Asymmetric oxidative Lewis base catalysis - Unifying iminium and enamine organocatalysis with oxidations

Article abstract of DOI:10.1039/c2cc16447g

Enantioselective oxidative domino reactions of allylic alcohols to functionalized aldehydes have been developed. The one pot domino oxidation-iminium activation represents a convenient strategy for the enantioselective addition of malonates to allylic alc

Full text of DOI:10.1039/c2cc16447g

View Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Organocatalysis
web themed issue
Guest editors: Professors Keiji Maruoka, Hisashi
Yamamoto, Liu-Zhu Gong and Benjamin List
All articles in this issue will be gathered together online at
www.rsc.org/organocatalysis

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 2201–2203
www.rsc.org/chemcomm
COMMUNICATION
Asymmetric oxidative Lewis base catalysis—unifying iminium and
enamine organocatalysis with oxidationswz
´
Magnus Rueping,* Henrik Sunden, Lukas Hubener and Erli Sugiono
Received 17th October 2011, Accepted 1st December 2011
DOI: 10.1039/c2cc16447g
Enantioselective oxidative domino reactions of allylic alcohols to
functionalized aldehydes have been developed. The one pot
domino oxidation-iminium activation represents a convenient
strategy for the enantioselective addition of malonates to allylic
alcohols and the asymmetric formation of formyl cyclopropanes.
Oxidation reactions are of fundamental importance in chemistry
and a lot of research effort has been devoted to the development of
mild and efficient reactions.1 One-pot domino oxidation procedures,
in which the oxidized intermediate is further elaborated, are highly
desirable not only because they offer a potential one-flask-access to
demanding and highly functionalized molecules in higher oxidation
states but also because of their inherent benefits in terms of time,
cost and environmental savings.2,3 Aldehydes in particular are
challenging substrates as they are sensitive to storage and degrade
in time. Recently, one-pot oxidation procedures involving their
in situ generation have been developed.4–6
Scheme 1 Oxidative-iminium domino reactions.
with a nucleophile was reported independently by Hayashi9a and
Wang9b during our investigations (Scheme 1, bottom). In these
reactions aldehydes which are often sensitive to air and moisture
were applied. Additionally, rather expensive oxidants were used
which needed to be separated by column chromatography.
We decided to start from stable allylic alcohols and prepare the
aldehydes in situ, thus avoiding the cumbersome purification of
aldehydes by distillation or column chromatography. It should be
noted that in iminum catalysis yields as well as selectivities are
typically considerably lower if the aldehyde is not freshly prepared.
This is due to aldehyde decomposition products, including acids
which unfavourably interact with the Lewis base catalyst.10
Herein, we report the first domino oxidative iminium strategy
towards the asymmetric synthesis of formyl cyclopropanes and
the enantioselective addition of malonates to in situ generated
a,b-unsaturated aldehydes from allylic alcohols.
These reactions are particularly useful as they avoid the
isolation of potentially unstable aldehydes. However, these
methodologies are mainly restricted to reactions where the
oxidized intermediate is further reacted with a stabilized ylide
in the oxidation–Wittig reaction.4a–g In this context, Taylor
and co-workers have developed a number of elegant MnO2
mediated domino oxidations starting from allylic alcohols.2,5
More recently, Scheidt and co-workers presented an oxidation
protocol where benzylic and allylic alcohols were converted to
esters employing a NHC-catalyst.6
In order to develop a most simple and economic procedure
we decided to evaluate cheap, non-toxic, heterogeneous oxidizing
reagents as they could be easily separated by filtration. Thus we
were delighted to see that MnO2 could be used as a cheap and
readily available oxidant in the presence of an amine and that no
oxidation of the catalyst could be detected. Furthermore, with the
application of the chiral TMS-prolinol ether the first asymmetric
formation of formyl cyclopropanes from allylic alcohols (Table 1)
could be developed. Full conversion was reached over night at
room temperature.11,12 Evaluation of temperature, solvent, base,
and catalyst allowed the identification of a reaction protocol
which affords the corresponding formyl cyclopropanes in good
yields and high enantiomeric excesses (Table 1). For example,
the diphenylprolinol TMS-ether 4a13 catalyzes the oxidative
iminium–enamine domino addition of diethyl bromomalonate
to cinnamyl alcohol, affording cyclopropane 3a in 78% yield
with 96% ee (Table 1, entry 1).
Asymmetric Lewis base catalyzed reactions involving the
in situ oxidation of alcohols have not been reported. Due to
our interest in Lewis base organocatalysis7 and the plethora of
domino reactions in the field,8 we became interested in an
oxidation protocol where the allylic alcohol is converted in situ
into the corresponding aldehyde which can then be manipulated
with asymmetric amine-catalysis (Scheme 1, top). A related
strategy which involves stoichiometric oxidation of the enamine
intermediate derived from an aldehyde and subsequent reaction
RWTH Aachen University, Institute of Organic Chemistry,
Landoltweg 1, D-52074 Aachen, Germany.
E-mail: magnus.rueping@rwth-aachen.de; Fax: +49 241 8092665
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
details and spectra. See DOI: 10.1039/c2cc16447g
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2201–2203 2201

Table 1 One-pot enantioselective cyclopropanation of allylic alcohols
Scheme 2 Oxidative esterification of formyl cyclopropane 3a.
Earlier reports have demonstrated that formyl cyclopropanes
undergo ring-opening11a,15 in the presence of a NHC-catalyst.16
We envisioned that the selectivity of these reactions could be
changed in the presence of MnO2 allowing the conversion of the
aldehyde to the ester6,17 without affecting the cyclopropane
ring. We found that, upon treating 3a with MnO2 in the
presence of carbene 7 in ethanol, indeed no ring opening was
observed and that cyclopropane ester 8a could be isolated in
78% yield with 95% ee (Scheme 2).
Entrya
Product
R
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
78
88
84
78
68
66
96
94
93
98
93
93
o-NO2–C6H4
p-NO2–C6H4
o-Br–C6H4
m-Br–C6H4
p-Br–C6H4
p-F–C6H4
p-Cl–C6H4
p-Me–C6H4
p-CF3–C6H4
67 (78)d
67
72
95 (93)d
93
95
Regarding the mechanism of the reaction, addition of
carbene 7 to the cyclopropane derivative 9 yields intermediate
11 which is oxidized to the acyl azolium intermediate 12 which
subsequently reacts with the alcohol (R0OH) to give the
appropriate cyclopropane ester derivative 10. In this case the
oxidation is fast enough, preventing thus the potential ring
opening pathway (Scheme 3).
3j
69
94
a
Reaction conditions: allylic alcohol 1, diethyl bromomalonate 2
(1.3 equiv.), MnO2 (10.0 equiv.), NEt3 (0.7 equiv.) and TMS-prolinol
b
4a (20 mol%) at 0.2 M concentration in CHCl3, rt, 18 h. Yield after
c
column chromatography. Enantiomeric excess was determined by
d
HPLC. Reaction run at 0 1C with 2,6-lutidine (1.0 equiv.).
Furthermore, allylic alcohols 1b–j bearing aromatic residues
with different substitution patterns and electronic properties
are tolerated in this reaction (entries 2–10). Halo-containing
allylic alcohols were subjected to this one pot procedure
yielding o-, m- and p-substituted halo-cyclopropanes in good
yields with high enantiomeric excesses (entries 3–8).
In summary, we have developed an enantioselective oxidative
domino reaction pathway. The newly developed procedure
prevents the necessary purification or distillation step associated
with the use of aldehydes in asymmetric organocatalysis. The
procedure allows the use of allylic alcohols, together with the
cheap and readily available oxidant MnO2 which can be simply
separated by filtration. Thus, the newly developed protocol
represents a valuable alternative to recently reported oxidative
procedures which employ aldehydes and more expensive or
difficult to handle oxidizing reagents, such as IBX and DDQ.9
The domino oxidative iminium reaction is viable for the
enantioselective formation of formyl cyclopropanes and addition
of malonates to allylic alcohols. The corresponding valuable
chiral aldehydes have been isolated in good yields with high
enantioselectivities. In contrast to earlier reports, we were also
able to demonstrate for the first time that cyclopropane aldehydes
can further be manipulated to their corresponding esters in a
highly chemoselective manner by using a carbene catalyst.
The generally mild reaction conditions of the oxidative processes
together with the operational simplicity and practicability render
this approach not only a useful procedure for the synthesis of
optically active chiral aldehydes and esters but, additionally,
To further expand the scope of the oxidative domino-
iminium protocol other nucleophiles such as malonates were
investigated (Table 2).14 It turned out that dimethyl malonate
5 is a suitable nucleophile for this oxidative domino protocol
and cinnamyl alcohol could be converted to the chiral aldehyde
6a in 78% yield and 90% ee (Table 2, entry 1).
Furthermore, dimethyl malonate is added to the in situ
generated o- and p-nitro cinnamic aldehydes (entries 2 and 3)
to give the desired products 6b and 6c in good yields with high
enantioselectivities (91 and 90% ee respectively). A slightly
lower selectivity was observed in the case of allylic alcohols
bearing methyl electron donating groups (entries 4 and 6).
Table 2 Enantioselective addition of malonates to allylic alcohols
Entrya
Product
R
Yieldb (%)
eec (%)
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
Ph
78
70
74
86
63
78
90
91
90
87
88
83
o-NO2–C6H4
p-NO2–C6H4
p-Me–C6H4
p-Br–C6H4
o,p-Me2–C6H3
a
Reaction conditions: allylic alcohol 1, dimethylmalonate
5
(1.3 equiv.), MnO2 (10.0 equiv.) and TMS-prolinol 4b (20 mol%)
b
at 0.2 M concentration in CHCl3, rt, 72 h. Yield after column
c
chromatography. Enantiomeric excess was determined by HPLC.
Scheme 3 Proposed mechanism for the oxidative carbene-catalyzed
esterification of aldehydes.
c
2202 Chem. Commun., 2012, 48, 2201–2203
This journal is The Royal Society of Chemistry 2012

expands further the repertoire of enantioselective covalent
catalysis.
10 Often a 1 : 1 mixture of acid and amine catalyst is employed in
iminium and enamine catalysis. However, an excess of acid leads
typically to reduced reactivity and selectivity.
11 For reviews on the concept of catalysis by combining a transition
metal catalyst and an organocatalyst, see: (a) Z. Shao and
H. Zhang, Chem. Soc. Rev., 2009, 38, 2745–2755; (b) P. de Armas,
D. Tejedor and F. Garcia-Tellado, Angew. Chem., Int. Ed., 2010,
49, 1013–1016; (c) C. Zhong and X. Shi, Eur. J. Org. Chem., 2010,
2999–3025; (d) M. Rueping, R. M. Koenigs and I. Atodiresei,
Chem.–Eur. J., 2010, 16, 9350–9365.
12 (a) R. K. Kunz and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 3240–3241; (b) R. Rios, H. Sunden, J. Vesely, G. L. Zhao,
P. Dziedzic and A. Cordova, Adv. Synth. Catal., 2007, 349,
1028–1032; (c) H. Xie, L. Zu, H. Li, J. Wang and W. Wang,
J. Am. Chem. Soc., 2007, 129, 10886–10894; (d) J. Vesely,
G. L. Zhao, A. Bartoszewicz and A. Cordova, Tetrahedron Lett.,
2008, 49, 4209–4212; (e) I. Ibrahem, G. L. Zhao, R. Rios, J. Vesely,
H. Sunden, P. Dziedzic and A. Cordova, Chem.–Eur. J., 2008, 14,
7867–7879; (f) X. Companyo, A.-N. Alba, F. Cardenas,
A. Moyano and R. Rios, Eur. J. Org. Chem., 2009, 3075–3080;
(g) V. Terrasson, A. van der Lee, R. M. de Figueiredo and
J. M. Campagne, Chem.–Eur. J., 2010, 16, 7875–7880;
(h) U. Uria, J. L. Vicario, D. Badıa, L. Carrillo, E. Reyes and
A. Pesquera, Synthesis, 2010, 701–713.
13 Reviews on prolinol TMS-ether catalysis: (a) C. Palomo and
A. Mielgo, Angew. Chem., Int. Ed., 2006, 45, 7876–7880;
(b) A. Mielgo and C. Palomo, Chem.–Asian. J., 2008, 3, 922–948;
(c) K. L. Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht and K. A. Jø,
Acc. Chem. Res., 2011, 38, DOI: 10.1021/ar200149w.
14 (a) N. Halland, T. Hansen and K. A. Jørgensen, Angew. Chem.,
Int. Ed., 2003, 42, 4955–4957; (b) K. R. Knudsen, C. E. T. Mitchell
and S. V. Ley, Chem. Commun., 2006, 66–68; (c) S. Brandau,
A. Landa, J. Franzen, M. Marigo and K. A. Jørgensen, Angew.
Chem., Int. Ed., 2006, 45, 4305–4309; (d) Y. Wang, P. Li, X. Liang
and J. Ye, Adv. Synth. Catal., 2008, 350, 1383–1389;
(e) V. Wascholowski, K. R. Knudsen, C. E. T. Mitchell and
S. V. Ley, Chem.–Eur. J., 2008, 14, 6155–6165; (f) Y.-Q. Yang
and G. Zhao, Chem.–Eur. J., 2008, 14, 10888–10891; (g) P. Li,
S. Wen, F. Yu, Q. Liu, W. Li, Y. Wang, X. Liang and J. Ye, Org.
Lett., 2008, 11, 753–756; (h) Z. Mao, Y. Jia, W. Li and R. Wang,
J. Org. Chem., 2010, 75, 7428–7430.
The authors acknowledge financial support by European
Research Council (ERC starting grant BIMOC).
Notes and references
1 (a) W. Adam, C. R. Saha-Moller and P. A. Ganeshpure, Chem.
Rev., 2001, 101, 3499–3548; (b) S. Caron, R. W. Dugger,
S. G. Ruggeri, J. A. Ragan and D. H. B. Ripin, Chem. Rev.,
2006, 106, 2943–2989; (c) J. Piera and J.-E. Backvall, Angew. Chem.,
Int. Ed., 2008, 47, 3506–3523; (d) R. A. Sheldon, I. W. C. E. Arends,
G.-J. Ten Brink and A. Dijksman, Acc. Chem. Res., 2002, 35,
774–781.
2 (a) For a review on tandem oxidation processes, see: R. J. K.
Taylor, M. Reid, J. Foot and S. A. Raw, Acc. Chem. Res., 2005, 38,
851–869.
3 (a) L. F. Tietze, Chem. Rev., 1996, 96, 115–136; (b) L. F. Tietze,
G. Brasche and K. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006.
4 One-pot oxidation–Wittig reaction: (a) X. Wei and R. J. K. Taylor,
Tetrahedron Lett., 1998, 39, 3815–3818; (b) L. Blackburn, X. Wei
and R. J. K. Taylor, Chem. Commun., 1999, 1337–1338; (c) X. Wei
and R. J. K. Taylor, J. Org. Chem., 1999, 65, 616–620;
(d) A. R. Bressette and L. C. Glover IV, Synlett, 2004, 738–740;
(e) S. Lang and R. J. K. Taylor, Tetrahedron Lett., 2006, 47,
5489–5492; (f) E. Quesada, S. A. Raw, M. Reid, E. Roman and
R. J. K. Taylor, Tetrahedron, 2006, 62, 6673–6680; (g) M. S. Majik,
J. Shet, S. G. Tilve and P. S. Parameswaran, Synthesis, 2007,
663–665; further selected tandem oxidation processes:
(h) S. A. Raw, C. D. Wilfred and R. J. K. Taylor, Org. Biomol.
Chem., 2004, 2, 788–796; (i) D. J. Phillips, K. S. Pillinger, W. Li,
A. E. Taylor and A. E. Graham, Chem. Commun., 2006,
2280–2282; (j) K. Zeitler and C. A. Rose, J. Org. Chem., 2009,
74, 1759–1762; (k) H. Kim, Y. Park and J. Hong, Angew. Chem.,
Int. Ed., 2009, 48, 7577–7581; (l) B. E. Maki and K. A. Scheidt,
Org. Lett., 2009, 11, 1651–1654.
5 (a) M. F. Oswald, S. A. Raw and R. J. K. Taylor, Org. Lett., 2004,
6, 3997–4000; (b) M. F. Oswald, S. A. Raw and R. J. K. Taylor,
Chem. Commun., 2005, 2253–2255; (c) G. D. McAllister,
M. F. Oswald, R. J. Paxton, S. A. Raw and R. J. K. Taylor,
Tetrahedron, 2006, 62, 6681–6694.
15 S. S. Sohn and J. W. Bode, Angew. Chem., Int. Ed., 2006, 45,
6021–6024.
6 (a) B. E. Maki, A. Chan, E. M. Phillips and K. A. Scheidt, Org.
Lett., 2007, 9, 371–374; (b) B. E. Maki, A. Chan, E. M. Phillips and
K. A. Scheidt, Tetrahedron, 2009, 65, 3102–3109.
16 (a) D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007,
107, 5606–5655; (b) N. Marion, S. Dıez-Gonzalez and S. P. Nolan,
Angew. Chem., Int. Ed., 2007, 46, 2988–3000; (c) V. Nair,
S. Vellalath and B. P. Babu, Chem. Soc. Rev., 2008, 37,
2691–2698; (d) J. Moore and T. Rovis, Top. Curr. Chem., 2009,
291, 77–144.
7 Selected publications: (a) M. Rueping, E. Sugiono and E. Merino,
Angew. Chem., Int. Ed., 2008, 47, 3046–3049; (b) M. Rueping,
E. Sugiono and E. Merino, Chem.–Eur. J., 2008, 14, 6329–6332;
(c) M. Rueping, E. Merino and E. Sugiono, Adv. Synth. Catal.,
2008, 350, 2127–2131; (d) M. Rueping, A. Kuenkel, F. Tato and
J. W. Bats, Angew. Chem., Int. Ed., 2009, 48, 3699–3702;
(e) M. Rueping, K. Haack, W. Ieawsuwan, H. Sunden, M. Blanco
and F. R. Schoepke, Chem. Commun., 2011, 47, 3828–3830;
(f) M. Rueping and T. Theissmann, Chem. Sci., 2010, 1, 473–476.
8 Reviews on organocatalytic domino reactions: (a) D. Enders,
C. Grondal and M. R. M. Huttl, Angew. Chem., Int. Ed., 2007,
46, 1570–1581; (b) X. Yu and W. Wang, Org. Biomol. Chem., 2008,
6, 2037–2046; (c) A. Dondoni and A. Massi, Angew. Chem., Int.
Ed., 2008, 47, 4638–4660; (d) A. N. Alba, X. Companyo,
M. Viciano and R. Rios, Curr. Org. Chem., 2009, 13, 1432–1474;
(e) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2,
167–178.
17 NHC catalyzed oxidations of aldehydes to esters: (a) K. Y.-K.
Chow and J. W. Bode, J. Am. Chem. Soc., 2004, 126, 8126–8127;
(b) N. T. Reynolds, J. R. de Alaniz and T. Rovis, J. Am. Chem.
Soc., 2004, 126, 9518–9519; (c) A. Chan and K. A. Scheidt, Org.
Lett., 2005, 7, 905–908; (d) S. S. Sohn and J. W. Bode, Org. Lett.,
2005, 7, 3873–3876; (e) N. T. Reynolds and T. Rovis, J. Am. Chem.
Soc., 2005, 127, 16406–16407; (f) K. Zeitler, Org. Lett., 2006, 8,
637–640; (g) E. M. Phillips, M. Wadamoto, A. Chan and
K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 3107–3110;
(h) J. Guin, S. De Sarkar, S. Grimme and A. Studer, Angew.
Chem., Int. Ed., 2008, 47, 8727–8730; (i) B. E. Maki and
K. A. Scheidt, Org. Lett., 2008, 10, 4331–4334; (j) C. Noonan,
L. Baragwanath and S. J. Connon, Tetrahedron Lett., 2008, 49,
4003–4006; (k) C. A. Rose and K. Zeitler, Org. Lett., 2010, 12,
4552–4555; (l) S. D. Sarkar, S. Grimme and A. Studer, J. Am.
Chem. Soc., 2010, 132, 1190–1191; (m) A. Biswas, S. De Sarkar,
R. Frohlich and A. Studer, Org. Lett., 2011, 13, 4966–4969.
9 (a) Y. Hayashi, T. Itoh and H. Ishikawa, Angew. Chem., Int. Ed.,
2011, 50, 3920–3924; (b) S.-L. Zhang, H.-X. Xie, J. Zhu, H. Li,
X.-S. Zhang, J. Li and W. Wang, Nat. Commun., 2011, 2, 211.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2201–2203 2203