3, CH2Cl2, RT, 1 h; B: 1 equiv
AgNO3, acetone/H2O 4:1, D, 0.5 h; C: 5 mol% [PtCl2(CH2=CH2)]2, 10
AHCTREUNG
1.5 h. ii) 5 mol% [PtCl2(CH2=CH2)]2, 10 mol% TDMPP, CH2Cl2, RT, 2b:
A
mol% TDMPP, CH2Cl2, RT, 6 h; D: 1.5 equiv MClx, CH2Cl2, sealed tube,
708C, BiCl3: 52 h, InCl3: 56 h, HfCl4: 48 h; E: 10 mol% FeCl3, DCE,
sealed tube, 808C, 24 h; F: 10 mol% HCl, DCE, sealed tube, 808C, 24 h.
[b] Yield of pure, isolated product with correct analytical and spectral
data. PMP=4-MeOC6H4. TDMPP=tris(2,6-dimethoxyphenyl)phosphine.
DCE=1,2-Dichloroethane.
6 h; 2c: 12 h. iii) 10 mol% FeCl3, DCE, sealed tube, 808C, 3b: 24 h; 3c:
20 h.
could be easily separated by gravity flowchromatography.
Full chirality transfer has been accomplished from the start-
ing enallenols syn-1e and anti-1e.
analysis of the crude reaction mixtures. Complete conver-
sion was observed by heating a solution of enallenol 1a in
dichloromethane at 708C in a sealed tube using 1.5 equiva-
lents of the metallic chloride (Table 1, entries 4–6). Since
iron-catalyzed reactions have captured much recent atten-
tion, we decided to test the catalytic efficiency of FeCl3. To
our delight, this FeIII salt was able to chemospecifically cata-
lyze the cyclization in favour of the alkene component to ex-
clusively afford the b-lactam-tetrahydrofuran hybrid 3a in
83% isolated yield (Table 1, entry 7).[9] The lower limit of
the iron-catalyst loading was 10 mol%. It deserves to be
mentioned that the allene moiety is not altered under the
oxycyclization reaction conditions. Besides the total chemo-
control, the reaction was regiospecific and only the five-
membered ring ether was formed, without the presence of
the isomeric six-membered ring. A control experiment that
would rule out the participation of HCl as the active catalyst
was undertaken. A strong difference of reactivity using
FeCl3 and HCl as catalysts was observed (compare entries 7
and 8). When enallenol 1a was treated with hydrochloric
acid (entry 8) with the same catalyst ratio, a 30% yield of
3a was obtained; highlighting the efficiency of FeCl3 in the
catalytic process.
Next, we decided to test these selective cycloetherification
reactions in substrates 1c and 1d. As expected, both the
gold- and platinum-catalyzed oxycyclizations did totally con-
trol the reaction toward the corresponding dihydrofurans 2d
and 2e (Scheme 2). Worthy of note, in contrast to the iron-
Scheme 2. Chemodivergent metal-catalyzed preparation of dihydrofurans
2 and morpholinones 4. i) 5 mol% AuCl3, CH2Cl2, RT, 2d: 1.5 h; 2e: 2 h.
ii) 5 mol% [PtCl2(CH2=CH2)]2, 10 mol% TDMPP, CH2Cl2, RT, 2d: 4 h;
A
2e: 5 h. iii) 10 mol% FeCl3, DCE, sealed tube, 808C, 4a: 1.5 h; 4b: 2.5 h.
catalyzed reaction of d-olefinic a-allenols 1a and 1b which
lead to tetrahydrofurans, the reaction of g-olefinic a-allenols
1c and 1d under identical conditions gave allenic morpho-
lin-3-ones 4a and 4b as the sole products (Scheme 2),[10]
through an exclusive 4-trig cyclization by attack of the hy-
droxy group to the proximal alkene carbon followed by b-
lactam ring opening.[11] Additionally, we performed an ex-
periment in which enallenol 1c was treated with 10 mol%
HCl and we observed the formation of morpholin-3-one 4a
To further probe the scope of these chemodivergent trans-
formations, we examined the olefinic phenylallenol 1b and
the non-b-lactam allenols 1e (allenol 1e was prepared as an
inseparable syn/anti mixture 70:30). Under similar condi-
tions, the corresponding dihydrofurans 2 and tetrahydrofur-
ans 3 were chemospecifically obtained in good yields by pre-
cious metal and iron catalysis, respectively (Scheme 1). For-
tunately, the diastereomeric adducts 2ca, 2cb, 3ca, and 3cb,
from the selective cyclization of allenols syn-1e and anti-1e,
in very lowyield (10%). This result indicates that FeCl is
3
the real catalytic species of our reactions.[12]
Probably, AuCl3 and [PtCl2(CH2=CH2)]2 enhance the reac-
A
tivity of the enallenol moiety through selective complexa-
tion to the 1,2-diene site;[13] while FeCl3 may activate the
Chem. Eur. J. 2008, 14, 7756 – 7759
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B. Alcaide, P. Almendros and T. Martínez del Campo
enallenol group by coordination to the hydroxyl moiety. The
formation of morpholin-3-ones 4 should proceed by a path-
Keywords: alkenes
heterocycles · iron
·
allenes
·
chemoselectivity
·
À
way that involve full, o partial, C O bond formation at the
b-lactam stage in the transition state. The hydroxyl–iron
complex 5 is formed initially through coordination of the
iron trichloride to the oxygen atom of enallenols 1. Accord-
ingly, the Lewis acid FeCl3 considerably increases the
Brønsted acidity of the hydroxyl protons of g-olefinic a-alle-
nols 1. Next, chemo- and regioselective intramolecular pro-
tonation of the alkene moiety with concomitant 4-exo oxy-
cyclization forms species 6, which rapidly evolves to inter-
mediates 7 through selective b-lactam ring cleavage. Finally,
demetalation affords heterocycles 4 and regenerates the iron
catalyst (Scheme 3). An alternative pathway involving coor-
dination of FeCl3 to the olefinic double bond cannot be
ruled out at the moment. The morpholin-3-one formation
must be driven by relief of the strain associated with the
four-membered ring on forming a more stable six-membered
ring.
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In conclusion, the chemodifferentiation between an
alkene and an allene moiety using iron- or precious-metal
catalysis, respectively, was presented, which showed unpre-
cedented chemodivergence. Besides, an iron-catalyzed
tandem cycloetherification/b-lactam ring cleavage to afford
allenic morpholin-3-ones was accomplished. Mechanistic
consideration and reactivity of differently substituted enalle-
nols are under investigation.
Acknowledgements
Support for this work by the DGI-MEC (Project CTQ2006-10292), Co-
munidad Autónoma de Madrid (CCG-07-UCM/PPQ-2308), and Univer-
sidad Complutense de Madrid (Grant GR74/07). T.M.C. thanks MEC for
a predoctoral grant.
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Chemodivergent Metal-Catalyzed Oxycyclization Of Enallenols
COMMUNICATION
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2
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[12] The role of the iron salt seems obvious, and a Brønsted acid cataly-
sis seems very unlikely.
[10] The search for newsyntheses of morpholin-3-ones is of interest be-
cause of the biological activity of these molecules. For selected refer-
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ates in organic synthesis; see, for example: c) S. V. Pansare, B. A.
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[13] Worthy of note, [PtCl2(CH2=CH2)]2 has been reported to catalyze
A
the cyclization of both g- and d-hydroxy alkenes and allenes. For al-
lenes, see: a) Z. Zhang, C. Liu, R. E. Kinder, X. Han, H. Qian,
R. A. Widenhoefer, J. Am. Chem. Soc. 2006, 128, 9066. For alkenes,
see: b) see ref. [8e].
Received: June 24, 2008
Published online: July 18, 2008
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