Enantioselective formation of substituted 3,4-dihydrocoumarins by a multicatalytic one-pot process

Article abstract of DOI:10.1021/ol302627u

The formation of optically active 3,4-dihydrocoumarins is presented by merging aminocatalysis with an N-heterocyclic carbene-catalyzed internal redox reaction. The products are formed in good to excellent yields and in general with excellent enantioselectivities. Moreover, the developed procedure demonstrates the potential of enantioselective, multicatalytic sequences. By employing an enantiopure aminocatalyst in the enantiodifferentiating step, the challenges related to achieving high stereoinductions by deployment of optically active NHC-catalysts can be circumvented.

Full text of DOI:10.1021/ol302627u

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5526–5529
Enantioselective Formation of Substituted
3,4-Dihydrocoumarins by a Multicatalytic
One-Pot Process
Christian Borch Jacobsen, Łukasz Albrecht, Jonas Udmark, and
Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, 8000 Aarhus C,
Denmark
kaj@chem.au.dk
Received September 24, 2012
ABSTRACT
The formation of optically active 3,4-dihydrocoumarins is presented by merging aminocatalysis with an N-heterocyclic carbene-catalyzed internal
redox reaction. The products are formed in good to excellent yields and in general with excellent enantioselectivities. Moreover, the developed
procedure demonstrates the potential of enantioselective, multicatalytic sequences. By employing an enantiopure aminocatalyst in the
enantiodifferentiating step, the challenges related to achieving high stereoinductions by deployment of optically active NHC-catalysts can be
circumvented.
In recent years, the utilization of asymmetric, organo-
catalytic, multicatalytic, domino, and one-pot reac-
tions has been widely explored in the development of
complex reaction sequences.1 In this regard, the reli-
ability of aminocatalysts in inducing enantioselectivity
in organocatalytic reactions has been combined with
the intriguing reactivity of N-heterocyclic carbenes
(NHC) for accessing molecular and stereochemical
diversity.2
3,4-Dihydrocoumarins and related structures are of
great interest for life science, as they are widely distributed
in nature and are core structures in certain pharmaceuticals.3
(3) For examples, see: (a) Borges, F.; Roleira, F.; Milhazes, N.;
Santana, L.; Uriarte, E. Curr. Med. Chem. 2005, 12, 887. (b) Murray,
R. D. H. Nat. Prod. Rep. 1995, 12, 477. (c) Iinuma, M.; Tanaka, T.;
Mizuno, M.; Katsuzaki, T.; Ogawa, H. Chem. Pharm. Bull. 1989, 37,
1813. (d) Hsu, F. L.; Nonaka, G.; Nishioka, I. Chem. Pharm. Bull. 1985,
33, 3142.
(1) For recent reviews on organocatalytic domino and multicatalytic
reaction sequences, see: (a) Wende, R. C.; Schreiner, P. R. Green Chem.
2012, 14, 1821. (b) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010,
2, 167. (c) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (d)
(4) Phillips, E. M.; Wadamoto, M.; Roth, H. S.; Ott, A. W.; Scheidt,
K. A. Org. Lett. 2009, 11, 105.
€
Enders, D.; Grondahl, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570.
(5) For other selected enantioslective formations of 4-substituted 3,4-
dihydrocoumarins illustrating different synthetic approaches, see: (a)
Chen, G.; Tokunaga, N.; Hayashi, T. Org. Lett. 2005, 7, 2285. (b) Dong,
C.; Alper, H. J. Org. Chem. 2004, 69, 5011. (c) Matsuda, T.; Shigeno, M.;
Murakami, M. J. Am. Chem. Soc. 2007, 129, 12086. (d) Kim, H.; Yun, J.
Adv. Synth. Catal. 2010, 352, 1881. (e) Gallagher, B. D.; Taft, B. R.;
Lipshutz, B. H. Org. Lett. 2009, 11, 5374. (f) Kuang, Y.; Liu, X.; Chang,
L.; Wang, M.; Lin, L.; Feng, X. Org. Lett. 2011, 13, 3814. (g) Teichert,
J. F.; Feringa, B. L. Chem. Commun. 2011, 47, 2679. (h) Allen, J. C.;
(2) For a recent review, see: (a) Grossmann, A.; Enders, D. Angew.
Chem., Int. Ed. 2012, 51, 314. For selected recent examples, see: (b)
Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628. (c) Jiang,
H.; Gschwend, B.; Albrecht, Ł.; Jørgensen, K. A. Org. Lett. 2010, 12,
5052. (d) Hong, B.; Dange, N. S.; Hsu, C.; Liao, J. Org. Lett. 2010, 12,
4812. (e) Hong, B.; Dange, N. S.; Hsu, C.; Liao, J.; Lee, G. Org. Lett.
2011, 13, 1338. (f) Ozboya, K. E.; Rovis, T. Chem. Sci. 2011, 2, 1835. (g)
Jacobsen, C. B.; Jensen, K. L.; Udmark, J.; Jørgensen, K. A. Org. Lett.
ꢀ
€
2011, 13, 4790. (h) Yankai, L.; Nappi, M.; Escudero-Adan, E. C.;
Kociok-Kohn, G.; Frost, C. G. Org. Biomol. Chem. 2012, 10, 32. (i) Lee,
Melchiorre, P. Org. Lett. 2012, 14, 1310.
Y.; Seo, S. W.; Kim, S. Adv. Synth. Catal. 2011, 353, 2671.
r
10.1021/ol302627u
Published on Web 10/17/2012
2012 American Chemical Society

In 2009, Scheidt et al. reported the synthesis of racemic 3,4-
dihydrocoumarins rac-2 by an NHC-catalyzed internal
redox process starting from the aryloxyacetaldehydes 1
(Scheme 1).4 Whereastheproducts wereisolated ingoodto
excellent yields, the development of an enantioselective
version of the protocol turned out to be challenging.5 As
such, an extensive screening of enantiopure NHCs never
resulted in an enantioenrichment of more than 10% ee.
This exemplifies the issue with the current lack of a
successful general catalytic system for such enantioselec-
tive NHC-catalyzed transformations.6
Scheme 2. Envisioned Approach for the Multicatalytic
Formation of Enantioenriched 3,4-Dihydrocoumarins 2
Scheme 1. Scheidt et al.’s Procedure for the Formation of
Racemic 3,4-Dihydrocoumarins rac-2a
form the active carbene from its precursor in the second
step might add to this challenge. (ii) The stereocenter
generated in the R-position to the aldehyde upon attack
of the enamine is destroyed in the subsequent NHC-
catalyzed step. As such, an approach as illustrated in
Scheme 2 is made difficult by the fact that, in order to
attain a highly enantioenriched product 2, it is a ne-
cessity that the initial addition step proceeds with good
stereoselectivity in the formation of the stereocenter
created on the Michael-acceptor part of 1.9 The cata-
lyst, controlling the formation of the stereocenters via
an enamine pathway, would be expected to primarily
control the stereocenter adjacent to aldehyde function-
ality. Therefore, excellent control of the stereocenter
the farthest away from the reactive enamine might be
difficult to obtain. (iii) Even though the 3,4-dihydro-
coumarins 2 have a simple molecular structure, the
envisioned process for their enantioselective synthesis
involves the formation and breaking of a number of
bonds. As such, a high yielding route to these com-
pounds can be challenging.
Despite these potential complications we decided to
investigate if the development of a highly enantiose-
lective formation of 3,4-dihydrocoumarins 2, through
a multicatalytic enamine/NHC sequence, was feasi-
ble. Our initial screening process was focused on de-
termining the optimal conditions for the initial ami-
nocatalyzed 1,4-addition (for optimization data, see
Supporting Information). Through screening of sol-
vents, acid additives, temperatures, and catalysts, we
established that catalyst 3a combined with catalytic
amounts of o-nitrobenzoic acid in o-xylene was opti-
mal for this initial step. Furthermore, the screening
of carbene precursors and bases established that the
carbene precursor 4 and DIPEA were superior for
catalyzing the subsequent internal redox reaction lead-
ing to 2 (Figure 1).
a Mes = mesityl.
Within the field of asymmetric organocatalysis, chiral
secondary amines have been employed as catalysts in a
range of diverse enantioselective functionalizations of en-
olizable aldehydes and enals.7 In this regard, the diaryl-
prolinol silyl ethers have proved to be general catalysts
for activating substrates by enamine or iminium-ion
intermediates.8 We envisioned that the unsuccessful pur-
suit of a chiral carbene for catalyzing the enantioselective
formation of 3,4-dihydrocoumarins (Scheme 1) might be
circumvented by merging the reactivity of enamines de-
rived from an enantiopure diarylprolinol silyl ether 3 with
the synthetic potential ofan achiral carbene (Scheme 2). As
such, the enantioselectivity would be induced in the step
preceding the NHC-catalyzed reaction.
However, as it appears from Scheme 2, such an ap-
proach entails three inherent issues: (i) The optical purity
introduced in the initial addition must be maintained
throughout the entire process. The necessity of a base to
(6) For selected examples on successful utilizations of enantioen-
riched NHCs in redox reactions employing R-functionalized aldehydes
as substrates, see: (a) He, M.; Beahn, B. J.; Bode, J. W. Org. Lett. 2008,
10, 3817. (b) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
15088. (c) Vora, H. A.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 2860. (d)
Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 16406.
(7) For selected reviews on aminocatalysis, see: (a) Dalko, P. I.
Enantioselective Organocatalysis; Wiley-VCH: Weinheim, 2007. (b) Chem.
Rev. 2007, 107, 12, special issue on organocatalysis. (c) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(d) MacMillan, D. W. C. Nature 2008, 455, 304. (e) Bertelsen, S.; Jørgensen,
K. A. Chem. Soc. Rev. 2009, 38, 2178. (f) Grondal, C.; Jeanty, M.; Enders,
D. Nat. Chem. 2010, 2, 167.
(9) An apparent thought would be that this issue might be solved by
employment of a chiral primary amine salt to activate the ketone moiety
in 1 by formation of an iminium ion. However, we found that such a
process was not feasible.
(8) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen,
K. A. Acc. Chem. Res. 2012, 45, 248.
Org. Lett., Vol. 14, No. 21, 2012
5527

We then employed these conditions in the investigation
of the scope of the developed one-pot process (Figure 1). It
was found that the aryl ketone moiety in 1 can be neutral,
electron-rich, and electron-poor in nature as demonstrated
by the formation of products 2aÀd. The yields of 51À68%
for these substrates are good especially considering that
their formation relies on a multicatalytic process involv-
ing the breaking and formation of numerous bonds. The
enantioselectivities for 2aÀd are in all cases very high
reaching up to 92% ee. The formation of 2d,e having a
fluorine substituent in either the para- or meta-position is
noteworthy, as fluorine holds a special place in medicinal
chemistry.10
these substituents can reside on the 5-, 6-, 7-, and
8-position on this ring illustrating the synthetic use-
fulness of this process. These products can all be
isolated in moderate to high yields (41À85%), while
maintaining high enantioselectivities up to 96% ee.
However, substituents in the 8-position lower the
enantioselectivity as exemplified by the formation
of 2h with 58% ee presumably due to steric reasons.
Finally, the introduction of two substituents on the
aromatic tether proved possible as demonstrated by
the synthesis of 2j.11
The absolute configuration of products 2 was deter-
mined to be S by single crystal X-ray analysis on the
product 2f (Figure 2, top). Figure 2 depicts the two
possible transition states leading to the observed en-
antiomer of 2. As we observed both the cis- and trans-
diastereomer in the NMR spectra of the crude reaction
mixtures, and as the enantiomeric excesses are in most
cases excellent, it can be anticipated that both diaste-
reoisomers are formed due to either low stereocontrol
or epimerization on the aldehyde R-stereocenter. How-
ever, as this stereocenter is destroyed in the carbene cata-
lyzed internal redox reaction, low diastereoselectivity does
not transfer to the products.
Figure 1. All reactions performed as follows: (Step 1) 1 (0.2 mmol),
3a (10 mol %), o-NO2ÀC6H4CO2H (20 mol %) in o-xylene
(1.0 mL) at 0 °C; (Step 2) 4 (5.0 mol %), DIPEA (30 mol %),
adding CH2Cl2 (0.2 mL) at 40 °C. Yields are isolated yields.
Enantiomeric excesses were determined by UPC. See Support-
ing Information for further details. a 3a (20 mol %) and o-NO2À
C6H4CO2H (40 mol %) used.
Figure 2. Assignment of absolute configuration and rationaliza-
tion of the stereochemical outcome.
In conclusion, we have developed a multicatalytic
one-pot reaction sequence relying on the well-established
general enantioselective catalytic capabilities of a di-
arylprolinol silyl ether catalyst and an achiral NHC-
catalyst for the formation of highly enantioenriched
3,4-dihydrocoumarins. The products were isolated
in moderate to high yields, and the enantioselectivities
The products 2fÀj exemplify selected, possible substitu-
tion patterns on the aromatic tether. As depicted, sub-
strates carrying both electron-donating and electron-
withdrawing substituents can be employed. Moreover,
(10) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
€
Soc. Rev. 2008, 37, 320. (b) Muller, K.; Faeh, C.; Diederich, F. Science
2007, 317, 1881. (c) Cahard, D.; Xu, X.; Couve-Bonnaire, S.; Pannecoucke,
X. Chem. Soc. Rev. 2010, 39, 558. (d) Ojima, I. Fluorine in Medicinal
Chemistry and Chemical Biology; Wiley-Blackwell: 2009.
(11) Attempts to extend the developed procedure to other Michael
acceptors, such as nitroolefins and alkyl ketones, gave less satisfactory
results.
5528
Org. Lett., Vol. 14, No. 21, 2012

were in most cases high. Moreover, the developed
process illustrates the possibility of solving the issue
with the lack of a general enantioselective carbene
catalyst, by introducing an additional enantiodif-
ferentiating aminocatalytic step. As such, this pro-
cess might inspire further developments of such
sequences.
Foundation. Thanks is expressed to Dr. Jacob Overgaard,
Department of Chemistry, Aarhus University, for perform-
ing the X-ray analysis.
Supporting Information Available. Detailed experimen-
tal procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was made possible by
grants from FNU, Aarhus University, and the Carlsberg
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
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