An unexpected organocatalytic asymmetric tandem Michael/Morita-Baylis- Hillman reaction

Article abstract of DOI:10.1002/anie.200704076

(Chemical Equation Presented) Simply complex: An organocatalytic tandem Michael/Morita-Baylis-Hillman reaction has been developed in which secondary amine catalysts allow for a very selective, scalable synthesis of highly substituted optically active cycl

Full text of DOI:10.1002/anie.200704076

Angewandte
Chemie
DOI: 10.1002/anie.200704076
Organocatalytic Tandem Reaction
An Unexpected Organocatalytic Asymmetric Tandem Michael/
Morita–Baylis–Hillman Reaction**
Silvia Cabrera, JosØ Alemµn, Patrick Bolze, Søren Bertelsen, and Karl Anker Jørgensen*
A new direction in organocatalysis[1] is the development of
cascade or tandem reactions.[2] These allow the rapid con-
struction of structurally complex molecules from simple
starting materials in only one operation, thereby minimizing
the cost, waste, and manual efforts.[3] One of the most
successful class of organocatalysts used for this purpose are
secondary amines. These catalysts allow the sequential
functionalization of aldehydes to give enamine[4] and iminium
ion[5] intermediates, that in combination with electrophiles or
nucleophiles, respectively, enables the stereoselective synthe-
ses of highly functionalized molecules by consecutive amine-
catalyzed reactions.
During the development of a new cascade reaction, we
started to investigate the reaction of a,b-unsaturated alde-
hydes 1 with the Nazarov reagent 2 using proline derivatives
as organocatalysts (Scheme 1). Surprisingly, the expected
A number of fascinating organocatalytic cascade reactions
have been reported during the last two years.[6] Some of the
most attractive reactions are exemplified by the triple cascade
reaction of aldehydes, a,b-unsaturated aldehydes, and nitro-
alkenes described by Enders et al., who employed a sequen-
tial enamine–iminium–enamine activation;[7] the iminium–
iminium–enamine triple activation of a,b-unsaturated alde-
hydes and activated methylene compounds developed by our
research group;[6e] and the tandem Michael–Henry reaction of
pentane-1,5-dial and nitroalkenes reported recently by Hay-
ashi et al.[6j]
The Morita–Baylis–Hillman reaction is a powerful tool for
the atom-economic construction of optically active a-meth-
ylene-b-hydroxycarbonyl derivatives using a chiral tertiary
amine or phosphine catalyst.[8] A few examples of the use of
chiral secondary amines—mainly proline—for this reaction
have been reported, and in all the cases the addition of a
tertiary amine as co-catalyst was found to be essential for
activation of the double bond.[9]
Scheme 1. Asymmetric organocatalytic tandem reaction.
compound 3, which should be formed by addition of Nazarov
reagent 2[10] to the a,b-unsaturated aldehyde 1 followed by
ring closure by enamine addition to the double bond, was not
observed. On the contrary, cyclohexenone 4 was obtained as
the main product through an intramolecular Morita–Baylis–
Hillman pathway. This observation led us to investigate the
reaction of cinnamaldehyde (1a) and Nazarov reagent 2a
under various catalyst and solvent conditions (Table 1). The
screening of the catalysts (Table 1, entries 1–5) was carried
out using 20 mol% of catalyst and benzoic acid as an additive
in toluene at room temperature. Under these conditions, all
the chiral secondary amines tested, except proline 5a,
catalyzed the tandem reaction to afford 4a, in its enolic
form, in good yields after 18 hours.
We report herein the diastereo- and enantioselective
Michael/Morita–Baylis–Hillman tandem reaction of a,b-
unsaturated aldehydes 1 with Nazarov reagent 2, with both
steps being catalyzed by a chiral secondary amine.
In terms of selectivity, the protected diaryl prolinol
derivatives 5d and 5e[11] (Table 1, entries 4 and 5) showed
both high diastereo- and enantioselectivity (92% and 94% ee,
respectively), while nearly racemic product 4a was obtained
when the unprotected catalyst 5c was used (Table 1, entry 3).
The substitution on the aromatic ring of the catalyst was
found to have a remarkable effect on the reactivity, and an
incomplete reaction was obtained after 40 hours using the
trifluoromethyl-substituted catalyst 5d. The best results were
achieved with (S)-2-(diphenyltrimethylsilanyloxymethyl)pyr-
rolidine 5e as the catalyst.
[*] Dr. S. Cabrera, Dr. J. Alemµn, Dr. P. Bolze, S. Bertelsen,
Prof. Dr. K. A. Jørgensen
Danish National Research Foundation: Center for Catalysis
Department of Chemistry
Aarhus University
8000 Aarhus C(Denmark)
Fax: (+45)8919-6199
E-mail: kaj@chem.au.dk
[**] This work was made possible by a grant from the Danish National
Research Foundation. S.C. and J.A. thank the Ministerio de
Educación y Ciencia of Spain for their post-doctoral fellowships.
Thanks are expressed to Dr. Jacob Overgaard for performing the
X-ray analysis.
Other solvents, such as CH2Cl2, Et2O, or CH3CN, and neat
conditions were also studied (Table 1, entries 7–10); however,
in all cases lower selectivity was obtained, relative to the use
of toluene. Full conversion was also obtained when the
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 121 –125
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1: Representative screening results for the reaction of cinnamal-
Table 2: Reaction of a,b-unsaturated aldehydes 1a–i with b-ketoesters
2.[a]
dehyde (1a) with b-ketoester 2a.[a]
Entry R1
R2
d.r.[b] Prod. Yield [%][c] ee [%][d]
1
2
3
4
Ph (1a)
Ph (1a)
Ph (1a)
Ph(1a)
Et (2a) 7:1 4a
Et (2a) 11:1 4a
tBu (2b) 5:1 4b
allyl (2c) 6:1 4c
Et (2a) 7:1 4d
55
53
68
45
94
À95[e,f]
94
94
Entry Cat. Solvent Conversion [%] d.r.[b] Yield [%][c] ee [%][d]
49 (76)[f] 93 (95)[f]
1
2
3
4
5
6
7
8
9
10
5a
5b
5c
5d
5e
5e
5e
5e
5e
5e
toluene n.r.[e]
toluene >98
toluene >98
toluene 80[f]
toluene >98
toluene >98
CH2Cl2 >98
–
9:1
–
52
–
49
2
92
94
94[g]
94
92
91
90
5
p-ClC6H4 (1b)
6
7
8
9
10
11
12
13
p-MeOC6H4 (1c) Et (2a) 9:1 4e
p-NO2C6H4 (1d) Et (2a) 4:1 4 f
p-NO2C6H4 (1d) tBu (2b) 4:1 4g
69
58
51
57
66
51
64
51
93
96
95
95
12:1 57
16:1 51
14:1 74
7:1
9:1
3:1
3:1
4:1
2-thienyl (1e)
2-furyl (1 f)
CO2Et (1g)
Et (1h)
Et (2a) 6:1 4h
Et (2a) 4:1 4i
Et (2a) 5:1 4j
Et (2a) 6:1 4k
Et (2a) 3:2 4l
92
55
63
71
75
55
98[f]
86[f,g]
92[f,g]
Et2O
CH3CN >98
neat >98
>98
(Z)-hex-3-enyl
(1i)
[a] All reactions were performed on a 0.2-mmol scale with PhCO2H
(10 mol%) as additive in 0.2 mL of toluene. [b] The diastereoisomeric
ratio was determined by 1H NMR spectroscopic analysis of the crude
mixture, which consisted of epimers at the alcohol. [c] Yield of the
diastereoisomeric mixture after flash chromatography. [d] Determined by
HPLCon a chiral stationary phase (see the Supporting Information).
[e] The R enantiomer of the catalyst 5e was used. [f] 20 mol% of catalyst
5e and PhCO2H were used. [g] The ee value was determined after
derivatization (see the Supporting Information).
[a] All reactions were performed on a 0.2-mmol scale with PhCO2H
(20 mol%) as additive in 0.2 mL of solvent and stopped after 18 h.
[b] The diastereoisomeric ratio was determined by H NMR analysis of
the crude mixture, which consisted of epimers at the alcohol position.
[c] Yield of the diastereoisomeric mixture after flash chromatography.
[d] Determined by HPLCon a chiral stationary phase (see the Supporting
Information). [e] No reaction. [f] The reaction was stopped after 40 h.
[g] 10 mol% of catalyst 5e and PhCO2H were used. TBDPS=tert-
butyldiphenylsilyl, TMS=trimethylsilyl.
1
catalyst loading was decreased to 10 mol%
(Table 1, entry 6), without any variation in
the enantioselectivity, although a slight drop
in the diastereoselectivity was observed. The
reaction can also be performed on a 2-mmol
scale with 20 mol% of the catalyst to give 4a
in 72% yield and 94% ee.
The scope of the Michael–Morita–Baylis-
Hillman reaction was studied for different
a,b-unsaturated aldehydes and b-ketoesters
in the presence of 10 mol% of catalyst 5e
and benzoic acid in toluene (Table 2). The
tandem reaction is a general reaction for b-
ketoesters 2 with different ester groups, and
similar yields as well as diastereo- and
enantioselectivities were obtained in all
cases (Table 2, entries 1, 3, 4, 8). A broad
range of groups—aromatic, heteroaromatic,
ester, and aliphatic—at the b-position of the
aldehyde could be tolerated, and afforded the
corresponding products 4 in high enantiose-
Scheme 2. Proposed mechanism for the Michael/Morita–Baylis–Hillman tandem reaction.
lectivities (86–98% ee) and good yields (49–
76%). The opposite enantiomer of product
4a could also be easily obtained by carrying out the reaction
with the R enantiomer of catalyst 5e (Table 2, entry 2).
We propose a two amine-catalyzed cycle mechanism for
the formation of the products 4 (Scheme 2). First, catalyst 5e
activates the a,b-unsaturated aldehyde 1, thereby forming an
iminium intermediate which undergoes a Michael addition
with Nazarov reagent 2a (Cycle I). Then, hydrolysis of the
intermediate A leads to intermediate 6 and recovery of the
catalyst. In the second cycle (Cycle II), we suggest that 5e—
now acting as a nucleophilic catalyst for the activation of the
double bond—is involved in the intramolecular Morita–
Baylis–Hillman reaction of 6. However, according to our
122
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knowledge, no reports of enantioselective Morita–Baylis–
Hillman reactions catalyzed by a secondary amine have been
described.
We reasoned that isolation of the intermediate 6 and the
determination of the role of the catalyst in the intramolecular
Morita–Baylis–Hillman reaction of the later (Cycle II) would
be important for providing support for the proposed mech-
anism.
It was found that an incomplete reaction takes place on
cooling the reaction temperature to 48C, and that 6 could be
isolated as an inseparable mixture of diastereoisomers
(d.r. 1:1).[12] Then, we studied the cyclization of 6 to 4a by
adding different catalysts to a solution of 6 in toluene. No
reaction took place in the absence of catalyst or by addition of
water or benzoic acid (Table 3, entries 1–3). However, the use
of 20 mol% of catalyst (S)-5e
addition was observed, as a result of the steric hindrance
associated with the Morita–Baylis–Hillman reaction.
All these mechanistic tests seem to support the active role
of catalyst 5e in the intramolecular Morita–Baylis–Hillman
reaction (Cycle II, Scheme 2).
The stereoselective synthesis of complex structures in a
short pathway is the main aim of synthetic chemists.[13] The
high level of functionalization presented in the tandem
products 4 indicated to us that simple transformations could
give a wide range of interesting products. In fact, we
developed a diastereo- and enantioselective synthesis of
cyclohexanones and cyclohexenones with up to four stereo-
centers in a two-step synthesis (starting from the a,b-
unsaturated aldehyde; Scheme 3). For example, following an
SN2’ mechanism, the addition of the tosyl sodium salt to a
afforded the Morita–Baylis–Hillman
product 4a as a 5:1 mixture of
diastereoisomers, with the major dia-
stereomer having 89% ee (Table 3,
entry 4), while the enantiomer ((R)-
5e) afforded the same diastereose-
lectivity and with the major diaste-
reomer in 94% ee (Table 3, entry 5).
Another secondary amine, pyrroli-
dine, and typical Morita–Baylis–Hill-
man catalysts, such as DABCO or
PPh3, also catalyzed the cyclization of
Scheme 3. Stereoselective synthesis of diverse products. Tol=tolyl, mCPBA=meta-chloroperoxy-
benzoic acid, Bn=benzyl.
6 to 4a (Table 3, entries 6–8). It
should also be noted that similar
enantioselectivities and the same
approach for the addition of this reaction step (pro-R face
with respect to the aldehyde) was achieved with all the
nonchiral catalysts, thus showing that the selectivity of this
step is controlled by the stereocenter at the b-position of the
aldehyde formed in the first cycle (Scheme 2).
The tandem reaction between 1a and the Nazarov reagent
substituted with a methyl group at the g- or d-positions of the
alkene did not take place, and only a sluggish Michael
solution of the corresponding cyclohexenone 4 in EtOH
afforded 7 in good yields (51–71%). The spiro compound 8
was obtained in 77% yield by a diastereoselective epoxida-
tion of the double bond in 4a using mCPBA. Furthermore,
conjugate addition of the corresponding amine or thiol to 4a
leads to the amino alcohol 9 and the thio alcohol 10,
respectively.
The absolute configuration of the tandem products 4 and
8–10 were assigned by a single-crystal X-ray analysis of 7a[14]
as well as by NMR spectroscopic studies.[15]
Table 3: Catalyst investigations for the Morita–Baylis–Hillman step.[a]
In conclusion, we have developed a new organocatalytic
tandem reaction of a,b-unsaturated aldehydes and Nazarov
reagent catalyzed by a diarylprolinol ether following a
Michael/Morita–Baylis–Hillman mechanism. The reaction
proceeds in high enantio- and diastereoselectivity for a wide
range of a,b-unsaturated aldehydes and different b-ketoest-
ers. Mechanistic studies indicate that the TMS-protected
prolinol also acts as the catalyst in the Morita–Baylis–Hillman
reaction, and is the first chiral secondary amine catalyst
reported for this reaction. Furthermore, a number of stereo-
selective transformations have been presented that lead to
various types of optically active cyclohexenone and cyclo-
hexanone derivatives with up to four stereocenters.
Entry
Catalyst
mol%
d.r.[b]
ee [%][c]
1
2
3
4
5
6
7
8
–
H2O
–
n.r.
n.r.
n.r.
5:1
5:1
6:1
11:1
>20:1
–
–
–
89
94
92
93
94
100
20
20
20
20
50
20
PhCO2H
(S)-5e
(R)-5e
pyrrolidine
DABCO
PPh3
[a] All reactions were performed in toluene with the diastereoisomeric
mixture of intermediate 6 and the corresponding catalyst. [b] Diastereo-
isomeric ratio determined by 1H NMR spectroscopic analysis of the
crude mixture. n.r.: no reaction. [c] Determined by HPLC(see the
Supporting Information). DABCO=1,4-diazabicyclo[2.2.2]octane.
Experimental Section
General procedure for the Michae/Morita–Baylis–Hillman reaction:
The corresponding b-ketoester 2a (0.2 mmol) was added to a stirred
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123

Communications
solution of catalyst 5e (0.02 mmol), benzoic acid (0.02 mmol), and the
[5] For recent examples of iminium activation, see for example: a) S.
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corresponding aldehyde 1a–i (0.6 mmol) in toluene (0.2 mL) in an
ordinary vial. After complete consumption of the b-ketoester, usually
1
within 14–18 h (as monitored by H NMR spectroscopy), the crude
product was directly charged on to silica gel and subjected to flash
chromatography. For example, (+)-4a was obtained after flash
chromatography (eluent 4:1, hexanes/Et2O) as a colorless oil (55%
yield). The ee value was determined by HPLC using a Chiralpak OD
column (hexane/iPrOH 90:10); flow rate 1.0 mLminÀ1
;
tminor
=
,
18.3 min, tmajor = 44.6 min (94% ee). [a]2D0 = + 4.0 (c = 0.3 gcmÀ3
CH2Cl2). 1H NMR (400 MHz, CDCl3): d = 12.27 (s, 1H), 7.26–7.13
(m, 5H), 6.07 (s, 1H), 5.67 (s, 1H), 4.39 (ddd, J = 10.4, 4.0, 2.0 Hz,
1H), 4.04–3.94 (m, 1H), 3.92–3.85 (m, 2H), 2.38–2.32 (m, 1H), 2.06–
2.02 (brs, 1H), 1.76–1.68 (m, 1H), 0.78 ppm (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d = 172.3, 163.4, 146.6, 142.1, 128.3
(2C), 126.7 (2C), 125.9, 115.4, 102.3, 68.6, 60.4, 41.7, 39.1, 13.5 ppm;
MS (TOF ES+): [M+Na]+ calcd for C16H18NaO4: 297.1103; found:
297.1102.
[6] For a review on organocatalytic domino reactions, see a) D.
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G.-L. Zhao, L. Eriksson, A. Córdova, Adv. Synth. Catal. 2007,
349, 827; e) A. Carlone, S. Cabrera, M. Marigo, K. A. Jørgensen,
Angew. Chem. 2007, 119, 1119; Angew. Chem. Int. Ed. 2007, 46,
1101; f) H. Li, L. Zu, H. Xie, J. Wang, W. Jiang, W. Wang, Org.
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[7] a) D. Enders, M. R. M. Hüttl, C. Grondal, G. Raabe, Nature
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[8] For recent reviews on the Morita–Baylis–Hillman reaction, see
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[9] a) J. E. Imbriglio, M. M. Vasbinder, S. J. Miller, Org. Lett. 2003,
5, 3741; b) S. H. Chen, B. C. Hong, C. F. Su, S. Sarshar,
Tetrahedron Lett. 2005, 46, 8899; c) C. E. Aroyan, M. M. Vas-
binder, S. J. Miller, Org. Lett. 2005, 7, 3849; d) A. Nakano, S.
Kawahara, S. Akamatsu, K. Morokuma, M. Nakatani, Y.
Iwabuchi, K. Takahashi, J. Ishihara, S. Hatekeyama, Tetrahedron
2006, 62, 381; e) M. M. Vasbinder, J. E. Imbriglio, S. J. Miller,
Tetrahedron 2006, 62, 11450; for two examples on aza-Morita–
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Tanaka, C. F. Barbas III, Angew. Chem. 2007, 119, 1910; Angew.
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Received: September 4, 2007
Published online: November 15, 2007
Keywords: aldehydes · amines · Nazarov reagent ·
.
organocatalysis · tandem reactions
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[14] CCDC-661574 contains the supplementary crystallographic data
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cam.ac.uk/data_request/cif..
[15] For more details about the determination of the absolute
configuration of all the compounds, see the Supporting
Information.
[12] After 18 h, the reaction was stopped and 1H NMR spectroscopic
analysis of the crude mixture showed a 90% conversion with a
7:1 ratio of the intermediate 6 to the tandem product 4a.
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