Sustainable synthetic methods: Domino construction of dihydropyridin-4-ones and β-amino esters in aqueous ethanol

Article abstract of DOI:10.1021/ol801911f

(Chemical Equation Presented) Domino reactions were designed to allow the byproduct of an upstream reaction to be internally recycled to catalyze a downstream reaction in a one-pot tandem sequence. Nitroarene reduction by In⁰ generates an amine and In^III byproducts. Addition of aldehyde followed by Danishefsky's diene or silyl ketene acetal provides access to dihydropyridin-4-ones or β-amino esters, respectively, in yields that are comparable or superior to the reported stepwise reactions.

Full text of DOI:10.1021/ol801911f

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5111-5114
Sustainable Synthetic Methods: Domino
Construction of Dihydropyridin-4-ones
and ꢀ-Amino Esters in Aqueous Ethanol
Peter J. Alaimo,* Robert O’Brien III, Adam W. Johnson, Sarah R. Slauson,
Jeannette M. O’Brien, Elizabeth L. Tyson, Amanda-Lynn Marshall,
Colleen E. Ottinger, Jon G. Chacon, Lorien Wallace, Corey Y. Paulino, and
Sarah Connell
Department of Chemistry, Seattle UniVersity, 901 12th AVenue,
Seattle, Washington 98122
alaimop@seattleu.edu
Received August 15, 2008
ABSTRACT
Domino reactions were designed to allow the byproduct of an upstream reaction to be internally recycled to catalyze a downstream reaction
in a one-pot tandem sequence. Nitroarene reduction by In0 generates an amine and InIII byproducts. Addition of aldehyde followed by Danishefsky’s
diene or silyl ketene acetal provides access to dihydropyridin-4-ones or ꢀ-amino esters, respectively, in yields that are comparable or superior
to the reported stepwise reactions.
Over the past 15 years, the development of “green” synthetic
methods has become an important frontier in chemistry; a
key objective is to eliminate the adverse environmental
effects of chemical synthesis.1 Toward this end, progress has
been made using reusable catalysts, renewable resources, and
alternative solvents such as water, sc-CO2, and ionic sol-
vents.2 Other advances include eliminating the generation
of toxic byproducts through discovery of safer reagents,
developing more efficient reactions (e.g., catalyzed reactions)
that do not require large energy inputs, and using domino
reaction cascades where the product of one reaction becomes
the starting material for the next step in situ.3 The domino
strategy minimizes waste by reducing the number of
purification stepssthe stage where the most waste is gener-
ated. Herein we describe our efforts to advance sustainable
synthetic methods by designing a rare example4 of a domino
cascade that internally recycles an upstream reaction byprod-
uct to provide a catalyst for a downstream reaction.5 We
disclose two versions of this strategy, which we expect will
be applicable to a range of transformations.
(4) An interesting example of internal recycling was reported by Loh
where an In0-mediated Barbier-type aldehyde allylation reaction generated
a γ-adduct, which rearranged to an R-adduct in an In3+-catalyzed manner.
(a) Loh, T.-P.; Tan, K.-T.; Hu, Q.-Y Tetrahedron Lett. 2001, 42, 8705. (b)
Tan, K.-T.; Chng, S.-S.; Cheng, H.-S.; Loh, T.-P. J. Am. Chem. Soc. 2003,
125, 2958.
(1) Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35, 686.
(2) (a) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (b)
Leitner, W. Acc. Chem. Res. 2002, 35, 746. (c) Miao, W.; Chan, T. H. Acc.
Chem. Res. 2006, 39, 897.
(5) A conceptually unique but related strategy called cascade catalysis
refers to the use of several different catalysts in one-pot procedures to
catalyze mechanistically distinct steps of a cascade reaction. The approach
presented here is fundamentally different but could, in theory, be used in
combination with cascade catalysis.
(3) Tietze, L. F.; Modi, A. Med. Res. ReV. 2000, 20, 304.
10.1021/ol801911f CCC: $40.75
Published on Web 10/24/2008
2008 American Chemical Society

We identified dihydropyridin-4-ones as a family of
targets to showcase the strategy because these compounds
are of great practical importance. In addition to being
found in alkaloids and enzyme inhibitors, these scaffolds
are key building blocks for numerous heterocycle syn-
theses because of their vinylagous amide moiety.6 To
assemble dihydropyridin-4-ones, we reasoned that the In0-
mediated reduction of nitroarenes followed by aldimine
formation (upon addition of aldehyde) would start the
domino sequence (Scheme 1). Performing the reduction
We also investigated the latter part of the cascade, the
three-component aza-Diels-Alder reaction of aniline,
benzaldehyde, and Danishefsky’s diene (eq 1), with the
goal of identifying reaction conditions compatible with
the previous nitrobenzene reduction step. This aza-
Diels-Alder reaction has been reported under the fol-
lowing conditions: in anhydrous CH3CN (In(OTf)3-
catalyzed),7 in water/MeOH (HBF4-catalyzed),11 in water
(AgOTf-catalyzed),12 and on soluble solid support [Zn-
(ClO4)2-catalyzed].13 Because this reaction has also been
reported to proceed in the absence of added Brønsted or
Lewis acid in methanol,14 we tested whether catalyst was
required. We found that the desired cycloaddition reaction
requires catalyst15 and that various indium salts are
competent catalysts in aqueous alcoholic media, consistent
with the findings of Frost, Akiyama, and Kobayashi.7,11,12
The significance of these results is that (i) the aza-
Diels-Alder reaction outcompetes diene degradation under
these conditions and (ii) nitroarene reduction and the
Diels-Alder reaction can be conducted under similar reaction
conditions in one pot.
Scheme 1. Domino Nitroarene Reduction-Aldimine
Formation-Aza-Diels-Alder Reaction Using Danishefsky’s
Diene
in the presence of NH4Cl should generate InCl3 as the
reaction byproduct. The Lewis acidic InCl3 complex is
now poised to assemble the product by catalyzing the aza-
Diels-Alder reaction between the imine and the added
diene. This sequence tests our hypothesis that the InCl3
generated in situ is internally recycled to catalyze the
cycloaddition reaction, since aza-Diels-Alder reactions
between Danishefsky’s diene and aldimines require a
catalyst. We focused our studies on the In0/In3+ redox
couple for the following reasons: (i) In0 is a selective three-
electron reductant, (ii) In3+, an oxidation product of In0,
has been shown to be a competent Lewis acid catalyst,7,8
and (iii) both In0 and In3+ are water-tolerant reagents,9
allowing the domino cascade to be performed in environ-
mentally benign media.
We first optimized the published procedure for In0-
mediated nitrobenzene reduction,9 which calls for 7 equiv
of In0 in a mixture of saturated aq NH4Cl/ethanol.10 Since
only 2 equiv of In0 should provide the six electrons
needed, and since lower [NH4Cl] might lessen acid-
mediated diene degradation, we sought to decrease the
amount of In0 and NH4Cl used. In fact, the reduction
proceeds in higher yield and purity with decreased In0
equivalents and a lower [NH4Cl]; common byproducts
found using 7 equiv of In0, such as nitrosobenzene,
azobenzene, and azoxybenzene, are almost entirely absent
from reactions using 2-4 equiv of In0 and 1-5 M NH4Cl.
Thus, we performed all subsequent reactions using these
modified conditions.
The key experiment involved testing whether the
reduction step can be combined with imine formation and
cycloaddition in one-pot. When the nitrobenzene reduction
and the three-component aza-Diels-Alder reaction were
conducted in one pot (by reacting a mixture of PhNO2,
In0, NH4Cl, PhCHO, and Danishefsky’s diene in refluxing
water/ethanol), we found that diene degradation resulted.
However, good results were obtained by carrying out the
nitroarene reduction under reflux for 5-12 h, cooling to
room temperature, and then adding aldehyde followed by
diene.
Best results were obtained using 5-6 equiv of aldehyde
(Table 1); unreacted aldehyde could be recovered easily
during column chromatography. GC-MS analysis of crude
reaction mixtures revealed that PhNO2 was completely
Table 1. Results of Domino Nitroarene Reduction-Aldimine
Formation-Aza-Diels-Alder Using Danishefsky’s Diene
entry
R
R′
product
yield (%)a
1b
2c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1a
1b
1c
1c
1d
1e
1f
77
84
99
88
99
66
72
67
72
69
3c
4-(MeO)C6H4
4-(O2N)C6H4
4-(O2N)C6H4
4-(HO)C6H4
2-furanyl
4-(Me)C6H4
Ph
4b
5d
6b
7c
(6) (a) Comins, D. L.; Joseph, S. P. In ComprehensiVe Heterocyclic
Chemistry, 2nd ed.; McKillop, A., Ed.; Pergamon: Oxford, UK, 1996; Vol.
5, p 37. (b) Young, D. W.; Comins, D. L. Org. Lett. 2005, 7, 5661.
(7) Ali, T.; Chauhan, K. K.; Frost, C. G. Tetrahedron Lett. 1999, 40,
8c
9d
10d
4-(Cl)C6H4
2-(MeO)C6H4
1g
1h
5621
.
Ph
(8) Loh, T.-P.; Chen, S.-L. Org. Lett. 2002, 4, 3647
(9) Moody, C. J.; Pitts, M. R. Synlett 1998, 1028.
.
a Isolated yield based on PhNO2. b Using 1 equiv of aldehyde. c Using
5 equiv of aldehyde. d Using 6 equiv of aldehyde.
(10) While this work was in progress, Banik reported an optimized
procedure. See: Org. Synth. 2005, 81, 188.
5112
Org. Lett., Vol. 10, No. 22, 2008

consumed and that only traces of unreacted aniline and
imine remained. This procedure works well for both
electron-rich and electron-poor benzaldehyde derivatives.
Entry 6 is noteworthy because it shows that this method
tolerates the presence of an unprotected phenol; such
substrates are rarely reported in similar studies.16 Entries
9 and 10 indicate that the reaction is tolerant of electron-
donating and electron-withdrawing substituents on the
nitroarene. Comparison of the reaction yields to literature
values for the stepwise reactions reveals that many of our
reactions provide 1 in higher overall yield. The use of
aliphatic aldehydes in the reaction afforded intractable
mixtures containing only 4-7% of the desired product.17
Since it would be useful to obtain the N-H-substituted
products, we tested numerous CAN-promoted oxidative
dearylationreactions of isomeric o-, m-, or p-methoxyphe-
nyl products 1h.18 Unfortunately, all attempts at N-
dearylation gave intractable mixtures containing less than
10% of the desired N-H product.19
The optimized procedure involves reducing nitrobenzene
with In0/NH4/NH4Cl in refluxing MeOH/water or EtOH/
water, cooling to room temperature, adding aldehyde
followed by silyl ketene acetal, and stirring for 24 h
(Scheme 2; Table 2). Because we were interested in
Scheme 2
.
Domino Nitroarene Reduction: Mannich-Type
Reaction
Table 2. Results of Domino Nitroarene Reduction: Mannich-
Given that the nitroarene reduction is highly efficient
and that the In3+ byproduct is a potent water-compatible
Lewis acid, we desired to test this internal recycling
strategy on a second tandem reaction. The Mannich
reaction is a valuable amine-forming reaction that provides
access to synthetically and biologically important ꢀ-amino
carbonyl compounds.20 Furthermore, the Mannich reaction
is an ideal choice for application of this method since Loh
has described an elegant, asymmetric, InCl3-catalyzed
three-component Mannich-type reaction.8 Therefore, as a
test of the scope of this method we designed a domino
reaction that would provide access to ꢀ-amino esters
2a-h.
Type Reaction Using a Silyl Ketene Acetal
entry
R
RCHO equivalents product yielda (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
1.2
5
2a
2a
2b
2c
2d
2e
2f
60
72
63
62
61
59
56
65
50
4-(MeO)C6H4
4-ClC6H4
4-(O2N)C6H4
4-(HO)C6H4
2-furanyl
1.2
1.2
1.2
1.2
1.2
1.2
1.2
4-(Me)C6H4
4-(Me2N)C6H4
2g
2h
a Isolated yield based on PhNO2.
(11) Akiyama, T.; Takaya, J.; Kagoshima, H. Tetrahedron Lett. 1999,
40, 7831.
understanding the efficiency of this reaction, we conducted
most experiments using only 1.2 equiv of aldehyde and 2
equiv of silyl ketene acetal. This gave isolated yields of
50-65%. Increasing the number of equivalents of alde-
hyde or silyl ketene acetal modestly improved the yields
(entries 1 and 2). An important feature of this reaction is
that it allowed the synthesis of a novel hydroxyl-containing
product (entry 6) without the need for protection/depro-
tection; but as before, use of aliphatic aldehydes was
unsuccessful.17 CAN-promoted N-dearylation reactions of
N-PMP protected ꢀ-amino esters have already been
reported to give the desired product in high yield and
purity, and thus was not repeated in this study.21
(12) Loncaric, C.; Manabe, K.; Kobayashi, S. AdV. Synth. Catal. 2003,
345, 475.
(13) Guo, H.; Wang, Z.; Ding, K. Synthesis 2005, 1061.
(14) Yuan, Y.; Li, X.; Ding, K. Org. Lett. 2002, 4, 3309.
(15) Reactions containing equimolar amounts of aniline, benzaldehyde,
and Danishefsky’s diene in aqueous NH4Cl and either ethanol or methanol
were complete (monitored by TLC and GC-MS) in 5 min in the presence
of 10 mol % of In(OTf)3, InCl3, or InBr3. In the absence of an In3+ salt, or
in the presence of In0 or NaOTf, <5% product was detected, even after 24
h.
(16) For example, see: Kobayashi, S.; Ueno, M.; Saito, S.; Mizuki, Y.;
Ishitani, H.; Yamashita, Y Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5476.
(17) Aldehydes tested include propionaldehyde, 2-methylpropionalde-
hyde, cyclohexanecarboxaldehyde, and pivaldehyde.
(18) Authentic samples of m- and p-methoxyphenyl products 1h were
used in these experiments. Each of the three isomers (o-, m-, and
p-substituted 1h) were treated with 1-8 equiv of CAN in MeCN/water or
MeOH/water at temperatures ranging from -12 °C to rt, under an
atmosphere of nitrogen, and also in air. All reactions afforded intractible
mixtures containing a poor yield of the desired product. For leading
references on N-dearylation, see: (a) Sakai, T.; Yan, F.; Uneyama, K. Synlett
1995, 753. (b) Chi, Y.; Zhou, Y. G.; Zhang, X. J. Org. Chem. 2003, 68,
4120. (c) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338.
(d) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982, 47,
2765.
These cascade reactions represent a significant step
forward in the development of sustainable synthetic
methods to generate valuable products in yields similar
to, or better than, stepwise literature precedents. These
reactions have the following noteworthy characteristics:
(i) they internally recycle a reaction byproduct to perform
as a catalyst,4 (ii) they can be performed using unprotected
phenolic substrates, (iii) they utilize low-toxicity solvents
and reagents, and (iv) they generate nontoxic bypro-
ducts.
(19) A reviewer suggested testing PhI(OAc)2 as an alternative method
to remove the PMP group from nitrogen. See: (a) Ibrahem, I.; Zou, W.;
Casas, J.; Sunden, H.; Co´rdova, A. Tetrahedron 2006, 62, 357. Disappoint-
ingly, the desired deprotected product was not detected (by 1H NMR
spctroscopy) in these reactions.
(20) (a) Risch, N.; Arend, M.; Westermann, B. Angew. Chem., Int. Ed.
1998, 37, 1044. (b) Volkmann, R. A. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol I, p 355
and references therein.
Org. Lett., Vol. 10, No. 22, 2008
5113

Acknowledgment. We thank Seattle University, the NSF
(0618784), and Research Corporation (CC6444 and 7292)
for financial support and Profs. J. M. Langenhan (Seattle
University) and K. P. McNeill (University of Minnesota)
for helpful discussions. The staff at JEOL and Bruker are
gratefully acknowledged for numerous NMR and MS
analyses.
Supporting Information Available: Experimental pro-
cedures and spectral data provided. This material is
availablefreeofchargeviatheInternetathttp://pubs.acs.org.
OL801911F
(21) (a) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem.
Soc. 2007, 129, 6756. (b) Hata, S.; Iguchi, M.; Iwasawa, T.; Yamada, K.;
Tomioka, K. Org. Lett. 2004, 11, 1721.
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