Nhc-catalyzed michael addition to α,β-unsaturated aldehydes by redox activation

Article abstract of DOI:10.1002/anie.201004593

Through oxidative carbene catalysis the reactivity of enals can be reversed at the β position from the typical electrophilic to nucleophilic (homoenolate chemistry) further to electrophilic reactivity by two consecutive umpolung processes. These redox-act

Full text of DOI:10.1002/anie.201004593

Communications
DOI: 10.1002/anie.201004593
Organocatalysis
NHC-Catalyzed Michael Addition to a,b-Unsaturated Aldehydes by
Redox Activation**
Suman De Sarkar and Armido Studer*
ꢀ
The formation of C C bonds undoubtedly belongs to the
most important transformations in organic chemistry, and
Michael reactions are important examples thereof.[1] Two
strategies have mainly been followed for the activation of
Michael acceptors to conduct conjugate addition reactions:
a) activation by using Lewis[2] or Brønsted[3] acids and
b) activation by iminium ion generation.[4] It has been
shown independently by Bode and Glorius[5] that a,b-
unsaturated aldehydes 1 react with N-heterocyclic carbenes
(NHCs) 2 to umpoled[6] intermediates of type A, which can
then react as homoenolates at the b position with various
electrophiles to give product B (Scheme 1).[7]
precedence in biosynthesis for such processes, and very
recently Lupton reported NHC-catalyzed 1,4-addition using
activated a,b-unsaturated acid derivatives via intermediates
of type C.[11–13] Starting with an a,b-unsaturated aldehyde our
planned process would comprise two consecutive umpolung
reactions at the b position of the a,b-unsaturated aldehyde by
a redox-type activation. To liberate the NHC catalyst, the
C nucleophile should bear an additional nucleophilic site
(Nu2) such that subsequent 1,2-addition to the acylazolium
ion D releases the NHC catalyst. Herein we present initial
results on this concept.
We first studied reaction of cinnamaldehyde (1a) with
acetyl acetone (3a) by using triazolium salt 2 as a carbene
precursor (10 mol%) and diazabicyclo[5.4.0]undecene (DBU,
10 mol%) in THF at room temperature. As an organic
oxidant, the readily available quinone 4 (1 equiv)[14] was used.
To our delight, the Michael addition/cyclization product 5a
was formed in 91% yield within 2 h along with bisphenol 6,
which can be readily transformed to 4 (Scheme 2, Table 1,
Scheme 1. Redox activation of a,b-unsaturated aldehydes and subse-
quent 1,4-addition.
Scheme 2. Reaction of cinnamaldehyde with acetyl acetone under
oxidative NHC catalysis.
We recently showed that Breslow intermediates A can be
readily oxidized with mild organic oxidants to acylazolium
ions of type C, which undergo efficient O acylation with
various O nucleophiles to give the corresponding esters.[8–10]
Based on these results we decided to use oxidatively
generated intermediates C as Michael acceptors to conduct
1,4-addition reactions using soft C nucleophiles. There is
Table 1: Reaction of 1a with 3a under different conditions.
Entry Cat. loading [mol%] Acetyl acetone [equiv] t [h] Yield [%][a]
1
2
3
4
10
5
2
2
2
3.0
3.0
3.0
1.5
1.5
1.1
1.5
2.0 91
2.0 89
2.5 87
2.5 91
6.0 86
2.5 78
6.0 89
5[b]
6
2
1
[*] S. De Sarkar, Prof. Dr. A. Studer
7
Organisch-Chemisches Institut, Westfꢀlische Wilhelms-Universitꢀt
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax: (+49)281-83-36523
[a] Yield of isolated product. [b] With 3 mol% DBU.
E-mail: studer@uni-muenster.de
[**] We thank the DFG for supporting our work within the priority
program “Organocatalysis” (SPP 1179). NHC=N-heterocyclic
carbene.
entry 1). For optimization, the reaction was repeated under
different conditions. The catalyst loading was reduced to
1 mol%, and the amount of 3a was lowered to 1.5 equivalents
without affecting the yield (Table 1, entries 2–4, 7). However,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004593.
9266
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Angewandte
Chemie
Table 3: Variation of the enal.
when a catalyst loading of 1 mol% was employed, the
reaction time had to be increased to 6 h (Table 1, entry 7).
The reaction was slowed by decreasing the amount of DBU
(entry 5) and reducing the amount of acetyl acetone to
1.1 equiv also led to a lower yield (Table 1, entry 6). There-
fore, most of the following experiments were conducted with
2 mol% of the catalyst and 1.5 equiv of the nucleophile.
To study the scope of the redox-activated Michael
addition, we tested various 1,3-dicarbonyl compounds in the
reaction with cinnamaldehyde (Table 2).[15] Symmetrical 1,3-
R1
R2
R3
Product
t [h]
Yield [%][a]
4-MeOC6H4
4-Me2NC6H4
4-MeOCOC6H4
2-NO2C6H4
2-thienyl
Me
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
Me
H
7b
7c
7d
7e
7 f
7g
7h
7i
1.5
4.0
1.5
1.5
1.5
2.5
2.5
2.5
48.0
36.0
89
85
82
86
75
81
92
91
Table 2: Variation of the nucleophile.
iPr
=
CH CHCH3
Ph[b]
7j
7k
34[c,d]
73
Me[b]
[a] Yield of isolated product. [b] With 10 mol% catalyst and 15 mol%
DBU. [c] Combined yield of both diastereoisomers. [d] Diastereoisomer
ratio 1.5:1.
R1
R2
Product
t [h]
Yield [%][a]
Et
Ph
Ph
OEt
OiPr
OMe
OMe
OEt
Et
5b
5c
5d
5e
5 f
5g
5h
5i
8.0
4.0
2.5
2.5
2.5
2.5
2.5
4.0
8.0
12.0
89
82
Ph
Me
Me
Me
Et
86[b,c]
80
give 7i (91%). The a-substituted a,b-unsaturated aldehyde 1j
afforded a lower yield even when a higher catalyst loading
was used (!7j, 34%). In this reaction both diastereoisomers
were formed (d.r. 1.5:1.0).[16] Importantly, the reaction of the
b-disubstituted enal 1k provided dihydropyranone 7k in 73%
yield, showing that our novel method can be used to build up
quaternary carbon centers. Note that a higher catalyst loading
and a longer reaction time were necessary in that case.
Importantly, we also found that a high stereoselectivity
can be achieved using the chiral b-ketoamide 3l as the
nucleophile in the reaction with para-methoxy cinnamalde-
hyde 1b (Scheme 3).[17]
74
81
76
81
76
51
=
CH2CH2CH CH2
Ph
4-MeOC6H4
Me
OMe
5j
5k
N-morpholinyl[d]
[a] Yield of isolated product. [b] Combined yield of both regioisomers.
[c] Regioisomer ratio 8:1. [d] With 5 mol% catalyst and 1.1 equiv DBU.
diketones bearing aliphatic and aromatic substituents
afforded the corresponding products 5b and 5c in good
yields. With these bulkier diketones the reaction was slower.
When the unsymmetrical 1,3-diketone 3d was used as a
nucleophile, both product regioisomers were formed. How-
ever, good regioselectivity was achieved (ratio 8:1). Probably
for steric reasons, the keto function next to the less bulky
methyl substituent preferably acted as the nucleophile in the
cyclization reaction to give 5d. We found that b-keto esters
are also efficient nucleophiles for NHC-catalyzed oxidative
1,4-additions (!5e–j, 74–81%). b-Alkyl b-keto esters
reacted significantly faster than b-aryl b-keto esters. The
reaction with b-keto amide 3k was slower and more catalyst
(5 mol%) and a stoichiometric amount of base were required
(!5k, 51%).
Scheme 3. Diastereoselective Michael addition using a chiral b-keto
amide.
We next examined the NHC-catalyzed Michael addition
of acetyl acetone 3a with various enals 1b–k (Table 3).
Electron-rich as well as electron-poor para-substituted cinna-
maldehyde derivatives provided the corresponding dihydro-
pyranones in high yields (!7b-d, 82–89%). ortho-Nitro
cinnamaldehyde underwent smooth redox-mediated addi-
tion/cyclization with acetyl acetone (!7e, 86%) and a
heteroaryl-substituted enal also worked well (!7 f, 75%).
The reaction with crotonal was efficient (!7g). With the
sterically more hindered isopropyl enal 1h, dihydropyranone
7h was isolated in excellent yield (92%). Regioselective
addition of 3a at the b carbon was achieved with dienal 1i to
The suggested catalytic cycle is depicted in Scheme 4. The
reaction between enal 1 and carbene 2 generates the electron-
rich enaminol A. Two-electron oxidation and deprotonation
of A with oxidant 4 provide the redox-activated Michael
acceptor C.[8] Conjugate addition of the likely deprotonated
1,3-dicarbonyl compound affords F. Proton transfer (!G)
and cyclization eventually lead to dihydropyranone 5 with
liberation of carbene 2.
To exclude other possible mechanisms we performed
control experiments. The reaction might also proceed by
kinetic O acylation of the enolate with C to form enol esters
Angew. Chem. Int. Ed. 2010, 49, 9266 –9269
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Communications
In conclusion, we have shown that enals react with various
1,3-dicarbonyl compounds as redox-activated Michael accept-
ors under oxidative NHC catalysis to provide dihydropyr-
anones. As the oxidant the readily available quinone 4 was
used. Most of the substrates used are commercially available
and only a low loading of a cheap carbene catalyst was
required. The reactions were conducted under mild condi-
tions and were easy to run. With a chiral b-keto amide, the
product was formed with high diastereoselectivity.
Received: July 26, 2010
Published online: October 21, 2010
Keywords: carbenes · Michael addition · redox activation ·
.
stereoselectivity · umpolung
[1] Reviews on Michael addition: a) B. E. Rossiter, N. M. Swingle,
Chem. Rev. 1992, 92, 771; b) J. Leonard, E. Diez-Barra, S.
Merino, Eur. J. Org. Chem. 1998, 2051; c) M. P. Sibi, S. Manyem,
Tetrahedron 2000, 56, 8033; d) N. Krause, A. Hoffmann-Rꢀder,
Synthesis 2001, 171; e) S. C. Jha, N. N. Joshi, ARKIVOC 2002,
VII, 167; f) J. L. Vicario, D. Badia, L. Carrillo, Synthesis 2007,
2065.
[2] a) J. Christoffers, Eur. J. Org. Chem. 1998, 1259; b) S. Pelzer, T.
Kauf, C. van Wꢁllen, J. Christoffers, J. Organomet. Chem. 2003,
684, 308; c) J. Comelles, M. Moreno-Manas, E. Pꢂrez, A.
Roglans, R. M. Sebastian, A. Vallribera, J. Org. Chem. 2004,
69, 6834; d) U. Kazmaier, Angew. Chem. 2009, 121, 5902; Angew.
Chem. Int. Ed. 2009, 48, 5790.
Scheme 4. The proposed catalytic cycle.
of type 9 (Scheme 5). Subsequent NHC-mediated fragmen-
tation would regenerate acylazolium ion C and the enolate,[12]
which could then undergo 1,4-addition to F (thermodynamic
addition product). We currently exclude kinetic O acylation,
since the test reaction of preformed 9 under optimized
reaction conditions afforded 5a in only 7% yield; the reaction
[3] a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289; b) P. M. Pihko,
Angew. Chem. 2004, 116, 2110; Angew. Chem. Int. Ed. 2004, 43,
2062; c) M. Rueping, C. Azap, Angew. Chem. 2006, 118, 7996;
Angew. Chem. Int. Ed. 2006, 45, 7832; d) T. Akiyama, J. Itoh, K.
Fuchibe, Adv. Synth. Catal. 2006, 348, 999; e) M. S. Taylor, E. N.
Jacobsen, Angew. Chem. 2006, 118, 1550; Angew. Chem. Int. Ed.
2006, 45, 1520; f) J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am.
Chem. Soc. 2008, 130, 14416; g) W. J. Nodes, D. R. Nutt, A. M.
Chippindale, A. J. A. Cobb, J. Am. Chem. Soc. 2009, 131, 16016.
[4] For leading references on secondary-amine-catalyzed conjugate
addition to a,b-unsaturated aldehydes: a) J. F. Austin, D. W. C.
MacMillan, J. Am. Chem. Soc. 2002, 124, 1172; b) N. A. Paras,
D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124, 7894; c) S.
Brandau, A. Landa, J. Franzꢂn, M. Marigo, K. A. Jørgensen,
Angew. Chem. 2006, 118, 4411; Angew. Chem. Int. Ed. 2006, 45,
4305; d) A. Carlone, M. Marigo, C. North, A. Landa, K. A.
Jørgensen, Chem. Commun. 2006, 4928; e) Y. K. Chen, M.
Yoshida, D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128, 9328;
f) A. Carlone, S. Cabrera, M. Marigo, K. A. Jørgensen, Angew.
Chem. 2007, 119, 1119; Angew. Chem. Int. Ed. 2007, 46, 1101;
g) M. Rueping, E. Sugiono, E. Merino, Chem. Eur. J. 2008, 14,
6329; h) M. Rueping, A. Kuenkel, F. Tato, J. W. Bats, Angew.
Chem. 2009, 121, 3754; Angew. Chem. Int. Ed. 2009, 48, 3699.
[5] a) C. Burstein, F. Glorius, Angew. Chem. 2004, 116, 6331; Angew.
Chem. Int. Ed. 2004, 43, 6205; b) S. S. Sohn, E. L. Rosen, J. W.
Bode, J. Am. Chem. Soc. 2004, 126, 14370. Other selected
papers: c) V. Nair, S. Vellalath, M. Poonoth, E. Suresh, J. Am.
Chem. Soc. 2006, 128, 8736; d) E. M. Phillips, T. E. Reynolds,
K. A. Scheidt, J. Am. Chem. Soc. 2008, 130, 2416; e) A. Chan,
K. A. Scheidt, J. Am. Chem. Soc. 2008, 130, 2740.
Scheme 5. Control experiments.
starting with cinnamaldehyde gave 91% yield. Thus, acylated
enolate 9 does not seem to be a kinetically competent
intermediate. Furthermore, we showed that dimethyl malo-
nate reacted under optimized conditions in the presence of
isopropanol (1.5 equiv) within 20 h in a three-component
reaction to give Michael product 10 (51%) along with ester 11
which arises from direct O acylation of isopropanol. Impor-
tantly, repeating this experiment in the absence of isopropa-
nol did not lead to any product, showing that 10 was not
formed through ring opening of the corresponding dihydro-
pyranone derivative with isopropanol.[18] Reaction of 3a with
cinnamaldehyde in the absence of oxidant 4 under otherwise
identical conditions did not occur. This clearly shows that the
redox activation is necessary for conjugate addition.
[6] a) D. Seebach, Angew. Chem. 1979, 91, 259; Angew. Chem. Int.
Ed. Engl. 1979, 18, 239; b) D. Seebach, R. Henning, J.
Gonnermann, Chem. Ber. 1979, 112, 234. For a recent report
on the characterization and isolation of a Breslow intermediate:
c) A. Berkessel, S. Elfert, K. Etzenbach-Effers, J. H. Teles,
9268 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chemie
Angew. Chem. 2010, 122, 7275; Angew. Chem. Int. Ed. 2010, 49,
7120.
[11] S. J. Ryan, L. Candish, D. W. Lupton, J. Am. Chem. Soc. 2009,
131, 14176. In contrast to the acyl fluorides and enol esters used
by Lupton, our approach starts with readily available a,b-
unsaturated aldehydes. Far lower catalyst loadings and milder
reactions conditions are used for our process.
[7] Recent reviews on NHC-catalyzed transformations: a) K. Zei-
tler, Angew. Chem. 2005, 117, 7674; Angew. Chem. Int. Ed. 2005,
44, 7506; b) D. Enders, O. Niemeier, A. Henseler, Chem. Rev.
2007, 107, 5606; c) N. Marion, S. Dꢃez-Gonzꢄlez, S. P. Nolan,
Angew. Chem. 2007, 119, 3046; Angew. Chem. Int. Ed. 2007, 46,
2988; d) V. Nair, S. Vellalath, B. P. Babu, Chem. Soc. Rev. 2008,
37, 2691.
[12] 1,4-Addition to a,b-unsaturated acylazolium ions in biosynthe-
sis: a) N. Khaleeli, R. Li, C. A. Townsend, J. Am. Chem. Soc.
1999, 121, 9223; b) M. Merski, C. ATownsend, J. Am. Chem. Soc.
2007, 129, 15750.
[8] a) J. Guin, S. De Sarkar, S. Grimme, A. Studer, Angew. Chem.
2008, 120, 8855; Angew. Chem. Int. Ed. 2008, 47, 8727; b) S.
De Sarkar, S. Grimme, A. Studer, J. Am. Chem. Soc. 2010, 132,
1190; c) S. De Sarkar, A. Studer, Org. Lett. 2010, 12, 1992.
[9] Selected examples of NHC-catalyzed esterifications using inter-
nal redox reactions: a) G. A. Grasa, T. Gꢁveli, R. Singh, S. P.
Nolan, J. Org. Chem. 2003, 68, 2812; b) K. Y.-K. Chow, J. W.
Bode, J. Am. Chem. Soc. 2004, 126, 8126; c) N. T. Reynolds, J. R.
deAlaniz, T. Rovis, J. Am. Chem. Soc. 2004, 126, 9518; d) S. S.
Sohn, J. W. Bode, Angew. Chem. 2006, 118, 6167; Angew. Chem.
Int. Ed. 2006, 45, 6021; e) E. M. Phillips, M. Wadamoto, A. Chan,
K. A. Scheidt, Angew. Chem. 2007, 119, 3167; Angew. Chem. Int.
Ed. 2007, 46, 3107; f) K. Zeitler, C. A. Rose, J. Org. Chem. 2009,
74, 1759; g) Y. Yamaki, A. Shigenaga, J. Li, Y. Shimohigashi, A.
Otaka, J. Org. Chem. 2009, 74, 3278.
[10] NHC-catalyzed oxidative esterification using MnO2 as the
oxidant: a) B. E. Maki, A. Chan, E. M. Phillips, K. A. Scheidt,
Org. Lett. 2007, 9, 371; b) B. E. Maki, K. A. Scheidt, Org. Lett.
2008, 10, 4331. Using organic oxidants: c) S. W. Tam, L. Jimenez,
F. Diederich, J. Am. Chem. Soc. 1992, 114, 1503; d) A. Miyashita,
Y. Suzuki, I. Nagasaki, C. Ishiguro, K.-I. Iwamoto, T. Higashino,
Chem. Pharm. Bull. 1997, 45, 1254; e) C. Noonan, L. Baragwa-
nath, S. J. Connon, Tetrahedron Lett. 2008, 49, 4003.
[13] During the preparation of this manuscript, Bode et al. reported
on NHC-catalyzed Claisen-type rearrangement via intermedi-
ately formed a,b-unsaturated acylazolium ions: J. Kaeobam-
rung, J. Mahatthananchai, P. Zheng, J. W. Bode, J. Am. Chem.
Soc. 2010, 132, 8810.
[14] M. S. Kharasch, B. S. Joshi, J. Org. Chem. 1957, 22, 1439.
Compound 4 is readily prepared by treatment of o,o’-di-tert-
butylphenol (Aldrich 29.1 US$ per 500 g) with O2.
[15] Synthesis of dihydropyranones by NHC-catalyzed hetero-Diels–
Alder reaction: a) M. He, G. J. Uc, J. W. Bode, J. Am. Chem. Soc.
2006, 128, 15088; b) M. He, B. J. Beahm, J. W. Bode, Org. Lett.
2008, 10, 3817. For other methods see: c) D. A. Evans, R. J.
Thomson, F. Franco, J. Am. Chem. Soc. 2005, 127, 10816; d) T.
Tozawa, H. Nagao, Y. Yamane, T. Mukaiyama, Chem. Asian J.
2007, 2, 123; e) M. A. Calter, J. Wang, Org. Lett. 2009, 11, 2205.
[16] Relative configurations of the isomers were not assigned.
[17] The absolute configuration at the newly formed stereogenic
center was assigned by derivatizing 8 and comparing this
derivative with a similar compound, see the Supporting Infor-
mation.
[18] This experiment shows that at least with dimethyl malonate as a
nucleophile, a Claisen rearrangement as recently described by
Bode et al. (see Ref. [13]) is not operative in our system.
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