Water freezing as a regiocontrol element in the multicomponent assembly of cyclic enones

Article abstract of DOI:10.1002/chem.201404670

Regioselective synthesis of dialkoxy 2-cyclopentenones and 2-cyclohexenones with novel substitution patterns has been accomplished by the one-pot combination of three simple starting materials (chromium carbene complex, Weinreb acetamide lithium enolate a

Full text of DOI:10.1002/chem.201404670

DOI: 10.1002/chem.201404670
Communication
&
Organic Synthesis |Hot Paper|
Water Freezing as a Regiocontrol Element in the Multicomponent
Assembly of Cyclic Enones
[
a]
Raquel De la Campa and Josefa Flꢀrez*
Chem. Eur. J. 2014, 20, 1 – 7
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Abstract: Regioselective synthesis of dialkoxy 2-cyclopen-
tenones and 2-cyclohexenones with novel substitution
patterns has been accomplished by the one-pot combina-
tion of three simple starting materials (chromium carbene
complex, Weinreb acetamide lithium enolate and 1-alkoxy-
allenyllithium) under either anhydrous conditions or
water-promoted solidification of the reaction mixture.
These results revealed an unprecedented water-freezing
effect that plays a key role to completely reverse the re-
gioselectivity of the intramolecular carbometalation of an
allene moiety.
Scheme 1. Three-component synthesis of novel 2-cyclopentenones and 2-cy-
clohexenones by sequential coupling of three starting materials.
synthesis of these significant families of compounds consti-
tutes an important ongoing challenge. In this report, we dis-
close a complementary and selective multicomponent con-
struction of two types of cyclic conjugated a-alkoxyenones
with a unique substitution pattern.
The sequential coupling reaction of a Fischer carbene complex,
a lithium enolate and an unsaturated organomagnesium re-
agent represents a multicomponent cyclization process that is
able to rapidly generate molecular complexity and diversity in
Improvements in terms of reaction rate and efficiency have
been reported by high pressure induced by external water-
[
1,2]
a single synthetic operation.
This basic concept has proved
[11]
to be a useful strategy for the modular generation of small or-
ganic molecules. The first examples of this multicomponent
synthetic technique were achieved in our group and allowed
the diastereoselective synthesis of pentasubstituted cyclopen-
tanols or tetrasubstituted 1,4-cyclohexanediols by combination
of a chromium alkoxycarbene complex, a ketone or ester lithi-
freezing or frozen solvent conditions. But, as far as we are
aware, the change of the reactivity of an organometallic inter-
mediate as a consequence of the solidification of the reaction
mixture by water addition at low temperature (water-freezing
effect) is unknown.
For the preliminary experiments we chose N-methoxy-N-
methyl amides (Weinreb amides, well-established as effective
[
3]
um enolate and allylmagnesium bromide. More recently, we
have described the enantioselective synthesis of 4-hydroxy-2-
[12]
acylating agents) and lithiated alkoxyallenes. Lithium enolate
2 was prepared by treatment of N-methoxy-N-methylaceta-
mide with either lithium diisopropylamide (LDA; THF, À788C,
[
4]
[5]
cyclohexenones and 6–5 bicyclic g-alkylidene-2-butenolides
by coupling of a methoxycarbene complex of chromium,
a chiral non-racemic imide lithium enolate and an initially pre-
pared propargylic organomagnesium reagent. In this context,
we became interested in developing new multicomponent
cyclization methodologies by using amide lithium enolates
which would allow the introduction of a ketone carbonyl
group in the corresponding cyclic structure. Here we report
the successful reaction of a Fischer carbene complex with an
amide lithium enolate and then with an 1-alkoxyallenyllithium
that selectively provides five- or six-membered-ring conjugated
enones depending on the reaction conditions (Scheme 1). In
addition, we communicate an unprecedented water-freezing
effect that promotes a total inversion of the regioselectivity in
the cyclization step.
[
13a]
30 min) or tBuLi (THF, À788C, 1 h).
1-Alkoxyallenyllithiums 3
were generated from the corresponding 1-alkoxyallene and
[14]
BuLi (THF, À788C, 30 min). Thus, the successive reaction of
a chromium methoxycarbene complex 1 with Weinreb acet-
amide lithium enolate 2 and then with an 1-alkoxyallenyllithi-
um 3a,b conducted under the reaction conditions summarized
in Table 1, led selectively, after hydrolysis and decoordination
[
a]
Table 1. Regioselective synthesis of 2,4-dialkoxy-2-cyclopentenones 4.
Cyclic enones are both high-value building blocks in organic
synthesis and key structural features in various biologically
[
6]
active natural products and pharmaceuticals. Although nu-
merous strategies for the preparation of substituted cyclopent-
1
2
[b]
Entry
1
1
R
3
R
4
Yield [%]
1a
1b
1c
1d
1e
1 f
1a
Ph
3a
3a
3a
3a
3a
3a
3b
Me
Me
Me
Me
Me
Me
PhCH2
4a
4b
4c
4d
4e
4 f
88
96
92
89
92
77
75
[
7,8]
[9,10]
en-2-ones
and cyclohexen-2-ones
are already available,
[c]
2
2-naphthyl
2-thienyl
(E)-2-thienylCH=CH
(E)-p-ClC
PhCꢀC
Ph
the development of new and more efficient methods for the
3
[
c]
4
5
6
7
6
H
4
CH=CH
[
a] Dr. R. De la Campa, Prof. Dr. J. Flꢀrez
Departamento de Quꢁmica Orgꢂnica e Inorgꢂnica and
Instituto Universitario de Quꢁmica Organometꢂlica “Enrique Moles”
Universidad de Oviedo
4g
[
a] Reaction conditions: 1) 2 (1.2 equiv), À788C, 20 min; 2) 3 (1.6 equiv),
À788C, 30 min; À558C, 12 h and then 208C, 15 min. Lithium enolate 2
was prepared from N-methoxy-N-methylacetamide and LDA (THF, À788C,
Juliꢂn Claverꢁa 8, 33006 Oviedo, Asturias (Spain)
Fax: (+34)985-103446
E-mail: jflorezg@uniovi.es
3
0 min). [b] Yield of isolated, analytically pure product based on carbene
complex 1. [c] In this reaction lithium enolate 2 was generated by treat-
ment of N-methoxy-N-methylacetamide with tBuLi (THF, À788C, 1 h).
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404670.
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of the metal species by exposure to air and light, to the corre-
sponding 2,4-dialkoxy-2-cyclopentenone 4. This reaction pro-
ceeded very efficiently with different carbene complexes 1a–f
In the context of the experiments carried out with deuteri-
um oxide we surprisingly found that all at once addition of
5 mL of D O instead of 2 mL promoted an instantaneous and
2
1
and presented a good generality (R group=aryl, heteroaryl,
complete freezing of the reaction mixture that finally led to
alkenyl and alkynyl). The reaction of amide enolate 2 with car-
bene complexes 1 occurs almost immediately at low tempera-
ture (À788C). Allenyllithium reagent 3 was added at À788C
and after keeping the reaction mixture at À558C overnight, it
was allowed to warm to room temperature before hydrolysis
the selective formation of a structural isomer of enones 4. The
initial result is shown in Table 2, entry 1. This reaction mix-
[15]
Table 2. Regioselective synthesis of 2,5-dialkoxy-2-cyclohexenones 8 and
[
a]
9.
(
NH Cl/H O). When prior to this hydrolysis step the reaction
4 2
mixture was treated at room temperature with deuterium
oxide, dideuterated 2-cyclopentenones were readily isolated.
[
15]
As shown in Scheme 2, the sequential coupling of carbene
1
[b]
Entry
1
R
8/9
H/D
Yield [%]
[
c]
1
2
3
1a
1b
1g
1h
1i
1i
1j
1k
1a
Ph
8a
8b
8c
8d
8e
8e
8 f
8g
9
H
H
H
H
H
H
H
H
D
78 (81)
83
58
84
84
82
82
72
2-naphthyl
p-ClC
p-BrC
p-MeOC
p-MeOC
p-TBSOC
6
H
4
[
[
[
d]
e]
f]
4
5
6
7
8
9
6
H
4
6
6
H
H
4
4
[
g]
6
H
4
5-TMS-2-furyl
Ph
[
h]
77 (79% D)
[
a] Reaction conditions: 1) 2 (1.2 equiv), À788C, 20 min; 2) 3a (1.6 equiv),
2
À788C, 30 min and then À558C, 12 h; 3) D O (277 equiv), À558C (freez-
ing) and then À55 to 08C, 1 h. [b] Yield of isolated, analytically pure prod-
uct based on carbene complex 1. [c] This initial experiment was carried
out twice over to check on the result. [d] In this experiment the reaction
temperature after the addition of D
08C for 3 h and then 208C, 2 h. [e] In this experiment the reaction mix-
ture formed after the addition of 3a was stirred at À788C for 12 h and
O was also added at À788C. [f] In this reaction, H O (5 mL) was added
instead of D O. [g] TBS=tert-butyldimethylsilyl. [h] In this experiment DCl
1m in Et O) was added at 208C instead of NH Cl/H O at 08C.
2
O was allowed to raise from À55 to
2
D
2
2
2
(
2
4
2
Scheme 2. Reactions with other electrophiles.
complex 1g, lithium enolate 2, 1-methoxyallenyllithium (3a)
ture was formed by combination of chromium complex 1a,
lithium enolate 2 and allenyllithium 3a and was treated at
and D O provided 5-deuterio-3-deuteriomethyl-2-cyclopente-
2
[16,17]
none 5a with excellent levels of deuterium incorporation.
À558C with an excess of D O (5 mL). A total solidification of
2
The deuterium atom in the methyl group at the C3-position of
the cyclopentenone ring might indicate the previous presence
of a carbon–metal bond at that position, while the deuterium
label at the a’-position of the carbonyl group could arise from
a hydrogen-deuterium exchange process favoured in the basic
the dark-brown reaction bulk immediately occurred. Keeping
the solid mixture for 1 h while the temperature was raised to
08C did not cause any appreciable change in their physical ap-
pearance. The subsequent addition of NH Cl/H O allowing the
4
2
mixture to warm to room temperature gave rise to a homoge-
neous brown solution. The final workup delivered 2,5-dime-
thoxy-2-cyclohexenone 8a, isolated as a single regioisomer
that does not contain any deuterium atom in its structure. To
explore the generality of this unexpected process we conduct-
ed additional experiments with different aryl- or heteroarylcar-
bene complexes of chromium 1b,g–k that likewise furnished
2-cyclohexenones 8b–g (Table 2, entries 2–8). Non-deuterated
cyclohexenone 8d was also isolated when the solid mixture
was permitted to warm to room temperature. After stirring for
2 h at 208C, the reaction mixture became a brown solution
medium generated after addition of D O at room temperature.
2
Monodeuterated compound 6 was obtained in an experiment
in which the source of deuterium was added at low tempera-
ture and the saturated aqueous solution of ammonium chlo-
ride was added at 0 instead of 208C. Thus, the reaction mixture
(
1a+2+3a) generated at À558C was quenched with deuter-
ated methanol at this same temperature and after 1 h allowing
the temperature to raise to 08C, furnished 3-deuteriomethyl-2-
cyclopentenone 6 with practically a quantitative isotope incor-
[16]
poration (Scheme 2). In contrast, the addition at room tem-
perature of ethyl chloroformate to a similar reaction mixture
afforded 3-methylenecyclopentene derivative 7 containing
a dienol carbonate moiety.
(entry 4). The addition of D O at À788C to a reaction mixture
2
stirred overnight at À788C provided an identical result, forma-
tion of cyclohexenone 8e (entry 5). This same enone 8e was
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[
21]
isolated when the solidification of the reaction mixture was ac-
complished with H O in place of D O (entry 6). Although the
[2 +2 +1 ] or [3 +2 +1 ] cyclization process, respectively.
A E C A E C
[3–5]
On this basis and according to our previous results,
we pro-
2
2
previous experimental procedure to obtain cyclohexenones 8
pose the mechanism shown in Scheme 4 to account for the
includes treatment with a big excess of D O, incorporation of
formation of compounds 4–9. The sequential coupling of the
2
deuterium was never observed. To get 3-deuterio-2-cyclohexe-
[
16]
none 9
it was necessary to treat the reaction mixture at
208C with an ethereal solution of deuterium chloride as indi-
cated in Table 2, entry 9.
Further experiments were conducted to shed some light on
this novel modification of the reactivity of an organometallic
intermediate by solidification of the reaction mixture with
[
15]
water at low temperature.
First, the reaction of carbene
complex 1a with lithium enolate 2 and then with allenyllithi-
um 3c was performed following the standard protocol, but
the whole reaction mass was not frozen after addition of the
same amount of D O (a minor part of the reaction mixture re-
2
mained liquid). Accordingly, this experiment led to a mixture
of cyclohexenone 8h (major product) and cyclopentenone 4h
(minor isomer) that were easily separated by column chroma-
tography (Scheme 3). In another experiment the solidification
Scheme 4. Mechanistic pathway for the formation of compounds 4–9.
three starting materials occurs at À788C by initial nucleophilic
addition of amide enolate 2 to the carbene carbon atom of
complex 1 to give carbamoyl functionalized alkylchromate in-
Scheme 3. Formation of compounds 8h and 4h under partial freezing con-
ditions.
[22]
termediate A, and subsequent nucleophilic addition of alle-
nyllithium reagent 3 to the amide carbonyl group of complex
A to form a new lithium alkylpentacarbonylchromate complex
B containing two contiguous C–C double bonds at the 4-posi-
of the entire reaction mixture was promoted by addition of
1,4-dioxane, under otherwise identical reaction conditions.
However, this reaction conducted with 1a, 2 and 3a yielded
[
13b,c]
[23]
the corresponding 2-cyclopentenone 4a.
Therefore, the
tion with respect to the CÀCr s bond. Upon rising the tem-
use of water to achieve freezing seems to be playing a critical
role besides the “physical” solidification of the reaction
medium. In a final experiment a reaction mixture formed by
sequential combination of 1a, 2 and 3a was allowed to warm
perature to À558C adduct B undergoes ring closure as a conse-
quence of the intramolecular insertion of the allene group into
[
24]
the CÀCr s bond (5-exo-dig cyclization).
Electronic factors
govern the regioselective formation of the CÀC bond with the
to room temperature before addition of D O (5 mL at À558C)
central allene carbon atom generating the most stable s-allyl-
2
[
13b]
[4,25]
that induced full freezing of the mixture.
This reaction mix-
ic/p-allylic chromate complex C.
Trapping this intermediate
ture was treated with a saturated aqueous solution of NH Cl at
C with MeOD at À558C provides after hydrolysis monodeuter-
ated cyclopentenone 6, whereas heating to room temperature
promotes a vinylogous b-elimination reaction resulting in the
formation of lithium dienolate D. The final reaction of this bi-
dentate nucleophile D with H O, D O or ClCO Et provides com-
4
0
8C and afforded selectively 3-deuteriomethylcyclopentenone
with a roughly complete deuterium labelling. This result
[
16]
6
clearly shows that the reaction intermediate generated at low
temperature (À558C) and that formed at room temperature
are of different nature.
2
2
2
pounds 4, 5 and 7 depending on the nature of the electro-
phile. On the other hand, when the reaction mixture generated
either at À78 or À558C was totally frozen by addition of water
(D O or H O), 4,5-hexadienylchromate complex B undergoes
The structures of products 4–9 were ascertained by 1D and
[
18]
2
D NMR spectroscopy and subsequently confirmed by two
single-crystal X-ray diffraction analyses of compounds 5a and
2
2
[
19,20]
11.
a regioselective 6-endo-dig intramolecular carbometalation of
the allene fragment furnishing alkenylchromate complex E
after reaching room temperature. Presumably, the highly heter-
oatom-substituted intermediate B interacts with the water
molecules forming a hydrogen-bonding network. It is likely
The ring core of cyclopentenones 4 and cyclohexenones 8
have been assembled by joining the carbene ligand (1C unit),
the enolate framework (2C unit) and the alkoxyallenyllithium
either as a two- or three-carbon synthon through a formal
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that this new supramolecular organization joined to the solid
state of the reaction mixture are changing the conformation of
this intermediate (“solution” conformation B’ to “frozen” con-
M. G. Suero, T. L. Sordo, M. I. Menꢃndez, J. Org. Chem. 2009, 74, 7059–
7066.
[
[
[
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[
24]
formation F) sufficiently to reverse the regiochemistry of the
ring closure (CÀC bond formation at the terminal allene
carbon atom). The final hydrolysis or deuterolysis of alkenyl-
chromate E leads to cyclohexenones 8 and 9, respectively.
In summary, we have developed a fundamentally novel, effi-
cient and regioselective three-component synthesis of alkoxy-
substituted 2-cyclopentenones or 2-cyclohexenones by choos-
ing the appropriate reaction conditions in the cyclization step
6] For reviews, see: a) A. J. H. Klunder, J. Zhu, B. Zwanenburg, Chem. Rev.
1
2
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1
5
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allenyl-substituted alkylchromate complex that under these
solid-state conditions undergoes the intramolecular carbome-
talation reaction with total reversion of the regioselectivity. In
addition, experiments conducted with different electrophiles
and under different reaction conditions provided access to
deuterated enones and enabled to trap reaction intermediates
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8] For selected FCC-mediated synthesis of 2-cyclopentenones, see: a) T.
2
[
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[
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[
26]
rendering support for the reaction pathway.
[
[
10] For a FCC-mediated synthesis of 2-cyclohexenones, see ref. [4].
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thesis: Water in Organic Synthesis (Ed.: S. Kobayashi), Thieme, Stuttgart,
Experimental Section
Experimental details are provided in the Supporting Information.
2
012.
Acknowledgements
[
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Financial support of this work by the Spanish MICINN (Grant:
CTQ2010—16790) is gratefully acknowledged. R.D.C. thanks
the MEC of Spain for a FPU predoctoral fellowship. We thank
Dr. A. L. Suꢂrez-Sobrino (University of Oviedo) for assistance
with the X-ray analyses. We are grateful to Prof. J. Barluenga
[13] See the Supporting Information for: a) additional references and b) ad-
ditional details; c) solidification of an analogous experiment with 1,4-di-
2
oxane (15 mL) containing 2 mL of D O afforded a roughly 1:1 mixture
of dideuterated cyclopentenone 5b and cyclohexenone 8a.
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N-methylacetamide and tBuLi (THF, À788C, 1 h).
[
(University of Oviedo) for helpful discussions.
[
[
16] The percentage of deuterium incorporation was determined from the
Keywords: carbene ligands
·
cyclization
·
enones
·
1
3
corresponding quantitative C NMR spectra (see the Supporting Infor-
mation).
multicomponent reactions · water freezing
[
17] In an analogous experiment we have observed that the proportion of
deuterium labelling in the Me group at the b-position of the enone
moiety was significantly lower when lithium enolate 2 was generated
using LDA. Presumably the presence of diisopropylamine provokes
some instability of the corresponding metallic intermediate.
[
1] Multicomponent reactions (MCRs) have been attracting continued inter-
est owing to their high synthetic efficiency and the facile construction
of valuable organic molecules as well as their economic and ecological
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1
13
[
[
18] H, C, DEPT, HSQC, HMBC, COSY and NOESY NMR spectra were mea-
sured. 2D NMR spectroscopy was performed on compounds 4a, 8a
and 8b.
19] Compound 11 was generated from 2-cyclohexenone 8 f after removal
of the TBS group (product 10 is formed) followed by spontaneous aro-
matization (see the Supporting Information for details).
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2] Fischer carbene complexes (FCCs) are well-recognized as versatile re-
agents in organic synthesis that allow the selective construction of
highly functionalized structures under mild conditions. For FCC-mediat-
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sis: Top. Organomet. Chem. Vol 13 (Ed.: K. H. Dçtz), Springer, Berlin,
[
2004; b) K. H. Dçtz, J. Stendel, Jr., Chem. Rev. 2009, 109, 3227–3274;
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3] a) J. Barluenga, I. Pꢃrez-Sꢂnchez, E. Rubio, J. Flꢀrez, Angew. Chem. Int.
Ed. 2003, 42, 5860–5863; Angew. Chem. 2003, 115, 6040–6043; b) J.
Barluenga, I. Pꢃrez-Sꢂnchez, M. G. Suero, E. Rubio, J. Flꢀrez, Chem. Eur. J.
[20] CCDC-893312 (5a) and -893311 (11) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
2006, 12, 7225–7235; c) P. Campomanes, J. Flꢀrez, I. Pꢃrez-Sꢂnchez,
Chem. Eur. J. 2014, 20, 1 – 7 www.chemeurj.org
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Communication
[
21] Topological identification of the cyclization reaction (A=allenyl group,
E=enolate anion, C=carbene ligand).
[25] Carbopalladation of allenes occurs highly regioselectively to form the
p-allylpalladium intermediate; see for example: a) S. Ma, Z. Gu, J. Am.
Chem. Soc. 2005, 127, 6182–6183; b) Y. Abe, K. Kuramoto, M. Ehara, H.
Nakatsuji, M. Suginome, M. Murakami, Y. Ito, Organometallics 2008, 27,
1736–1742. See also: c) H. Wang, F. Glorius, Angew. Chem. Int. Ed. 2012,
51, 7318–7322; Angew. Chem. 2012, 124, 7430–7434.
[26] Further investigations to explore the generality of this water-freezing
effect, as well as to better understand the reaction mechanism, are in
progress.
[
22] a) This intermediate A has been characterized by 1D and 2D NMR spec-
troscopy. These results will be reported separately; b) The 1,2-addition
reaction of an amide lithium enolate to the carbene carbon atom of
a Group 6 Fischer carbene complex is reported for the first time.
23] The reaction of Weinreb amides with 1-alkoxyallenyllithium reagents
has been previously reported: M. A. Tius, C.-K. Kwok, X.-q. Gu, C. Zhao,
Synth. Commun. 1994, 24, 871–885.
[
[
24] “Solution” conformation B’ and “frozen” conformation F.
Received: July 31, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
&
Organic Synthesis
R. De la Campa, J. Flꢀrez*
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Water Freezing as a Regiocontrol
Element in the Multicomponent
Assembly of Cyclic Enones
Water-promoted freezing: Three
ponent transformations allenyl-substi-
tuted alkylchromate complexes undergo
a 5-exo-dig cyclization when maintained
in an anhydrous solution but a 6-endo-
dig cyclization when a water solidified
environment is created.
simple starting materials and a deuteri-
um source are selectively coupled to
produce isotopically labelled oxygenat-
ed 2-cyclopentenones or 2-cyclohexe-
nones (see scheme). In these multicom-
Water-Freezing Regiocontrol
An efficient modular and regioselective synthesis of
deuterated cyclic enones has been achieved by successive
coupling of three simple starting materials and a deuterium
source. Dialkoxy 2-cyclopentenones were generated under
anhydrous conditions, whereas dialkoxy 2-cyclohexenones
were formed under water-promoted solidification of the
reaction mixture. This unprecedented water-freezing effect
induced a total inversion of the regioselectivity in the
intramolecular cyclization of allenyl-substituted
alkylchromate intermediates. For more details, see the
Communication by J. Flꢀrez et al. on page && ff.
Chem. Eur. J. 2014, 20, 1 – 7
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ