A mild and selective reduction of β-lactams: Rh-catalyzed hydrosilylation towards important pharmacological building blocks

Article abstract of DOI:10.1002/ejoc.201403655

Four-membered N-heterocyclic compounds exhibit a broad range of pharmacological activities. Herein, we report a useful rhodium-catalyzed protocol for the activation of phenylsilane to reduce tertiary β-lactams. Reaction with the tertiary amides was select

Full text of DOI:10.1002/ejoc.201403655

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403655
A Mild and Selective Reduction of β-Lactams: Rh-Catalyzed Hydrosilylation
towards Important Pharmacological Building Blocks
Christoph Bornschein,[a] Alastair J. J. Lennox,[a] Svenja Werkmeister,[a] Kathrin Junge,[a]
and Matthias Beller*[a]
Keywords: Azetidines / Hydrosilylation / Lactams / Reduction / Rhodium
Four-membered N-heterocyclic compounds exhibit a broad
range of pharmacological activities. Herein, we report a use-
ful rhodium-catalyzed protocol for the activation of phenyl-
silane to reduce tertiary β-lactams. Reaction with the tertiary
amides was selective over secondary amides, esters, olefins
and nitriles, with no erosion of stereochemistry. A one-pot
protocol from commercially available starting materials and
a selective reduction of a complex penicillin derivative dem-
onstrate the synthetic utility of this facile procedure.
primarily due to the fact that their preparation is highly
cumbersome, owing to the internal strain that causes facile
ring opening. One of the most applied approaches to their
synthesis is by intramolecular cyclization reactions.[8,10] The
scaffold can equally be constructed through a formal [2+2]
cycloaddition of ketimines with allenoates,[11] iodocycli-
zation of homoallylamines[12] or ring expansion of azirid-
ines.[13] Unfortunately, many of these methods suffer from
major drawbacks including low yields, harsh reaction con-
ditions, toxic reagents and limited substrate scope. In gene-
ral, the method of choice for the synthesis of azetidines
should be the reduction of the more versatile and readily
accessible β-lactam moiety. However, typical amide reduc-
tants such as LiAlH4 or boranes lead to rapid ring opening.
In-situ formed AlHxCly can give the desired products in
reasonable yields,[14] and NaBH4 will reduce β-lactams con-
taining adjacent unsaturation.[15] However, these methods
employ excess reagent and are unselective towards moieties
sensitive to reduction.
Introduction
The azetidine moiety is a remarkable functional group
that has received a flourish of recent interest,[1] particularly
in the life science industries. The naturally occurring azitid-
ine-2-carboxylic acid was first discovered to exhibit bio-
logical activity, and since then its incorporation into drug-
like molecules has been impressive.[2] Compounds contain-
ing the four-membered heterocyclic functionality have
shown activity in blood cholesterol reduction,[3] dopamine
antagonists,[2d,4] antifungals[1b,5] and antibacterials[6] (Fig-
ure 1). Azetidines have also found application as organocat-
alysts, or chiral auxiliaries, in enantioselective transforma-
tions,[7] and in the formation of larger N-heterocycles.[8] In
addition, spirocyclic azetidine systems constitute useful sur-
rogates for heterocycles, e.g. morpholine, in medicinal
chemistry, offering higher metabolic stability and bioavail-
ability.[9]
Recently, and during the course of this work, the re-
duction of β-lactams was reported by Alcaide and co-
workers.[16] Employing hydrosilanes and a Zn catalyst, 3-
oxygenated β-lactams were reduced in the presence of
esters, nitriles and olefins. Moderate to good yields were
observed employing excess hydrosilane, comparably high
catalyst loading (10 mol-%) and elevated temperatures
(90 °C) in sealed reaction vessels. Furthermore, Navarro et
al.[17] showed the applicability of RhH(CO)(PPh3)3 in cata-
lyzing the reduction of amino acid derived β-lactams.
Again, employing excess diphenylsilane, a limited range of
tertiary four-membered amides were reduced in moderate
to high yields. It is worth noting that ester and urethane
moieties were tolerated under the applied conditions, but
the protocol was not demonstrated on sterically demanding
3,4-disubstituted β-lactams.
Figure 1. Two examples of important azetidine-derived drugs.
Azetidines are, however, the least studied representative
among its four-membered heterocyclic cousins. This being
[a] Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
E-mail: matthias.beller@catalysis.de
http://www.catalysis.de/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403655.
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C. Bornschein, A. J. J. Lennox, S. Werkmeister, K. Junge, M. Beller
SHORT COMMUNICATION
were prepared using the Kinugasa reaction[21] or a Staud-
inger-type cycloaddition.[22] Since two chiral centers are
Results and Discussion
Based on our general interest in selective amide re- formed during these cyclizations, the observed dia-
ductions, we report herein on the optimization of a mild stereomers were separated by column chromatography fol-
and high yielding reduction system that exhibits impressive lowed by partial crystallization. The results of the reduction
chemoselectivity towards tertiary β-lactams. The commer- are displayed in Figure 2. We began testing the reactivity of
cially available 1-(3-bromophenyl)-3,3-dimethylazetidin-2- 3-oxygenated β-lactams (1b–g) under our optimized condi-
one (1a) was employed as a model system for reaction opti- tions {2.5 mol-% [Rh(COD)2]BF4, 5 mol-% dppp, 2 equiv.
mization. We first tested non-noble metal based systems PhSiH3 in THF, 50 °C, 3 h}. Compared to previously re-
known for the reduction of amides[18] including Zn- ported hydrosilylations,[16,17] in almost all cases higher iso-
(OAc)2,[16,18b] but unfortunately, under the criteria we set to lated yields were obtained at lower temperatures, no excess
use mild conditions, none led to any reasonable conversion hydrosilane and minimal catalyst loadings. The ester func-
(GC; Table S1, Entries 1–7). Based on our recent progress tionality of 1e and the unsaturation in 1g was left com-
on the selective hydrosilylation of amino acid derivatives,[19] pletely untouched. The stereochemistry of all substrates was
we began to investigate various rhodium precursors in the maintained during reaction, with the only exception of
presence of 1,3-bis(diphenylphosphanyl)propane (dppp) as compound 1g [racemization of the OAllyl group (1H
ligand and phenylsilane. Among the different pre-catalysts NMR)]. The slight deterioration observed may be due to
[Rh(COD)2]BF4 (2.5 mol-%) proved to be the most success- the presence of unsaturation in the molecule, which can fa-
ful in combination with dppp (5 mol-%) (Table 1, Entry 4) cilitate stabilization of catalytic intermediates involved in an
at 50 °C. However, reducing the reaction temperature to epimerization pathway. However, the single diastereomer is
ambient conditions caused the reactivity to significantly readily accessed by chromatography. Pleasingly, when the
drop (Table 1, Entry 5). Switching from a coordinating scale of the reaction was increased eightfold (2 mmol),
(THF) to a non-coordinating (toluene) solvent, (Table S1, product isolation is facilitated and consequently the yield
Entry 15) led to only a slight decrease in reactivity that was was found to increase.
completely attenuated in methanol (Table S1, Entry 16). We
After establishing the reactivity of the 3-oxygenated
turned our attention to the influence of the reductant on series (1b–g), the conditions were tested on a broader range
the reaction progress, where – interestingly – only phenyl- of amides. The para-methoxyphenyl group (PMP) was
silane gave detectable conversions (Table S1, Entries 17–19). cleaved using an oxidative method,[23] and the electronic
We clarified that only one of the three possible hydrides is properties in the 4-position were explored, whilst a phenyl
sufficiently activated to react, as the use of just 1.5 equiv. group possessed the 3-position (1h–o). Electron-donating
of the hydride source gave only 72% conversion (Table 1, and -withdrawing aryl substituents behaved well under the
Entry 8), which almost perfectly correlates with this as- conditions, although problems were encountered with sub-
sumption. As expected when the reductant Ph2SiD2 was strate 1m, most probably caused by nitrile interaction with
employed, deuterium was fully incorporated into the de- the active catalyst. In all cases no erosion of the stereo-
sired azetidine, demonstrating the possibility to access selec- chemical integrity was observed and, only the cis dia-
tively labeled compounds in a straightforward manner.[20]
The amenability of the optimized conditions on the sub-
stereoisomer was isolated.
Interestingly, when the secondary amide 1r was subjected
strate scope was subsequently tested. The starting materials to this hydrosilylation protocol, no conversion was ob-
Table 1. Optimization of key variables in the hydrosilylation of 1-(3-bromophenyl)-3,3-dimethylazetidin-2-one (1a).[a,b]
Entry
[Rh] [mol-%]
PhSiH3 [equiv.]
Temp. [°C]
(Conv.) yield [%][c]
1
2
3
[Rh(COD)2]BF4 5.0
[Rh(COD)2]BF4 1.5
[Rh(COD)2]BF4 2.5
[Rh(COD)2]BF4 2.5
[Rh(COD)2]BF4 2.5
Rh(COD)acac 2.5
[Rh(NBD)Cl]2 2.0
[Rh(COD)2]BF4 2.5
4
2
2
2
2
2
2
1.5
80
80
65
50
(Ͼ 99) 60
(ca. 10) n.d.
(Ͼ 99) 72
4
(Ͼ 99) 80
5
room temp.
(ca. 32) n.d.
(ca. 65) n.d.
(Ͼ 99) 73
6[d]
7
50
50
50
8
(ca. 72) n.d.
[a] General reaction conditions: 0.25 mmol 1a, 0.00375–0.0125 mmol [Rh], 0–0.025 mmol dppp, 0.37–1 mmol phenylsilane, 1 mL of THF,
Δ, 3 h. [b] For the complete optimization table, see the Supporting Information. [c] Conversion of starting material was determined by
GC. Isolated yield not determined (n.d.) in cases of conversion Ͻ 80%. [d] No dppp added; acac = acetylacetonate.
2
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Mild and Selective Reduction of β-Lactams
thio-, ester-, alkenyl-, alcohol- and ether-containing mol-
ecules, which themselves all remained intact.[25] However,
primary amines, primary amides and nitriles quenched the
reduction.
We next turned our attention towards enlarged ring sys-
tems to emphasize the adaptability of the developed meth-
odology. Indeed, the reductions of five- (3), six- (5) and
seven-membered (4) tertiary amides were all reliably accom-
modated and yielded the corresponding volatile amines in
full conversion. Consistently, no conversion of secondary
amides occurred when incorporated into the larger ring sys-
tems (6 and 7).
The impressive chemoselectivity of our protocol is illus-
trated by the reduction of the bioactive penicillin derivative
8. At room temperature solely the tertiary amide carbonyl
functionality, surrounded by an unsaturated thia-aza-bi-
cyclic system, was hydrosilylated and reduced. The unsatu-
rated ester, halide and secondary amide moieties were left
intact (Scheme 1) to give a moderate yield of this complex
and sensitive molecule.[26]
Scheme 1. Selective reduction of the tertiary amine in penicillin de-
rivative 8.
Finally, the methodology was extended by demonstrating
the synthesis of azetidine 2b in a one-pot procedure from
cheap and commercially available substrates (Scheme 2).
Scheme 2. Synthesis of 2b by sequential “one-pot” Staudinger
cycloaddition and reduction.
Figure 2. Substrate scope for the hydrosilylation of β-lactams. Re-
action conditions: β-lactam
1 (0.25 mmol), [Rh(COD)2]BF4
(0.00625 mmol), dppp (0.0125 mmol), PhSiH3 (0.5 mmol), THF
(1 mL), 50 °C, 3 h; PMP = para-methoxyphenyl; isolated yields of
pure, single diasteriomeric (cis) compound. [a] 18 h reaction time.
[b] 3:1 diasteromeric ratio initially obtained, yield given is isolated
pure cis isomer. [c] Calibrated GC yield. [d] Product contains low
Using the classical Staudinger-type cycloaddition[27] to
generate the β-lactam in situ, it was shown that the subse-
quent addition of rhodium catalyst, ligand and reductant
proportions of siloxane co-product after purification procedure. triggered the formation of the corresponding azetidine in a
[e] Pure isolated product degraded over 5 d at room temp. under
mixture of diasteroisomers that could be easily separated by
air. [f] Uncalibrated GC–MS only showed the volatile product
chromatography.[26]
peak. [g] by GC.
Conclusions
served, and only starting material remained, illustrating the
exclusive amenability towards tertiary amide systems. This
A straightforward hydrosilylation of a variety of substi-
selectivity is further demonstrated by running the reaction tuted tertiary β-lactams has been developed to give good to
in the presence of other functionalized compounds.[20,24] excellent yields of the corresponding azetidene products.
Hence, β-lactam 1a was reduced exclusively in a mixture of The combination of [Rh(COD)2]BF4 and dppp allows the
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C. Bornschein, A. J. J. Lennox, S. Werkmeister, K. Junge, M. Beller
SHORT COMMUNICATION
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Experimental Section
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Representative Procedure: A 10 mL oven-dried Schlenk tube con-
taining a magnetic stir bar was charged with [Rh(COD)2]BF4
(2.5 mol-%, 0.05 mmol, 20.3 mg), dppp (5 mol-%, 0.1 mmol,
41.3 mg) and substrate 1a (1 equiv., 2 mmol, 508.2 mg). Dry THF
(4 mL) and phenylsilane (2 equiv., 4 mmol, 494 μL) were added af-
ter purging the Schlenk tube with argon and evacuating it three
times. The resultant mixture was stirred at 50 °C for 3 h before
being cooled to 0 °C; then 0.1 mL of a saturated solution of NH4F
in water was added and the mixture stirred at room temperature
overnight. The organic compounds were carefully extracted with
ethyl acetate (3ϫ 10 mL), and the combined organic layers were
washed with brine (2ϫ 15 mL), dried with anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The desired product 2a
was purified, by silica gel chromatography using a mixture of pent-
ane/ethyl acetate (25:1) as eluent, to give 451.3 mg (94%) of the
pure clear liquid.
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Mild and Selective Reduction of β-Lactams
[25] The easily reduced nitro, aldehyde and ketone functionalities
were hydrosilylated under these conditions.
[26] The quenching with NH4F(aq) during workup was found to be
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Received: November 3, 2014
Published Online: ᭿
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C. Bornschein, A. J. J. Lennox, S. Werkmeister, K. Junge, M. Beller
SHORT COMMUNICATION
Azetidine Synthesis
C. Bornschein, A. J. J. Lennox,
S. Werkmeister, K. Junge,
M. Beller* ......................................... 1–6
A Mild and Selective Reduction of β-
Lactams: Rh-Catalyzed Hydrosilylation
towards Important Pharmacological Build-
ing Blocks
A selective Rh-catalyzed protocol to reduce
β-lactams to important pharmacologically
active azetidines is presented. Reaction
with tertiary amides was selective over sec-
ondary amides, esters, olefins and nitriles,
with no erosion of stereochemistry. A one-
pot protocol from commercially available
starting materials and a selective reduction
of a complex penicillin derivative demon-
strate the high synthetic utility of this pro-
cedure.
Keywords: Azetidines / Hydrosilylation /
Lactams / Reduction / Rhodium
6
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