A highly diastereoselective tertiary amine-catalyzed cascade michael-michael-henry reaction between nitromethane, activated alkenes and α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1002/adsc.200900657

A new tertiary amine-catalyzed cascade Michael-Michael-Henry reaction between nitromethane, a doubly activated alkene and an α,β-unsaturated carbonyl compound is described, which provides a convenient and efficient synthesis for densely functionalized cyclohexanes and some bicyclic compounds in moderate to excellent yields with high diastereoselectivity.

Full text of DOI:10.1002/adsc.200900657

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DOI: 10.1002/adsc.200900657
A Highly Diastereoselective Tertiary Amine-Catalyzed Cascade
Michael–Michael–Henry Reaction between Nitromethane,
Activated Alkenes and a,b-Unsaturated Carbonyl Compounds
Bo Zhang,a Lingchao Cai,a Haibin Song,a Zhihong Wang,a and Zhengjie Hea,*
a
The State Key Laboratory of Elemento-Organic Chemistry and Department of Chemistry, Nankai University, 94 Weijin
Road, Tianjin 300071, Peopleꢀs Republic of China
Fax : (+86)-22-23501520; e-mail: zhengjiehe@nankai.edu.cn
Received: September 23, 2009; Revised: November 24, 2009; Published online: December 22, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900657.
Abstract: A new tertiary amine-catalyzed cascade
Michael–Michael–Henry reaction between nitrome-
thane, a doubly activated alkene and an a,b-unsatu-
rated carbonyl compound is described, which pro-
vides a convenient and efficient synthesis for dense-
ly functionalized cyclohexanes and some bicyclic
compounds in moderate to excellent yields with
high diastereoselectivity.
lectivity have been developed during the past few
years.[5]
Among the reported organocatalytic domino reac-
tions,[1c,4] most of them involve a two-step cascade, in
which the first step is intermolecular and the second
is intramolecular. The recently reported double cas-
cade modes include Michael–Michael reaction,[5a–e]
Michael-aldol reaction,[5f,g] Michael–Henry reac-
tion,[5h–m] Michael–Morita–Baylis–Hillman reaction,[5n]
Michael-alkylation reaction,[5o,p] Knoevenagel–Diels–
Alder reaction,[5q] and others.[5r–t] Such organocatalytic
domino reactions with a triple or higher cascade se-
quence, however, have been much less explored,[6] al-
though a pioneering magnum opus involving a triple
cascade course was disclosed by Enders et al. in
2006.[6a] Theoretically, by manipulating the functional-
Keywords: activated alkenes; cascade reactions;
multicomponent reactions; nitromethane; organo-
catalysis
Organocatalysis has grown rapidly to become one of ity on the substrates with an adequate arrangement,
the most exciting and current fields in contemporary much higher-order cascade and multi-component re-
organic chemistry.[1] Besides such characteristics as actions can be achieved. Therefore, the development
being metal-free, usually non-toxic, readily available, of innovative higher-order cascade sequences to
and often robust, a significant advantage of many or- achieve better synthetic efficiencies is highly desira-
ganocatalysts like secondary amines is the capability ble.
of promoting several types of reactions through differ-
Both the Michael addition reaction[7] and the
ent activation modes.[1c,2] This ability makes an organ- Henry reaction[8] are most important carbon-carbon
ic catalyst ideal for application in cascade/domino re- bond forming tools with the capability to readily im-
actions, which provide an efficient means to construct plement useful functionality into the target molecule.
complex molecules from simple precursors in a single Combining these two reactions into a synthetic cas-
process. As well-recognized, domino reactions avoid cade should be a highly efficient strategy to construct
time-consuming and costly protection/deprotection densely functionalized building blocks. In the past few
processes and the purification of intermediates as years, several pioneering organocatalytic domino re-
well.[3] Intrinsically, organocatalytic domino reactions actions involving both Michael addition and Henry
inherit such advantages from both the organocatalysis reaction in a sequence were reported, demonstrating
and the domino reaction, featuring high synthetic effi- the high efficiency of this strategy in organic synthe-
ciencies and green chemistry factors.[1c,4] It is not as- sis.[5h–m,6i,m]
tonishing that organocatalytic domino reactions repre-
In conjunction of our efforts on exploring new
sent a new and active area in organic chemistry. Many carbon-carbon bond forming reactions via nucleophil-
interesting reactions with high chemo- and stereose- ic organocatalysis,[9] we intended to investigate the
Lewis base-catalyzed cross-coupling between different
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97

Bo Zhang et al.
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activated alkenes, since this type of coupling is still DABCO (1,4-diazabicycloACHTNUGTRNEUNG[2.2.2]octane), and triethyl-
challenging for the organic chemistry community due amine were effective and better yields were obtained
to the inherent preference of the homo-coupling over in toluene with DABCO and triethylamine (Table 1,
the desired hetero-coupling. Encouragingly, some suc- entries 1, 3–6). Conversely, the non-nucleophilic
cessful examples of organocatalytic cross-coupling be- Lewis base DBU (1,8-diazabicycloACHTUNTRGNEUNG[5.4.0]undec-7-
tween two different activated olefins have been re- ene)[11] and the weak inorganic base potassium car-
cently developed by Shi[10] and other groups.[5e,6e] bonate were both ineffective for this reaction (en-
Herein, we wish to report a new tertiary amine-cata- tries 2 and 7). However, use of a strong base like po-
lyzed cascade Michael–Michael–Henry reaction be- tassium tert-butoxide also resulted in the formation of
tween nitromethane, doubly activated alkenes and 3a in a low yield (entry 8). Further screening of sol-
a,b-unsaturated carbonyl compounds, which provides vents was carried out with common solvents (en-
a convenient and efficient synthetic approach for tries 9–16), and a protic solvent, 2-propanol, emerged
polyfunctionalized cyclohexanes and some bicyclic as the best, giving 3a in 84% yield (entry 10).
compounds.
With optimized conditions in hand, the substrate
Our investigation was initiated with the model reac- scope was then tested. Acyclic a,b-unsaturated car-
tion between phenylmethylidenemalononitrile (1a), bonyl compounds like methyl vinyl ketone (2a) and
methyl vinyl ketone (2a) and nitromethane. Gratify- acrolein (2b) were both effective in the reaction
ingly, a three-component annulation reaction between (Table 2). Under the catalysis of Et3N (10 mol%) and
these substrates occurred, affording the densely func- at room temperature, both aryl- and heteroaryl-substi-
tionalized cyclohexane 3a (Table 1). Preliminary opti- tuted methylenemalononitriles (1a–k) smoothly un-
mization of the reaction conditions revealed that a derwent a three-component annulation reaction with
few nucleophilic organic Lewis bases such as PPh3, nitromethane and 2a, giving polysubstituted cyclohex-
DMAP (4-N,N-dimethylaminopyridine), imidazole, anes 3a–k as a single diastereomer in 61–95% yields
after a single column chromatographic isolation
(Table 2, entries 1–11). Under similar conditions, the
aliphatic cyclohexyl-substituted methylenemalononi-
trile (1l) also gave rise to the corresponding cyclohex-
Table 1. Screening of the catalyst and solvent.[a]
ane 3l in 69% yield, although an elongated reaction
time (24 h) was required (entry 12). For acrolein 2b,
Table 2. Synthesis of densely functionalized cyclohexanes 3
from acyclic a,b-unsaturated carbonyl compounds.[a]
Entry
Catalyst
Solvent
Yield of 3a [%][b]
1
2
3
4
5
6
7
8
PPh3
DBU
DMAP
imidazole
Et3N
DABCO
K2CO3
t-BuOK
DABCO
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
i-PrOH
i-PrOH
CHCl3
THF
DMF
CH3CN
1,4-dioxane
ether
25
trace
21
44
66
63
trace
21
50
84
32
49
18
36
31
11
Entry R1
R2
Time [h] Yield [%][b]
[c]
1
2
3
4
5
6
7
8
C6H5 (1a)
p-CH3C6H4 (1b)
p-CH3OC6H4 (1c) CH3 4.5
CH3
CH3
6
7
3a, 84
3b, 88
3c, 95
3d, 71
3e, 77
3f, 82
3g, 61
3h, 91
3i, 69
3j, 82
3k, 87
3l, 69
3m, 52
3n, 44
9
10
11
12
13
14
15
16
p-ClC6H4 (1d)
o-ClC6H4 (1e)
p-FC6H4 (1f)
p-CF3C6H4 (1g)
p-NO2C6H4 (1h)
3-pyridyl (1i)
2-furyl (1j)
2-thienyl (1k)
cyclohexyl (1l)
C6H5 (1a)
CH3
CH3
CH3
CH3 4.5
CH3
CH3 12
CH3 20
CH3
9
6
4
4
9
10
11
12
13[c]
14[c]
[a]
Reaction conditions: unless otherwise noted, a mixture of
nitromethane (2.5 mmol), phenylmethylene malononitrile
1a (0.5 mmol), methyl vinyl ketone 2a (0.6 mmol), and
the catalyst (0.05 mmol) in the specified solvent (2.0 mL)
was stirred at room temperature for 24 h (entries 1–8) or
6 h (entries 9–16).
3
CH3 24
H
H
36
24
p-ClC6H4 (1d)
[a]
For experimental details, see Experimental Section.
Isolated yield based on 1.
The catalyst DABCO (0.05 mmol) was used instead.
[b]
[c]
[b]
[c]
Isolated yield as a single diastereomer based on 1a.
The catalyst loading was 1.0 mmol.
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Diastereoselective Tertiary Amine-Catalyzed Cascade Michael–Michael–Henry Reaction
works.[13] This organocatalytic three-component annu-
Table 3. Synthesis of densely functionalized bicyclic com-
pounds 4 and 5 from cyclic a,b-unsaturated ketones.[a]
lation of cyclic unsaturated ketones provides a novel
and convenient synthetic method for the type of bicy-
clic system. Also, the diverse functionality including
versatile nitro and cyano groups in products 4 and 5
will facilitate further organic transformations on
them.
Under the optimized conditions, other nitroalkanes
than nitromethane were also surveyed. Under the cat-
alysis of either triethylamine or DABCO (10–
20 mol%), neither nitroethane nor 2-phenyl-1,3-dini-
tropropane gave any expected annulation products
with activated olefin 1a and a,b-unsaturated ketone
2a or 2c. The dependence of this amine-catalyzed an-
nulation on the substrates including nitroalkane,
doubly activated olefin and a,b-unsaturated carbonyl
compound deserves more efforts to further explore.
The structures of cyclohexanes 3 and bicyclics 4
Entry
R1
n
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
C6H5
2 (2c)
2 (2c)
2 (2c)
2 (2c)
2 (2c)
3 (2d)
3 (2d)
12
6
4a, 57
p-CH3C6H4
p-CH3OC6H4
p-NO2C6H4
2-furyl
C6H5
2-furyl
4b, 62
52
14
48
12
12
4c, 66[c]
4d, 65[c]
4e, 74[c]
5a, 45
1
and 5 were identified by H and 13C NMR spectrosco-
py, as well as X-ray crystallography in some cases (for
3d and 3n: CCDC 742978 and 742979 contain the sup-
plementary crystallographic data for this paper. These
data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif. For spectroscopic data of
all new compounds, see Supporting Information). For
all of the compounds 3, 4 and 5, a large axial coupling
constant (3JH,H =ca. 12.0 Hz) between two adjacent
hydrogens which are located respectively at the R1
5b, 48
[a]
For experimental details, see Experimental Section.
Isolated yield based on 1.
The reaction was run with nitromethane (1.5 mmol) in 2-
[b]
[c]
propanol (2.0 mL).
the catalyst DABCO (10 mol%) was best used to and nitro-substituted carbons was observed. This ob-
effect the annulation with selected arylmethylidene servation confirmed the assignment of a trans-config-
malononitriles (1a, 1d), affording the corresponding uration with respect to R1 and the nitro groups. For
cyclohexanes 3m and 3n in moderate yields (en- cyclohexanes 3, a cis-configuration for hydroxy and
tries 13 and 14).
nitro groups was assigned by a small equatorial cou-
In Table 3 are summarized the results from the in- pling constant (3JH,H =ca. 2.4 Hz) between two vicinal
vestigation on cyclic a,b-unsaturated ketones. Conju- hydrogens in the cyclohexane ring (3m, 3n), and by
gated cyclopentenone (2c) and cyclohexenone (2d) X-ray crystallographic analysis (3d, 3n) as well. For
were both effective substrates: under mild conditions bicyclic compounds 4 and 5, however, the hydroxy
and the catalysis of DABCO (10 mol%), both cyclic group occupies a trans position against the nitro
1
ketones 2c and 2d readily underwent a three-compo- group, as identified by their H NMR data including
nent annulation with the representative aryl- or heter- NOESY analysis (see Supporting Information).
oaryl-substituted methylenemalononitriles 1 and ni-
tromethane, giving the corresponding highly function- were obtained in moderate to excellent yields as a
alized bicyclo[3.2.1]octanes and bicyclo- single diastereomer after conventional column chro-
ACHTUNGTRENNUNG[3.3.1]nonanes 5 as a single diastereomer in modest matographic isolation. Other diastereomers were not
In all cases, the annulation products (3, 4, or 5)
A
4
yields. In comparison with those carried out with a 3- detected even in crude products from those clean an-
fold amount of nitromethane in 2-propanol (en- nulation reactions (such as 3a–c, 3h) by 1H NMR
tries 3–5), the reaction rates were remarkably acceler- spectroscopy. This stereochemical outcome, as well as
ated when the annulation was run in excess nitrome-
thane as solvent (Table 3, entries 1, 2, 6 and 7), but
the yields of the bicyclic products were not obviously
enhanced. The bicyclic compounds 4 and 5 with a hy-
droxy group positioned at a bridgehead carbon repre-
sent important structural components in some biologi-
cally interesting alkaloids,[12] and few tandem or
domino sequences have been before reported for con-
struction of these characteristic bicyclic frame- reochemical outcomes in representative products 3 and 5.
Figure 1. Proposed chair conformations leading to the ste-
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99

Bo Zhang et al.
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the high diastereoselectivity, could be rationalized in
fore.[11b,15] Additionally, results from the catalyst
ACHTUNGTRENNUNG
terms of the conformational stability of the six-mem- screening (Table 1) are consistent with this proposal:
bered ring transition state (Figure 1). The importance those nucleophilic Lewis bases including basic amines
of the conformational stability in the highly stereose- and weakly basic phosphanes are effective for the an-
lective construction of polysubstituted cyclohexanes nulation model reaction; in contrast, the non-nucleo-
has been demonstrated in a few cascade react- philic DBU and weak inorganic base K2CO3 are inef-
A
fective.
A catalytic cycle for the three-component annula-
ponent annulation reaction remains unclear, on the tion is then proposed as follows: the nitrocarbanion
basis of the experimental results in this study, a pro- first reacts with substituted methylenemalononitrile 1
posed mechanism is shown in Scheme 1. Presumably, to afford a Michael adduct 6, which subsequently un-
the annulation reaction is initiated with the genera- dergoes another Michael addition to the unsaturated
tion of a nitrocarbanion. Even though the possibility carbonyl compound 2, leading to the formation of a
could not be completely ruled out that the catalyst double Michael addition product 7. Intermediate 7
Lewis base (LB) acts as a base in the deprotonation then converts to intermediate 8 via a proton transfer.
of nitromethane (Path B), it is most likely that the An intramolecular Henry reaction of intermediate 8,
catalyst LB acts as a nucleophilic trigger which under- followed by protonation with nitromethane, accom-
goes a Michael addition to the unsaturated carbonyl plishes the formation of the annulation product 3 and
compound 2, leading to the formation of a strongly the regeneration of the nitrocarbanion (Scheme 1).
basic zwitterionic enolate intermediate. Subsequently,
The following experimental results provide solid
the enolate base deprives nitromethane of a proton to evidence for the above catalytic cycle (Scheme 2).
produce the nitrocarbanion (Path A). Similar mecha- Under the same reaction conditions for the prepara-
nisms for the generation of a strong base by use of a tion of 4a – except that the catalyst I was used instead
strong nucleophile have been documented be- – the reaction between 1a, 2c and nitromethane was
re-investigated. After 5 h, the reaction was quenched
and consequently the first Michael adduct 9 and the
double-Michael adduct 10 were isolated in 9% and
41% yields, respectively. In another scenario, when
the reaction was run continuously for 24 h, the final
annulation product 4a was obtained in 85% yield with
slight enantioselectivity (9% ee). In comparison,
under the catalysis of DABCO (10 mol%), the isolat-
ed 10 was readily converted into 4a in 89% yield.
These results definitely imply that this three-compo-
nent annulation reaction proceeds in a triple Mi-
chael–Michael–Henry cascade sequence which com-
prises two intermolecular steps and one intramolecu-
lar step.
In conclusion, a highly diastereoselective tertiary
amine-catalyzed three-component annulation reaction
between nitromethane, doubly activated alkenes and
a,b-unsaturated carbonyl compounds has been dem-
onstrated, which provides convenient and efficient ac-
cesses toward densely functionalized cyclohexanes
and bicyclic frameworks including those of the
bicycloACTHUNRTGENNUG[3.2.1]octane and bicycloACHUTNGTRENN[GUN 3.3.1]nonane type.
On the basis of the experimental results in this study,
this organocatalytic annulation reaction supposedly
proceeds in
a
Michael–Michael–Henry cascade
course. It represents an efficient and higher-order cas-
cade mode: a three-component and triple cascade
comprising two intermolecular steps and one intramo-
lecular step. Further studies on this reaction in our
laboratory will be directed towards its asymmetric
variant, generality and application in organic synthe-
sis. Results from such investigations will be reported
in due course.
Scheme 1. A plausible catalytic cycle of the three-compo-
nent cascade annulation.
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Adv. Synth. Catal. 2010, 352, 97 – 102

Diastereoselective Tertiary Amine-Catalyzed Cascade Michael–Michael–Henry Reaction
Scheme 2. Isolation and Identification of intermediates 9 and 10.
Experimental Section
Acknowledgements
The authors gratefully acknowledge generous financial sup-
port from National Natural Science Foundation of China
(Grant nos. 20672057; 20872063).
Synthesis of Cyclohexanes 3 (General Procedure)
To a stirred mixture of a,b-unsaturated carbonyl compound
2a or 2b (0.6 mmol), nitromethane (2.5 mmol) and the
amine catalyst Et3N (0.05 mmol, for 3a–l) or DABCO
(0.05 mmol, for 3m, n) in i-PrOH (2.0 mL), was added the
substituted methylenemalononitrile 1 (0.05 mmol) at room
temperature. The resulting reaction mixture was vigorously
stirred until 1 was completely consumed (monitored by
TLC). The solvent and volatile components were then re-
moved on a rotary evaporator under reduced pressure and
the residue was subjected to column chromatography on
silica gel (eluant: petroleum ether/ethyl acetate 5:1, v/v) to
give diastereomerically pure 3 (Table 2).
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