Decarboxylative Mannich reactions

Article abstract of DOI:10.1002/ejoc.201201644

p-Methoxyphenylimines obtained from enolizable aldehydes react in the absence of catalysts at room temperature with β-keto carboxylic acids through a decarboxylative Mannich reaction. The Mannich products were obtained with a high degree of anti selectivity. By use of chiral oxygen-containing aldehydes, operationally simple access to aminohydroxylated polyketide substructures is possible. The results of catalyst-free, decarboxylative Mannich reactions of enolizable imines are described. When the reaction is performed with imines obtained from chiral aldehydes, access to optically pure Mannich products is possible. Copyright

Full text of DOI:10.1002/ejoc.201201644

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201644
Decarboxylative Mannich Reactions
[a]
[a]
[a]
Maximillian Böhm, Kerstin Proksch, and Rainer Mahrwald*
Keywords: Synthetic methods / C–C coupling / Decarboxylation / Mannich bases / Chirality / Aldehydes / Imines
p-Methoxyphenylimines obtained from enolizable aldehydes
react in the absence of catalysts at room temperature with
β-keto carboxylic acids through a decarboxylative Mannich
reaction. The Mannich products were obtained with a high
degree of anti selectivity. By use of chiral oxygen-containing
aldehydes, operationally simple access to aminohydroxyl-
ated polyketide substructures is possible.
Introduction
decarboxylative Mannich reactions of N-tosyl imines of
aromatic aldehydes to obtain the corresponding β-amino
thioesters with high degrees of enantioselectivity. Lu and
Nature generates carbon–carbon bonds under very mild
conditions by using various different methods for activating
substrates. Decarboxylation[1] is one activation mode that
allows C–C bonds to be constructed simultaneously under
physiological conditions. This mild and operationally sim-
ple transformation is found as a key step in the aldol pro-
[9]
co-workers described decarboxylative Mannich reactions of
[10]
aromatic imines in the presence of chiral thioureas. Dur-
ing our ongoing studies in the field of amine-catalyzed di-
rect aldol additions, we successfully developed a direct
amine-catalyzed decarboxylative aldol addition of β- and α-
cesses of polyketides[ and carbohydrate biochemical
pathways. Moreover, decarboxylative Mannich reactions
are also known and play an important role in nature in
the construction of alkaloids with a defined configuration.
Prominent examples of this transformation are the bio-
syntheses of pyrrolidine-containing alkaloids of the tropane
series, including tropinone, calystegine, and atropine. The
simplicity and logic of these natural transformations have
2]
[3]
[11]
keto carboxylic acids with enolizable aldehydes.
Follow-
ing these results, we attempted a decarboxylative Mannich
reaction under similar reaction conditions. The results of
this investigation are described below.
Results and Discussion
challenged synthetic chemists for a long time. An overview
In initial experiments, compound 1a, which is the p-
of developments in this area has been published,[ as have methoxyphenylimine (PMP-imine) of ethyl glyoxylate, was
4]
reports of metal-catalyzed decarboxylative Mannich reac- treated with benzoyl acetic acid (2a) in the presence of a
[
5]
tions. Also, organocatalytic solutions of this transforma- catalytic amount of a tertiary amine (10 mol-%). PMP-pro-
tion have been attempted. To this end, malonic acid half tected β-amino ketone 3a was isolated in moderate yield
thioesters were treated with imines of aromatic aldehydes in (45%). Upon decreasing the amount of catalyst, an increase
the presence of stoichiometric or catalytic amounts of terti- in the yield was observed. In the absence of a catalyst, a
[
6]
ary amines. Amine-catalyzed symmetric decarboxylative high yield was detected in a clean reaction at room tempera-
Mannich reactions in the total syntheses of natural prod- ture (61%, Scheme 1). Similar results were obtained for cat-
ucts were reported early on,[ but only three examples be- alyst-free aldol additions with 1,3-dicarbonyl com-
7]
[
12]
came known as organocatalyzed asymmetric decarboxyl- pounds.
ative Mannich reactions. Ricci et al. described reactions of
malonic acid half thioesters with imines in the presence of
cinchona alkaloids. The corresponding β-amino thioesters
were obtained with ee values up to 79%.[ Tan and co-
workers used chiral bicyclic guanidines as catalysts in the
8]
[
a] Department of Chemistry, Humboldt University Berlin,
Brook-Taylor Str. 2, 12489 Berlin, Germany
Fax: +49-30-2093 5553
E-mail: rainer.mahrwald@rz.hu-berlin.de
Homepage: http://www.chemie.hu-berlin.de/forschung/
mahrwald/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201644.
Scheme 1. Decarboxylative Mannich reaction of benzoyl acetic acid
(2a) and imine 1a.
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Decarboxylative Mannich Reactions
A competitive decarboxylation of the starting β-keto reduced yields, even in a catalyst-free and neutral me-
carboxylic acid initiated by the tertiary amine with a higher dium.[14] For this reason, imines 1b–d of enolizable alde-
rate of formation than C–C bond formation is assumed. hydes were formed and treated at –40 °C with β-keto
Detection of varying amounts of acetophenone depending carboxylic acids, whereas imines 1a and 1f–g (non-enoliz-
on the amount of the tertiary amine used in the reaction able aldehydes) were used at room temperature. Imines 1h–
supports this theory. Moreover, quantitative decarboxyl- n of oxygen-containing, chiral aldehydes were formed at
ation of the β-keto carboxylic acid in the presence of a cata- 0 °C and used at room temperature. The reactions were
lytic amount of the tertiary amine within 15 min at room monitored by thin-layer chromatography and were mostly
temperature was detected independently by NMR spec- complete after 1–2 h. The results of the investigations with
troscopy. Systematic investigations with other tertiary imines 1a–g are depicted in Scheme 2.
amines yielded the same results.
Accounts of the synthesis of optically pure Mannich ad-
This competitive decarboxylation of the β-keto carb- ducts through the direct decarboxylative Mannich reactions
oxylic acid was detected at room temperature as well of the imines of enolizable aldehydes have not been re-
[
15]
as at –40 °C. Also, when N-tosyl imine was used ported. Thus, by using the imines of chiral enolizable al-
instead of p-PMP-imine, an uncatalyzed decarboxylative dehydes, access to optically pure, β-amino ketones with a
Mannich reaction was detected, although to a lesser extent. defined configuration is possible. In preliminary experi-
The basicity of the imine is clearly strong enough to ments, we treated 1h, which is the imine of glyceraldehyde,
induce the decarboxylation of the starting β-keto carboxylic with differently substituted β-keto carboxylic acids 2a, 2c,
acids.
and 2d (Scheme 3).
To explore the scope and limitations of the uncatalyzed
Completion of the reaction was observed after 60 min
Mannich reaction, p-PMP-imines 1a–g were treated in a at room temperature. PMP-protected β-amino ketones 3l–
first series with β-keto carboxylic acids 2a–c. The PMP- n were obtained as a diastereomeric mixture. A slight anti
[
13]
imines were produced by optimized literature reports and selectivity was detected. Separation by column chromatog-
were used without further purification in the subsequent raphy yielded diastereoisomers 3l and 3m in optically pure
Mannich reaction. As a result of the variable stabilities of form. Racemization of the starting chiral aldehydes was not
the different imines, three optimized protocols for the Man- detected under these reaction conditions.
nich reaction were elaborated according to the nature of the
By further investigations, we extended this transforma-
1
R substituent. Imines 1b–d of enolizable aldehydes proved tion. To demonstrate the broad scope of this operationally
to be the most problematic substrates in the course of this simple protocol, we treated imines 1h–n, obtained from dif-
1
reaction (R = Et, iPr, iBu). Because of their reactivity, they ferent chiral aldehydes, with 2a. Results of these investi-
tend to undergo undesired side reactions, which leads to gations are depicted in Scheme 4.
Scheme 2. Catalyst-free decarboxylative Mannich reaction. Reaction conditions: dichloromethane, r.t. [a] syn/anti = 45:55. [b] Reaction
conditions: dichloromethane, –40 °C.
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M. Böhm, K. Proksch, R. Mahrwald
SHORT COMMUNICATION
reaction mixtures were quenched at –15 °C. Under these
conditions, the Mannich products were obtained with high
yields and stereoselectivities (Scheme 5).
Scheme 3. Decarboxylative Mannich reactions of PMP-imine 1h.
Reaction conditions: dichloromethane, r.t.
Scheme 5. Optimization of the reaction conditions. [a] Reaction
conditions: dichloromethane, 0 °C. [b] Reaction conditions: dichlo-
romethane, –15 °C. [c] Reaction conditions: dichloromethane,
–15 °C, 1l (2 equiv.).
The high anti selectivity can be explained by Felkin–Anh
1
considerations. The steric demand of the R substituent (di-
oxolane ring) favors model A to yield the anti-configured
Mannich product (Figure 1).
Scheme 4. Direct decarboxylative Mannich reaction of benzoyl
acetic acid (2a) with chiral imines. Reaction conditions: dichloro-
1
methane, 0 °C. [a] Reaction conditions: r.t., R = CMe
2
.
Figure 1. Felkin–Anh models.
Reactions were carried out at 0 °C and were mostly com-
plete after 1–2 h. Mannich products 3l–s were isolated in
moderate to good yields. A reasonable anti-diastereoselec-
tivity was obtained. Racemization was not observed during
these reactions. Diastereomeric Mannich adducts 3l–s were
isolated in enantiopure form.
To demonstrate the utility of this transformation in the
total synthesis of carbohydrate derivatives, protected syn-
configured Mannich adduct 3m was converted into 2-de-
oxy-3-aminoketose 4 (Scheme 6).
By additional investigations several details were iden-
tified that are responsible for the reduction in both the yield
and the stereoselectivity. To overcome the moderate stereo-
selectivities, imines 1l and 1o were treated with 2a at –15 °C.
Longer reaction times were required for full conversion un-
der these conditions. Indeed, the stereoselectivities were sig- Scheme 6. Synthesis of 2-deoxy-3-aminoketoses.
nificantly enhanced, but the yields were greatly reduced.
For the reaction with imine 1l, the yield decreased from
This can be easily accomplished by deprotection of acetal
56% at 0 °C to 12% at –15 °C (compare conditions b in syn-3m followed by spontaneous cyclization to give com-
Scheme 5 with those of Scheme 4). A retro-Michael reac- pound 4. NMR spectroscopic experiments revealed the
tion was suspected, which could be operative under these existence of an acyclic and a cyclic pyranoid structure in
[
16]
conditions. For that reason, an excess amount of the cor- about a 1:1 ratio. For structural elucidation, see the Sup-
[
13]
responding imine was used in these experiments, and the porting Information.
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Eur. J. Org. Chem. 2013, 1046–1049

Decarboxylative Mannich Reactions
[
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Conclusions
In conclusion, we have described the catalyst-free decar-
boxylative Mannich reaction of PMP-protected imines with
β-keto acids. Furthermore, insight into the mechanism and
configurative course of this reaction is given. Important is
the existence of a retro-Michael process, which requires re-
action and workup conditions to isolate the products in
high yields with high stereoselectivities. This operationally
simple protocol provides very easy access to aminohydrox-
ylated carbohydrate derivatives with a defined configura-
tion. Further investigations of an asymmetric and catalytic
version of this transformation are under way.
[
[
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Experimental Section
General Procedure: A solution of isopropylidene-protected d-
glyceraldehyde (1l; 348 mg, 2.68 mmol) in dichloromethane
2
913–2914; c) gelsemine derivatives: H. Conroy, J. K. Chakrab-
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(40 mL) was cooled to 0 °C. After the successive addition of
MgSO (5.0 g) and p-anisidine (300 mg, 2.41 mmol, 0.9 equiv.), the
4
mixture was stirred for 30–60 min. The formation of the imine was
monitored by TLC. After full conversion of the aldehyde into the
corresponding imine, the suspension was filtered, cooled to –15 °C,
and benzoyl acetic acid (2a; 220 mg, 1.34 mmol) was added to the
filtrate. The reaction mixture was stirred for 2–3 h while monitoring
the reaction by TLC. After the reaction was complete, the reaction
mixture was quenched at –15 °C and extracted with saturated aque-
[
[
[
8] A. Ricci, D. Pettersen, L. Bernardi, F. Fini, M. Mochi, R. P.
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[
[
ous NH Cl solution (3ϫ). The organic layer was separated, dried
4
Na SO ), and filtered, and the solvent was removed in vacuo. The
4
(
2
13] See the Supporting Information.
residue was purified by column chromatography (hexane/ethyl acet-
ate, 95:5) to yield product 3l (702 mg, 82%, anti/syn = 85:15).
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[8]
Supporting Information (see footnote on the first page of this arti-
[15] With the sole exception of ref. , Ricci and co-worker have used
cyclohexylcarboxaldehyde and hydrocinnamaldehyde in these
transformations. The corresponding Mannich products were
isolated with moderate enantioselectivities.
cle): Full experimental procedures, characterization data, and cop-
1
13
ies of the H/ C NMR spectra of all new compounds.
[
16] This assumption was supported by the following observations.
The corresponding α,β-unsaturated ketones were detected to a
more or less substantial extent. Furthermore, reactions of the
corresponding aldehydes with 2a do not yield α,β-unsaturated
ketones under these conditions.
Acknowledgments
The authors thank Pharma AG, Bayer Services GmbH, BASF AG,
and Sasol GmbH for financial support. Roy Herrmann is gratefully
acknowledged for X-ray structure analysis.
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Received: December 5, 2012
Published Online: January 24, 2013
Eur. J. Org. Chem. 2013, 1046–1049
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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