One-pot synthesis of pentasubstituted cyclohexanes by a Michael addition followed by a tandem inter-intra double Henry reaction

Article abstract of DOI:10.1002/chem.200900894

An experiment was conducted to demonstrate that a one-pot process that combines diarylprolinol ether 4 and TBAF results in an effective synthesis of cyclohexanes with five chiral centers from α-βunsaturated aldehydes, β-dicarbonyl compounds, and nitrometh

Full text of DOI:10.1002/chem.200900894

DOI: 10.1002/chem.200900894
One-Pot Synthesis of Pentasubstituted Cyclohexanes by a Michael Addition
Followed by a Tandem Inter–Intra Double Henry Reaction
Josꢀ Luis Garcꢁa Ruano,* Vanesa Marcos, Juan Antonio Suanzes, Leyre Marzo, and
Josꢀ Alemꢂn*[a]
The rapid construction of structurally complex molecules
from simple starting materials, aimed at the development of
cascade, tandem, or multicomponent reactions,[1] is a new di-
rection in organocatalysis.[2] These one-pot reactions[3] mini-
mize cost, waste, and manual efforts. A large number of at-
tractive organocatalytic cascade reactions, in which the dif-
ferent steps involved are promoted by the same catalyst,
have been reported in the last two years.[4] The cornerstone
in this field is the cascade reaction developed by Enders
with aldehydes, a,b-unsaturated aldehydes, and nitroalkenes
that react following an enamine–iminium–enamine sequen-
tial activation with silyl prolinol ether derivatives.[4a,b] Other
attractive examples involving similar catalysts are the imini-
um–iminium–enamine triple activation of a,b-unsaturated
aldehydes in the presence of activated methylene com-
pounds,[4c] the tandem Michael/Henry reaction of pentane-
1,5-dial and nitroalkenes,[4d] and the tandem Michael/
Morita–Baylis–Hillman reaction[4e] of the Nazarov reagent
with a,b-unsaturated aldehydes. This strategy has been
widely applied for the synthesis of six-membered rings,
which is the case for reactions of 1,3-dinitroalkanes with
a,b-unsaturated aldehydes (Michael/Henry processes)[4f] and
also those of aliphatic aldehydes and a,b-unsaturated alde-
hydes with doubly activated alkenes[4g] (Michael/Michael
aldol). The creation of up to five chiral centers in a one-pot
reaction confers a large synthetic relevance to these process-
es even though their diastereomeric excesses are usually not
too high.
organocatalytic processes remain scarce[5j] despite their pre-
sumed advantages for combining reactions of different
nature. Therefore, the search for two organocatalysts that
could be used in a one-pot multistep process is a question of
crucial importance. Herein, we present our results regarding
the synthesis of cyclohexanes with five chiral centers in one
pot by using two organocatalytic species. According to the
synthetic sequence shown in Scheme 1, this could be realiz-
Scheme 1. Synthesis of pentasubstituted cyclohexanes.
ed by the combination of proline-type organocatalysts (facil-
itating the iminium activation of the unsaturated aldehyde)
with fluoride-type organocatalysts (promoting the double
addition of nitromethane) and initiating a Michael addition
of dicarbonyl compounds 2 to a,b-unsaturated aldehydes 1
followed by a tandem inter–intra double Henry reaction
with nitromethane.
To check the efficiency of the fluoride-containing promot-
ers that give the double Henry reaction,[6] we initially stud-
ied the reaction of simple dicarbonyl compounds with nitro-
alkanes and a catalytic amount of TBAF as the promoter.[7]
The reaction of 2,4-hexanedione did not proceed, which was
Multicatalytic processes that combine organocatalysts
with metal catalysts have been reported,[5a–i] however, multi-
[a] Prof. Dr. J. L. Garcꢀa Ruano, V. Marcos, J. A. Suanzes, L. Marzo,
Dr. J. Alemꢁn
Departamento de Quꢀmica Orgꢁnica (C-I)
Universidad Autꢂnoma de Madrid
Cantoblanco, 28049-Madrid (Spain)
Fax : (+34)91497466
E-mail: joseluis.garcia.ruano@uam.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900894.
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Chem. Eur. J. 2009, 15, 6576 – 6580

COMMUNICATION
Table 1. Screening results for the reaction of aldehyde (1a) with 1,3-
dione (2a).[a]
not unexpected due to the lower reactivity of ketones in
these processes. Fortunately, treatment of dialdehyde 8 with
nitromethane under neat conditions and catalyzed by
20 mol% of TBAF led to exclusive formation of 9a in 66%
isolated yield (Scheme 2). The complete stereocontrol
Reagent (mol%)
d.r.[b]
Yield [%]
ee[c] [%]
1
2
3
4
5
6
7
8
DABCO (40)
KF (40)
KF/aluminia (40)
CsF (40)
TMAF (20)
TBAF (20)
TBAF (20)
TBAF (20)
–
n.r.[d]
28
32
40
17
–
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
74
92
59
74
99
–
45
[e]
–
–
[f]
Scheme 2. Inter–intramolecular double Henry reaction. Compound 3a:
R=H; compound 3b: R=Me; compound 9a: R=H, yield 66%, d.r.>
98:2; compound 9b: R=Me, yield 78%, d.r.>98:2.
–
[a] All reactions were performed on a 0.2 mmol scale in 0.2 mL of solvent
at RT for 4 h for the Michael reaction and 18 h for the inter–intramolecu-
lar Henry reaction. Abbreviations used: DABCO=1,4-diazabicyclo-
AHCTUNGERTG[NNUN 2.2.2]octane, TMAF=tetramethylammonium fluoride, TBAF=tetrabu-
shown in this reaction was maintained from nitroethane. In
this case, 9b was exclusively obtained in 78% yield
(Scheme 2).
tylammonium fluoride. [b] Diastereoisomeric ratio determined by
1H NMR spectroscopic analysis of the crude mixture. [c] Determined by
HPLC (see the Supporting Information). [d] No reaction. [e] Purification
performed with Fluorisil (see text). [f] Purification performed with silan-
ized silica gel 60 (see text).
On the basis of these results we reasoned that reactions of
enantiomerically pure nonsymmetrical dicarbonyl com-
pounds (thus precluding the formation of meso compounds)
could provide optically enriched carbocycles with highly
controlled diastereoselectivity. One of the best organocata-
lytic methods for generating this type of precursor is the Mi-
chael addition of 1,3-diketones to a,b-unsaturated alde-
hydes, promoted by iminium activation.[8] When the organo-
catalysts used in the first step were not compatible with the
fluoride source required for the double Henry reaction, it
would necessary to increase the amount of fluoride source
in order to make possible a one-pot synthesis of highly sub-
stituted cyclohexanes (Scheme 1).
We first studied the treatment of 1,3-diphenyl-1,3-pro-
panedione (2a) with (E)-2-pentenal (1a) and nitromethane
by using (S)-2-[bis(3,5-bistrifluoromethylphenyl)trimethylsi-
lyloxymethyl]pyrrolidine 4[9] as the catalyst for iminium acti-
vation and different bases for the promotion of the Henry
additions (Table 1). To avoid addition of nitromethane to
the a,b-unsaturated aldehyde,[10] the reaction was carried
out in one pot but the nitromethane and the base were
added after the Michael addition was finished. Therefore,
we studied the effect of different bases on the reaction
course. No reaction was observed with DABCO (Table 1,
entry 1). KF, CsF, KF/alumina, and TMAF gave 7a in low
yield as a single diastereoisomer (Table 1, entries 2–5) with
moderate to good enantioselectivity (58–92% enantiomeric
excess (ee)). The use of TBAF[11] provided the best results,
allowing the formation of 7a as a single diastereoisomer in
45% yield and with almost complete enantioselectivity
(99% ee; Table 1, entry 6). In all these cases, purification
was made on neutralized silica gel. The use of other purifi-
cation methods, such as Iatrobeads or Fluorisil (Table 1, en-
tries 7 and 8), gave lower yields and the products could not
be separated from the starting material. Despite a yield of
only 45% for 7a, it is worth noting some useful features of
this reaction: high optical purity, simple conditions, and the
molecular complexity of the resulting five-chiral-center-con-
taining compounds.[12]
We then applied these optimized conditions to the reac-
tions of nitromethane with different a,b-unsaturated alde-
hydes (1a–i)[13] and 1,3-diketones (2a–c). These results are
summarized in Table 2. The best results for diketone 2a
(R2 =R3 =Ph) were obtained with 1b (R1 =Me), which gave
enantiomerically pure 7b in 55% yield as a single diastereo-
isomer (Table 2, entry 2). A similar result was obtained
when the reaction was scaled up to 2.0 mmol (Table 2,
entry 2, results in parentheses). On the other hand, the en-
antiomer of 7b (ent-7b) was obtained under similar condi-
tions by using (R)-4 as the catalyst (Table 2, entry 3). Alkyl-
substituted a,b-unsaturated aldehydes 1c–g with longer ali-
phatic chains also afforded compounds 7c–g as single diaste-
reoisomers in good to excellent enantioselectivities (Table 2,
entries 4–8). Conditions were compatible with the presence
of double bonds or aromatic groups in the aliphatic chain
(Table 2, entries 9 and 10). Symmetrical dione 2b (R2 =R3 =
PMP) also reacted with 1b to give 7j with good enantio-
and diastereoselectivity but in
a slightly lower yield
(Table 2, entry 11). Interesting results were also obtained for
the reactions of nonsymmetrical diketone 2c (R2 =Ph, R3 =
Me) with crotonaldehyde 1b and pentenaldehyde 1a. They
afforded 7k and 7l, respectively, which exhibited high levels
of regio- and stereoselectivity (Table 2, entries 12 and 13).
This indicates that the methylcarbonyl group is much more
reactive than the phenylcarbonyl group towards the intra-
molecular attack of the a-nitro anion. Unfortunately, no re-
action was observed for aromatic a,b-unsaturated aldehydes
(Table 2, entry 14).
The absolute configuration of cyclohexane 7b was un-
equivocally established as (1S,2R,3R,4S,6R) by X-ray diffrac-
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J. Garcꢀa Ruano, J. Alemꢁn et al.
Table 2. Results obtained from treatment of aldehydes (1a–i) with 1,3-
diones (2a–c) and nitromethane.[a]
R1
R2
R3
Product d.r.[b]
Yield
[%]
ee
[%][b]
1
2
3
4
5
6
7
8
9
Et
Me
Me
n-propyl
n-pentyl
n-nonyl
n-butyl
n-hexyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7a
7b
ent-7b
7c
7d
7e
7 f
7g
7h
>98:2 45
99
>98:2 55 (47)[d] >99 (99)[d]
>98:2 57
>98:2 46
>98:2 40
>98:2 40
>98:2 43
>98:2 42
>98:2 42
>99[e]
92
>99
92
92
>99
94
(Z)-n-hex-3- Ph
enyl
10 PhCH2CH2
11 Me
12 Me
13 Et
14 Ph
Ph
Ph
7i
>98:2 46
>98:2 35
>98:2 44
>98:2 47
>99
98
98
94
–
PMP PMP 7j
Ph
Ph
Ph
Me
Me
Ph
7k
7l
–
–
n.r.[e]
[a] All reactions were performed with (S)-4 on a 0.2 mmol scale in
0.2 mL of solvent at 08C (RT for entries 1 and 2) for 12 h (4 h for en-
tries 1 and 2) for the first step and at RT for 48 h (18 h for entries 1 and
2) for the second step. PMP=p-methoxyphenyl. [b] Diastereoisomeric
Figure 1. X-ray structure of compound 7b.
1
ratio determined by H NMR spectroscopic analysis of the crude mixture.
[c] Determined by HPLC (see the Supporting Information). [d] Reaction
performed on a 2.0 mmol scale. [e] Compound (R)-4 was used as the cat-
alyst. [e] No reaction.
Michael addition of nucleophile 2 to a,b-unsaturated alde-
hyde 1 activated by catalyst 4, is well established.[8,9] The re-
sulting adduct, 5, reacts with the anion of nitromethane
(generated by the fluoride anion) according to an intermo-
lecular Henry reaction in Cycle II to give nitroalcohol 6,
tion studies (Figure 1).[14] The
most relevant aspect of this
structure is the equatorial ar-
rangement of all substituents
except for the hydroxyl group
at C1, which is intramolecularly
associated to the nitro group
(2.06 ꢄ). The equatorial ar-
rangement of the bulkier sub-
stituents of the five chiral cen-
ters suggests that the formed
diastereoisomer is the most
stable one of all possible iso-
mers with the same substitution
pattern. Similar reaction cours-
es and spectroscopic similarities
for the rest of compounds 7 in
Table 2 were observed, which
suggests that they all have the
same configuration and spatial
arrangement of substituents.
The proposed mechanism for
the reaction course of this
transformation is summarized
in Scheme 3. The course of the
first cycle (Cycle I), that is, the Scheme 3. Proposed mechanism for the one-pot reaction.
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One-Pot Synthesis of Pentasubstituted Cyclohexanes
COMMUNICATION
which undergoes a subsequent intramolecular Henry reac-
tion catalyzed by the fluoride anion in Cycle III to give 7 as
the final cyclohexane (Scheme 3). According to previously
reported models,[8,9] the stereochemistry of the chiral center
created in the first step is controlled by the configuration of
catalyst 4 (in Scheme 3 the attack of nucleophile 2 on the
Re face of planar iminium ion 10 is favored on steric
grounds). Although configurational control at the four
chiral centers created in the last two steps (Henry reactions)
could be exerted by the chiral center created in the first step
(Michael addition), the way in which such control is ach-
ieved is not evident from Scheme 3. Taking into account
that the diastereoselectivity of these reactions is almost
complete (>98:2 d.r.) and the structure of compounds 7 cor-
respond to the most stable diastereoisomer (see above), we
propose that the Henry reactions are not kinetically con-
trolled and, therefore, give mixtures of all possible diaste-
reoisomers. The complete stereoselectivity observed in these
reactions must be a consequence of the reversibility of Cy-
cles II and III in Scheme 3, which results in the formation of
the thermodynamically favored product.[15] According to this
explanation, the lower ee observed with fluoride sources
other than TBAF (Table 1, entries 2–5) suggests that these
sources are inducing the retro-Michael addition to a higher
degree and thus decreasing the enantioselectivity.[16]
According to this mechanistic proposal, the enantioselec-
tivity is defined in the first cycle of the one-pot reaction
and, therefore, the ee is based on the temperature of the Mi-
chael addition. To confirm this hypothesis, the first step of
the reactions shown in Table 2 were performed at room tem-
perature (instead of 08C), which resulted in lower enantio-
meric excesses in all cases (see the Supporting Information
for more details).
In conclusion, we have shown that a one-pot process that
combines diarylprolinol ether 4 and TBAF results in an ef-
fective synthesis of cyclohexanes with five chiral centers
from a,b-unsaturated aldehydes, b-dicarbonyl compounds,
and nitromethane. This process involves a Michael addition
followed by tandem inter–intramolecular Henry reactions
that proceed with high enantio- and diastereoselectivity for
a wide range of substrates. We are now studying the scope
of the double Henry reaction of dicarbonyl compounds in
an effort to prepare optically pure cycles of different sizes.
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Acknowledgements
Financial support of this work by the Ministerio de Educaciꢂn y Ciencia
(CTQ2006-06741/BQU) is gratefully acknowledged. V.M. and J.A. thank
the Ministerio de Ciencia e Innovaciꢂn for a predoctoral fellowship and
a “Juan de la Cierva contract”, respectively. L.M. thanks the Ministerio
de Educaciꢂn, Polꢀtica Social y Deporte for a undergraduate fellowship.
Keywords: carbocycles
·
diarylprolinol
ethers
·
homogeneous catalysis · one-pot reactions · organocatalysis
Chem. Eur. J. 2009, 15, 6576 – 6580
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[11] These reactions required the use of 20 mol% of fluoride source be-
cause a 10 mol% was consumed by the silyl prolinol ether 4.
[12] Lower yields were obtained if the reaction was performed in two
consecutive reactions. Under these conditions, the Michael adduct
was obtained in 80% yield, which suggests an average yield of
around 75% for each one of the Henry reactions involved in the
one-pot process.
[13] We have tried aromatic a,b-unsaturated aldehydes under different
conditions and catalysts without any conversion.
[14] CCDC-718713 (7b) contains the supplementary crystallographic
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.
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which is expected because the presence of an additional methyl
group on the ring distorts the ideal all-trans relationship achieved
for all substituents in compounds 7, indicating that several diastereo-
isomers have a similar stability.
[16] To confirm this suggestion, samples of Michael adduct 5a (94% ee),
which was isolated in the first step, were exposed to 40 mol% CsF.
After 18 h we recovered the compound in 62% ee, demonstrating
that the catalyst (CsF) initiated the retro-Michael reaction.
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Received: April 3, 2009
Published online: June 2, 2009
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Chemistry–A European Journal Early View. The Editor.
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