A Diels-Alder reaction conducted within the parameters of aqueous organocatalysis: Still just smoke and mirrors

Article abstract of DOI:10.1016/j.tetlet.2010.10.134

Conducting reactions using water as solvent is a highly prized goal for the organic chemist. Based upon recent literature and our continuing interest in the field of aqueous organocatalysis, we tested the scope of an enamine based Diels-Alder reaction usi

Full text of DOI:10.1016/j.tetlet.2010.10.134

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Tetrahedron Letters 52 (2011) 2085–2087
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Tetrahedron Letters
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A Diels–Alder reaction conducted within the parameters of aqueous
organocatalysis: still just smoke and mirrors
⇑
G. Neil Stowe, Kim D. Janda
Departments of Chemistry, Immunology and Microbial Science The Skaggs Institute for Chemical Biology and Worm Institute of Research and Medicine (WIRM),
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 2 November 2010
Conducting reactions using water as solvent is a highly prized goal for the organic chemist. Based upon
recent literature and our continuing interest in the field of aqueous organocatalysis, we tested the scope
of an enamine based Diels–Alder reaction using ( )-nornicotine, proline, and a proline derivative as aque-
ous organocatalysts. Unfortunately, none of the examined catalysts under aqueous conditions proved
useful, leaving the aqueous Diels–Alder reaction as an elusive goal.
Keywords:
Nornicotine
Organocatalysis
Diels–Alder
Aqueous
Ó 2010 Elsevier Ltd. All rights reserved.
The ever-expanding field of organocatalysis offers the capacity
of conducting a wide variety of synthetically useful transforma-
tions such as Michael,1–5 Diels–Alder,6–10 Mannich,11–14 and
Henry15–17 reactions, to name a few. In addition to the capacity
for the use of non-stoichiometric quantities of catalyst, the inher-
ent chirality present in many organocatalysts offers the capability
to conduct asymmetric reactions with extremely high selectivity.
Some advantages of organocatalysis are: (1) operational simplicity;
it can often be conducted without the need for an inert atmosphere
under ambient temperature and pressure, (2) lack of expensive
transition metals necessary for organometallic transformations,
and (3) the possibility for the use of water as reaction solvent. Of
these listed organocatalysis advantages, we consider the use of
aqueous solvent of special importance due to its inherent character
as a low impact, environmentally sustainable solvent without the
carbon footprint embodied by traditional organic solvents.
value. As such, we set out to study the same Diels–Alder reaction
as performed by Xu et al. using ( ) nornicotine as organocatalyst
(Scheme 3A). We felt ( ) nornicotine presented an excellent
opportunity to test our theory for optimization of aqueous
R
R
O
N
N
O2N
H 2-4
Ph
7
O
Ph
NO2
1
5
6
R =
S
H
N
N
S
S
N
N
N
2
3
4
Given our previous success in the field of aqueous organocatal-
ysis18–21 and our continuing interest in the synthesis of analogs of
commonly abused drugs22,23 we became intrigued by the recently
published work of Xu et al. who used proline derivatives at room
temperature to conduct enamine catalyzed Diels–Alder reactions
of cyclohex-2-enone and b-nitrostyrene employing brine or seawa-
ter as the solvent of choice (Scheme 1).24 In addition to the use of
seawater/brine as solvent, this work employed a variety of organic
acid additives, such as benzoic acid and derivatives thereof, to opti-
mize reaction conversion and selectivity (Scheme 2).
Scheme 1. Previous approach and mechanistic interpretation of organocatalyzed
Diels–Alder reactions via an enamine intermediate.
O
Ph
O2N
Ph
Catalyst
H2O
+
NO2
O
7
6
1
However, we reasoned these organic acid additives could be
entirely unnecessary, and that the reaction could be optimized
equally as well using an organocatalyst and buffer of correct pH
O
R = H, 4-NO2,
3-NO2, 4-CF3
and others
Acid Additive =
OH
8
R
⇑
Corresponding author.
E-mail address: kdjanda@scripps.edu (K.D. Janda).
Scheme 2. Aqueous Diels–Alder and acid additives of Xu et al.24
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.134

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G. N. Stowe, K. D. Janda / Tetrahedron Letters 52 (2011) 2085–2087
amounts (20%) of ( )-nornicotine in brine as well as three differ-
ent buffer pH values (pH = 6.0, 7.0, 8.0) did not mediate any reac-
tion. In fact, we discovered that only when a stoichiometric
quantity of ( )-nornicotine was used did we detect any product
for both solvent systems. We were able to isolate Diels–Alder
product 7 from these experimental variations using NaPi buffer
or brine as reaction solvent, but poor yields were obtained for
each trial (Table 1).
Given these suboptimal results using ( )-nornicotine 10 as an
aqueous organocatalyst, we synthesized proline derivative 4 of
Xu et al. in an attempt to repeat their Diels–Alder reaction protocol
using brine as solvent and benzoic acid as the organic acid additive.
Using this procedure, Xu reported a conversion of >99% at a 20%
loading of catalyst and benzoic acid. Unfortunately, we did not ob-
serve any reaction to occur employing these conditions. Instead,
we found that only after we increased the loading of catalyst and
benzoic acid to 40% did we observe any reaction product at a dis-
appointing 10% isolated product yield (Table 1). However, the use
of Xu’s catalyst and benzoic acid additive at 40% loading did yield
bicyclic reaction product 7 with diastereomeric ratio of >25:1 and
enantiomeric excess of 83%, in agreement with the reported values
(Table 1).
Thus, we conclude our hypothesis of ( )-nornicotine catalyzing
the aqueous enamine-based Diels–Alder reaction to be nontenable,
despite our previous success with aldol reactions in aqueous sol-
vent employing what we believe to be a similar mechanism. We
are currently unsure of the underlying reason for the disappointing
results obtained, but it could stem from aqueous instability of the
transient imine or enamine necessary for reaction completion.
Additional research will be required to examine these supposi-
tions. We also stress that while the selectivity of Xu’s catalyst
was similar to reported values (>25:1 dr, 82% ee), we were not able
to obtain their outstanding yields with catalyst loads of 20% and
40%.
A)
N
O
N
H
O2N
Ph
Ph
10
+
NaPi Buffer
NO2
N
O
1
7
6
B)
N
S
N
N
N
N
H
H
4
11
10
Scheme 3. (A) Catalysis by ( )-nornicotine in buffer solvent. (B) Structures of Xu’s
catalyst 4, ( )-nornicotine 10 and ( )-nicotine 11.
organocatalysis without the need for acid additives given its struc-
tural similarities to the catalysts 2–4 used by Xu et al. We did not
employ nicotine 11 in this study since the required enamine reac-
tion intermediate would not be generated by the tertiary amine of
this compound, as determined by our previous research.20
We were aware at the onset of this study that using racemic
nornicotine would not confer any enantio- or diastereomeric ex-
cess to the reaction product. However, we decided that initial opti-
mization of Diels–Alder reaction conversion in buffer was critical
before attempting to confer chiral selectivity in the reaction
process.
Our initial test of the enamine-based Diels–Alder reaction uti-
lized 30% proline in DMSO solvent following Cordova’s proce-
dure.25 We were pleased to observe that proline did indeed
behave as a reasonable organocatalyst, providing the product in
80% yield as a >25:1 diastereomeric ratio (dr), although this result
was tempered by a disappointing enantiomeric excess (ee) of 8%
(Table 1).
After this proof of concept experiment, we conducted the
aqueous Diels–Alder reaction using ( )-nornicotine as organocat-
alyst and either brine (benzoic acid additive) or sodium phos-
phate (NaPi) buffer as the solvent. Disappointingly, catalytic
In summary, we conclude that high-yielding aqueous organoc-
atalysis of the enamine-based Diels–Alder reaction still remains
an elusive goal, and the bar is reset for future investigations in this
realm of research.
Table 1
Acknowledgments
Diels–Alder reaction using proline, proline derivative 4 and ( )-nornicotine 10
The authors acknowledge the support of The Scripps Research
Institute, Skaggs Institute for Chemical Biology and the National
Institutes of Health under contract number R01-DA026625.
O
Ph
O2N
Ph
Catalyst
+
NO2
O
7
6
1
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.134.
Amine
Catalyst load Solvent pH Acid Yield (%)d dre
eef (%)
Proline 30%
DMSO
DMSO
NaPib
NaPi
NaPi
NaPi
—
—
—
—
—
—
—
—
—
—
8a
8a
8a
80%
>25:1
—
—
—
—
—
—
—
—
8
References and notes
10
10
10
10
10
10
10
10
4
50%
20%
20%
20%
100%
100%
100%
100%
20%
N.R.
N.R.
N.R.
N.R.
<10%
<10%
<10%
<10%
N.R.
10%
—
—
—
—
—
—
—
—
—
6.0
7.0
8.0
6.0
7.0
8.0
—
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