Organocatalytic asymmetric triple domino reactions of nitromethane with α,β-unsaturated aldehydes

Article abstract of DOI:10.1055/s-0029-1218282

An organocatalytic asymmetric multicomponent domino reaction employing the bulk chemical nitromethane and (α,β-unsaturated aldehydes as substrates is described. The new triple cascade reaction based on two subsequent Michael additions and an intramolecula

Full text of DOI:10.1055/s-0029-1218282

LETTER
3175
Organocatalytic Asymmetric Triple Domino Reactions of Nitromethane with
a,b-Unsaturated Aldehydes
Asymmetric
T
riple
i
Domi
e
t
s
er Enders,*a Matthieu Jeanty,a Jan W. Batsb
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
b
Institute of Organic Chemistry and Chemical Biology, University Frankfurt, Marie-Curie-Str. 11, 60439 Frankfurt am Main, Germany
Received 11 September 2009
aldol
condensation
Abstract: An organocatalytic asymmetric multicomponent domino
reaction employing the bulk chemical nitromethane and a,b-unsat-
urated aldehydes as substrates is described. The new triple cascade
reaction based on two subsequent Michael additions and an in-
tramolecular aldol condensation provides an atom-economic entry
to diastereo- and enantiomerically pure 5-nitrocyclohexene carbal-
dehydes after flash chromatography.
Ph
Ph
OTMS
O
O
N
H
(S)-2
CHO
R
catalyst
R
R
MeNO
+
2
*
R
EN
IM IM
Michael
addition
NO2
3
triple cascade
Michael
addition
1
Key words: domino reaction, organocatalysis, Michael addition,
nitroalkane, aldol condensation
Scheme 1 Organocatalytic asymmetric multicomponent domino
reaction of nitromethane with enals
The conjugate addition of nitroalkanes to a,b-unsaturated
carbonyl compounds constitutes an important carbon–
carbon bond-forming reaction in organic synthesis.1 After
the pioneering work of Hanessian et al. and Corey et al. in
the year 2000, many reports appeared in the literature and
proved that organocatalysts such as secondary amines can
promote this key reaction with high enantioselectivities.2,3
Parallel to this development, domino reactions have
gained considerable attention. This powerful tool for the
construction of complex molecules in a simple operation
is efficient in terms of atom and step economy, while
avoiding protecting-group manipulations, one of the main
drawbacks of classical synthesis.4 For example, our group
reported recently a secondary amine-catalyzed domino
Michael–nitroalkane Michael–aldol condensation reac-
tion for the stereoselective synthesis of tri- and tetrasub-
stituted cyclohexene carbaldehydes.5,6 A related approach
was recently reported by Jørgensen et al. using activated
methylene compounds such as malonitrile, cyanoacetates,
or nitro esters as nucleophiles and enals as electrophiles.7
We started our investigations by reacting cinnamaldehyde
(1, R = Ph) with nitromethane in various solvents in the
presence of 20 mol% of catalyst (S)-2 to find out the best
conditions (Table 1).
Surprisingly, toluene as solvent did not provide any con-
version under the test conditions (entry 1), and the same
result was obtained with THF. In ethanol the triple cas-
Table 1 Solvent Screening for the Reaction of Cinnamaldehyde
with Nitromethane
Ph
Ph
OTMS
N
H
CHO
Ph
(S)-2 (20 mol%)
Ph
MeNO2
+
CHO
*
1a
Ph
NO2
3a
Entrya
Solvent
toluene
THF
Yield (%)b drc
ee (%)d
–
1
0
–
To explore this field further and taking advantage of the
nitroalkane specific reactivity, we envisaged the develop-
ment of an organocatalytic domino nitroalkane Michael–
nitroalkane Michael–aldol condensation sequence using
one equivalent of nitromethane and two equivalents of
a,b-unsaturated aldehydes.
2
0
–
–
3
EtOH
23
70
35
65
52:48
65:35
64:36
64:36
–
4
CHCl3
CHCl3
CHCl3
>99
>99
>99
5e
6f
We now wish to report such a triple domino reaction
based on an iminium–iminium–enamine activation mode
for the asymmetric synthesis of 5-nitrocyclohexene carb-
aldehydes 3 catalyzed by diphenylprolinol TMS ether (S)-
2 as organocatalyst (Scheme 1).
a All reactions were performed on a 0.5 mmol scale at r.t. for 18 h with
20 mol% of catalyst and 2.5 equiv of cinnamaldehyde.
b Yield of the two diastereomers after flash chromatography.
c Determined by GC analysis of the crude product.
d Determined by HPLC analysis on a chiral stationary phase; only the
ee of the major diastereomer was measured.
SYNLETT 2009, No. 19, pp 3175–3178
x
x
.x
x
.2
0
0
9
e Reaction performed at 0 °C.
Advanced online publication: 08.10.2009
DOI: 10.1055/s-0029-1218282; Art ID: G32009ST
f Reaction performed with 2.2 equiv of cinnamaldehyde.
© Georg Thieme Verlag Stuttgart · New York

3176
D. Enders et al.
LETTER
cade product was isolated in low yield and with no diaste- The results summarized in Table 2 show that this triple
reoselectivity. Chloroform gave a dramatic improvement, domino reaction can be applied with a variety of aromatic
and the domino product was isolated in 70% yield with a and heteroaromatic enals. Substrates similar to cinnamal-
low diastereomeric ratio and a practically complete enan- dehyde gave comparable results in terms of yields and
tiomeric excess (entry 4). Despite the low diastereoselec- diastereoselectivity and showed virtually complete enan-
tivity, the enantiopure major diastereomer could be tiomeric excesses (3b–d). a,b-Unsaturated aldehydes
isolated after flash chromatography. Carrying out the re- bearing bulkier aromatic substituents at the b-position led
action at low temperature (0 °C) did not improve the dia- to increased diastereomic ratios while keeping the excel-
stereomeric ratio, and the reaction was not complete after lent enantioselectivities (3e,f). The triple cascade was also
18 hours (entry 5). Finally, we proved that 2.2 equivalents possible with enals bearing an aromatic heterocyclic sub-
of cinnamaldehyde are sufficient to allow a good conver- stituent, although the yield was lower (3g). First test ex-
sion (entry 6). In order to demonstrate the practicability of periments with b-alkyl-substituted enals indicated a
the new protocol the reaction was carried out on a 10 limitation of the protocol, and no domino product could be
mmol scale without any loss of the enantiomeric purity isolated.
but with a somewhat lower yield (44%). This scale-up
The relative and absolute configuration of the cyclohex-
process afforded 760 mg of the enantiopure aldehyde 3a.
1
ene carbaldehyde 3a was determined as 4S,5R,6R by H
We then investigated the present reaction with respect to NMR NOE experiments and by single crystal X-ray struc-
different a,b-unsaturated aldehydes 1 (Scheme 2). The ture analysis (Figure 1), which is in agreement with the
starting enals were purchased from commercial sources or relative topicity observed in other diphenylprolinol-
were synthesized via a Heck reaction from the corre- silylether-catalyzed Michael additions to enals.2
sponding aromatic halide.8
Ph
Ph
OTMS
N
H
CHO
R
(S)-2 (20 mol%)
R
+
MeNO2
CHO
CHCl3, r.t., 20 h
1
R
NO2
3a–g
Scheme 2 Asymmetric synthesis of 5-nitrocyclohexene carbalde-
hydes 3 from nitromethane and various enals 1
Figure 1 X-ray crystal structure of 3a9
Table 2 Yields and Stereoselectivities of the Organocatalytic Triple
A proposal for the catalytic cycle is presented in
Scheme 3. The enal 1 is first activated as the iminium ion
4 by the chiral amine catalyst (S)-2, then undergoes the
first nitromethane Michael addition to afford the nitro-
alkane enamine 5. Subsequent hydrolysis generates the
nitroaldehyde 6 and the catalyst, which can promote a sec-
ond Michael addition with another equivalent of the imi-
nium ion 4. The intermediate enamine 7 reacts via an
intramolecular aldol cyclization to give 8. After hydroly-
sis, the catalyst (S)-2 is regenerated, and the intermediate
alcohol 9 can dehydrate to afford the desired product 3.
Domino Reactiona
3
R
Yield
(%)b
drc
de
ee
(%)d
(%)e
3a
3b
3c
3d
3e
3f
Ph
65
57
60
52
40
57
64:36
73:27
73:27
70:30
92:8f
>98
>98
>98
>98
>98
>98
>98
>99
>99
>99
>99
>99
>98
>99
2-MeOC6H4
4-MeOC6H4
p-tolyl
p-diphenyl
2-naphthyl
In summary, we have developed a simple and convenient
organocatalytic triple domino reaction employing the
bulk chemical nitromethane and a,b-unsaturated alde-
hydes as substrates. The triple cascade follows an imini-
um–iminium–enamine activation mode involving two
sequential Michael additions and an intramolecular aldol
condensation. After a final flash chromatography, the 5-
nitrocyclohexene carbaldehydes are obtained in accept-
able yields as pure stereoisomers bearing three contiguous
stereocenters.10 The method is of high atom economy with
water as the simple waste product.11
78:22f
82:18f
3g
5-N-methylindolyl 30
a Reactions were performed on a 1 or 1.5 mmol scale with 20 mol%
of catalyst and 2.2 equiv of cinnamaldehyde.
b Yield of the two diastereomers after flash chromatography.
c Determined by GC analysis of the crude product.
d Determined by NMR spectroscopy of the major diastereomer after
chromatography.
e Determined by HPLC analysis on a chiral stationary phase, only the
ee of the major diastereomer was measured.
f Determined by 1H NMR spectroscopy of the crude product.
Synlett 2009, No. 19, 3175–3178 © Thieme Stuttgart · New York

LETTER
Asymmetric Triple Domino Reactions
3177
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O
R
H2O
R
O
R
HO
NO2
Ph
3
O
R
1
9
NO2
Ph
OTMS
R
N
H
H2O
(S)-2
Ph
Ph
OTMS
Ph
Ph
N+
O–
(3) For recent reviews on organocatalysis, see: (a) Berkessel,
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Gericke, K. Domino Reactions in Organic Synthesis; Wiley-
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N+
OTMS
4
R
R
R
MeNO2
H2O
NO2
8
IM
IM
EN
IM
triple cascade
EN
Ph
Ph
OTMS
Ph
Ph
N
N
R
O
OTMS
5
R
H2O
IM
R
O
NO2
NO2
7
Ph
Ph
(S)-2
R
OTMS
NO2
N+
6
R
4
Scheme 3 Proposed mechanism of the triple domino reaction
Acknowledgment
(5) (a) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G.
Nature (London) 2006, 441, 861. (b) Enders, D.; Hüttl,
M. R. M.; Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem.
Int. Ed. 2007, 46, 467. (c) Enders, D.; Hüttl, M. R. M.;
Raabe, G.; Bats, J. W. Adv. Synth. Catal. 2008, 350, 267.
(6) For reviews on organocatalytic domino reactions, see:
(a) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem.
Int. Ed. 2007, 46, 1570. (b) Yu, X.; Wang, W. Org. Biomol.
Chem. 2008, 6, 2037.
This work was supported by the Deutsche Forschungsgemeinschaft
(priority program Organocatalysis) and the Fonds der Chemischen
Industrie. We thank the former Degussa AG and BASF AG for the
donation of chemicals.
References and Notes
(1) For a recent review on nitroalkane additions to a,b-
unsaturated carbonyl compounds, see: Ballini, B.; Bosica,
G.; Fiorini, G.; Palmieri, A.; Petrini, M. Chem. Rev. 2005,
105, 933.
(2) For selected examples, see: (a) Hanessian, S.; Pham, V.
Org. Lett. 2000, 2, 2975. (b) Corey, E. J.; Zhang, F.-Y. Org.
Lett. 2000, 2, 4257. (c) Halland, N.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331.
(7) Carlone, A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2007, 46, 1101.
(8) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Org. Lett. 2003, 5,
777.
(9) CCDC-743470 (3a) contains the supplementary
crystallographic data for this paper. More data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via www. ccdc.cam.ac.uk/
data_request/cif.
(10) General Procedure
(d) Tsogoeva, S. B.; Jagtap, S. B. Synlett 2004, 2624.
(e) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem.
Commun. 2005, 5346. (f) Prieto, A.; Halland, N.; Jørgensen,
K. A. Org. Lett. 2005, 7, 3897. (g) Vakulya, B.; Varga, S.;
Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967. (h) Ooi, T.;
Takada, S.; Fujioka, S.; Maruoka, K. Org. Lett. 2005, 7,
5143. (i) Hanessian, S.; Shao, Z.; Warrier, J. S. Org. Lett.
2006, 8, 4787. (j) Enders, D.; Narine, A. A.; Benninghaus,
T. R.; Raabe, G. Synlett 2007, 1667. (k) Zu, L.; Xie, H.; Li,
In an ordinary vial equipped with a magnetic stirring bar, the
a,b-unsaturated aldehyde 1 (2.2 mmol, 2.2 equiv) was
dissolved in CHCl3 (1 mL). The catalyst (S)-2 (0.2 mmol, 0.2
equiv) and nitromethane (1 mmol, 1 equiv) were added to the
solution. The vial was sealed, and the mixture was stirred for
20 h at r.t. The crude reaction mixture was diluted in CH2Cl2,
Synlett 2009, No. 19, 3175–3178 © Thieme Stuttgart · New York

3178
D. Enders et al.
LETTER
washed with H2O, and dried over MgSO4. After
concentration, the crude product was purified by flash
chromatography (silica gel, pentane–EtOAc). All new
compounds gave satisfactory spectroscopic and analytical
data. As a typical example, the data of the compound 3a are
given.
(dd, J = 1.9, 3.0 Hz, 1 H, H5), 7.03–7.07 (m, 2 H, HPh-para),
7.22–7.38 (m, 9 H, HPh and H2), 9.57 (s, 1 H, HCHO). 13
C
NMR (100 MHz, CDCl3): d = 28.0 (C3), 37.3 (C4), 43.2 (C6),
91.3 (C5), 127.3 (CH), 128.0 (CH), 128.9 (CH), 129.2 (CH),
137.9, 138.0, 138.8 (CPh, C1), 150.4 (C2), 191.65 (CHO).
HRMS (EI): m/z calcd for C19H1703N1: 307.1203; found:
307.1208.
(4S,5R,6R)-5-Nitro-4,6-diphenylcyclohex-1-ene
carbaldehyde (3a, Figure 2)
2
Isolated as a yellow solid (202 mg, 65%). The ee (>99%)
was determined by HPLC on a chiral stationary phase
[Chiralcel OD; n-heptane–i-PrOH (8:2); 1.0 mL/min,
tR = 9.93 min(major), 18.25 min (minor, based on the
racemic mixture)]; mp 108 °C; [a]D20 –123 (c 1.1, CHCl3).
IR (ATR): 3060, 2807, 2718, 2323, 2115, 1684, 1653, 1547,
1494, 1450, 1410, 1366, 1247, 1162, 1078, 946 cm–1. 1H
NMR (400 MHz, CDCl3): d = 2.89 (ddd, J = 5.2, 5.2, 20.0
Hz, 1 H, H3); 3.25 (dddd, J = 2.4, 11.2, 11.2, 20.0 Hz, 1 H,
H3¢), 3.35–3.40 (m, 1 H, H4), 4.32–4.38 (m, 1 H, H6); 4.96
1
CHO
3
4
6
5
NO2
Figure 2
(11) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
Synlett 2009, No. 19, 3175–3178 © Thieme Stuttgart · New York