One-Step Synthesis of 3,4-Disubstituted 2-Oxazolidinones by Base-Catalyzed CO2 Fixation and Aza-Michael Addition

Article abstract of DOI:10.1002/chem.201902451

2-Oxazolidinones are saturated heterocyclic compounds, which are highly attractive targets in modern drug design. Herein, we describe a new, single-step approach to 3,4-disubstituted 2-oxazolidinones by aza-Michael addition using CO₂ as a carbonyl source and 1,1,3,3-tetramethylguanidine (TMG) as a catalyst. The modular reaction, which occurs between a γ-brominated Michael acceptor, CO₂ and an arylamine, aliphatic amine or phenylhydrazine, is performed under mild conditions. The regiospecific reaction displays good yields (av. 75 %) and excellent functional-group compatibility. In addition, late-stage functionalization of drug and drug-like molecules is demonstrated. The experimental results suggest a mechanism consisting of several elementary steps: TMG-assisted carboxylation of aniline; generation of an O-alkyl carbamate; and the final ring-forming step through an intramolecular aza-Michael addition.

Full text of DOI:10.1002/chem.201902451

A Journal of
Accepted Article
Title: One-step Synthesis of 3,4-Disubstituted 2-Oxazolidinones via
Base-catalyzed CO₂-Fixation and Aza-Michael Addition
Authors: Jere Kristian Mannisto, Aleksi Sahari, Kalle Lagerblom,
Teemu Niemi, Martin Nieger, Gábor Sztanó, and Timo Juhani
Repo
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To be cited as: Chem. Eur. J. 10.1002/chem.201902451
Link to VoR: http://dx.doi.org/10.1002/chem.201902451
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One-step Synthesis of 3,4-Disubstituted 2-Oxazolidinones via
Base-catalyzed CO2-Fixation and Aza-Michael Addition
Jere K. Mannisto, Aleksi Sahari, Kalle Lagerblom, Teemu Niemi, Martin Nieger, Gábor Sztanó and
Timo Repo*
Abstract: 2-Oxazolidinones are saturated heterocyclic compounds,
which are highly attractive targets in modern drug design. Here we
describe a novel, single step approach to 3,4-disubstituted 2-
oxazolidinones via aza-Michael addition using CO2 as a carbonyl
source and 1,1,3,3-tetramethylguanidine (TMG) as a catalyst. The
modular reaction, which occurs between a γ-brominated Michael
acceptor, CO2 and an arylamine, aliphatic amine or phenylhydrazine,
is performed under mild conditions. The regiospecific reaction
displays good yields (avg. 75 %) and excellent functional group
compatibility. In addition, late-stage functionalization of drug and drug-
like molecules is demonstrated. The experimental results suggest a
mechanism consisting of several elementary steps: TMG-assisted
carboxylation of aniline; generation of an O-alkyl carbamate; and the
final ring-forming step via an intramolecular aza-Michael addition.
Despite being widely used for 2-oxazolidinone synthesis, these
methods are constrained by the toxicity of the reagents.
There is an increasing interest in the use of carbon dioxide
as an alternative, safer and more cost-efficient carbonyl source
as compared to phosgene and isocyanates.[31] Indeed, several
strategies for CO2-based preparation of cyclic carbamates have
been reported. In the most studied approach, primary amines are
first coupled to an electrophilic group such as an alkyne[32–36], a
strained ring[37–40], or an activated alcohol[41] followed by the CO2-
driven cyclization (Scheme 1C). All the above syntheses (Scheme
1A-C) are two-step processes, and consequently, relatively
laborious routes.
To resolve the above-discussed challenges, we turned our
attention to the aza-Michael addition. Herein we report our results
on direct unprecedented single-step synthesis of 3,4-disubstituted
2-oxazolidinones by a base-catalyzed aza-Michael addition, using
organic carbamates generated in situ from (aryl)amines and CO2
(Scheme 1D). The reaction is performed under mild conditions
and displays good yields (avg. 75 %) and excellent functional
group compatibility, and the method allows for late-stage
functionalization of complex molecules. Additionally, quantitative
13C nuclear magnetic resonance (NMR) studies, control
experiments and isolation of a mechanistically relevant acylic
carbamate shed light on a possible mechanism.
Development of new and improved pharmaceutically active
molecules is a complex process with many considerations, and
interesting trends have emerged.
For example, nitrogen
containing heterocycles are important, as they are found in 59 %
of FDA approved small-molecule drugs.[1] It is also shown that a
higher fraction of sp3 hybridized carbons (Fsp3) and the presence
of chiral centers correlates with the clinical success of drug
candidates.[2] One group of compounds, that meets both of these
criteria, is the 2-oxazolidinones, a type of five-membered cyclic
carbamates. They are particularly attractive synthetic targets due
to their wide-ranging biological activity and central role in several
state-of the-art drugs[3–6] including antibiotics[7–10] and anti-cancer
drugs.[11,12] Consequently, the 2-oxazolidinone core can be seen
as a promising “isostere”, a replacement of conventionally used
(flat aromatic) structures in biological environments; it is a
saturated, nitrogen-containing heterocycle with
structure. As current methods of introducing such saturated
heteroatom ring systems are fairly limited[13]
new and
a tunable
,
straightforward synthetic methods are desired to introduce
isosteres, such as 2-oxazolidinones, into core scaffolds.[14–17]
The most conventional 2-oxazolidinones synthesis is
carried out by cyclizing amino alcohols with phosgene, followed
by C-N coupling (Scheme 1A).[18–22] These steps may also be
executed in reverse order.[7,23–25] A less common approach
involves reacting the corresponding isocyanate with an
electrophilic alcohol, which is then cyclized (Scheme 1B).[26–30]
Scheme 1. Synthetic pathways to substituted 2-oxazolidinones. A-C: Two-step
syntheses. D: Single step synthesis. RE = electrophilic group. EWG = electron
withdrawing group.
[a]
J. K. Mannisto, A. Sahari, K. Lagerblom, T. Niemi, M. Nieger, G.
Sztanó, T. Repo*
We initiated our study by using commercial methyl 4-
bromocrotonate 1 as a Michael acceptor and aniline 2a under a
CO2 atmosphere with various solvents and organic bases. Under
optimized conditions 2-oxazolidinone 3a formed regioselectively
in 99 % yield, using 1,1,3,3-tetramethylguanidine (TMG, 20 mol%)
in combination with Cs2CO3 (4 equiv) in dimethylformamide
Department of Chemistry
University of Helsinki
P.O. Box 55, A.I. Virtasen aukio 1, 00014 Helsinki, Finland
E-mail: timo.repo@helsinki.fi
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/xxxxxx
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10.1002/chem.201902451
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(DMF) (Table 1, entry 1). The formation of N-alkylated byproduct
4a was eliminated by a slow addition (over 4 h) of Michael
acceptor 1. Regioisomer 3a’ was not observed at any point. For a
detailed discussion of our optimization studies, see the
Supporting Information (SI).
amines (3n-3p, 71-73 %) and phenylhydrazine (3q, 58 %). A slow
addition of the Michael acceptor 1 (over 12 h) was necessary to
avoid formation of corresponding N-alkylated by-products (4n-4p).
This can be ascribed to the higher nucleophilicity of aliphatic
amines in comparison to anilines. Finally, we conducted a
mechanistic investigation with N-methylaniline 2r, which we
assumed should be able to capture CO2, but not undergo the
subsequent aza-Michael addition. As predicted, an acylic O-alkyl
carbamate was obtained (3r, 57 %).
The catalytic effects of various organic bases were
compared to TMG (pKa 23.4 in acetonitrile[42]). It was found that
2-tert-butyl-1,1,3,3-tetramethylguanidine (tBuTMG, pKa 26.5[43]),
1,8-diazabicyclo(5.4.0)undec-7-ene (DBU, pKa 24.3[42]), 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD, pKa 26.0[42]) and 7-methyl-
1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD pKa 25.44[42]) gave
slightly lower yields of 3a, despite a similar high Brønsted basicity
compared to TMG (Table 1, entries 2-5, 89-91 % yields). Weaker
Table 1. Evaluation of reaction components.
bases such as triethylamine (pKa 18.8[42]
)
and 4-
(dimethylamino)pyridine (DMAP pKa 18.0[42]) gave significantly
lower yields (entries 6-7, 43-44 % yields). In light of these results,
the catalytic base must have a sufficiently high basicity (pKa > 23
in acetonitrile) to effectively facilitate the reaction. However,
basicity alone is not the only factor influencing the catalysts’
activity; tBuTMG, DBU, TBD and MTBD have basicities similar to
TMG and might be expected to give a similar yield; but instead,
slightly lower yields were obtained, although the difference was
not critical. In the neutral state, tBuTMG, DBU and MTBD are
aprotic bases, whereas TMG and TBD are protic. The latter two
differ structurally from each other. In TMG the proton is proximal
(Hp) to the basic lone pair, while in TBD the proton is distal (Hd).
Considering the above, it is likely that TMG stands out due to a
secondary catalytic effect by hydrogen bonding of the proximal
proton (Hp) of TMG, which stabilizes the forming enolate of the
conjugate addition, in contrast to the distal proton (Hd) of TBD (see
mechanistic discussion below).
The effect of different reaction components was evaluated
by a series of control experiments. Only trace amounts of 2-
oxazolidinone 3a were formed without a CO2 atmosphere and the
major product was N-alkylated 4a (entry 8). In the absence of
Cs2CO3, 2-oxazolidinone 3a was obtained in 85 % yield, providing
strong evidence that the carbonyl in 3a originates from CO2, and
not from the carbonate anion (entry 9). In the absence of TMG,
the yield of 3a was significantly decreased (46 %, entry 10), which
was comparable to entries 6 and 7, suggesting triethylamine and
DMAP had no catalytic effect. Other inorganic bases gave inferior
yields, even with tetrabutylammonium iodide (TBAI) or CsBr as
phase transfer-catalysts (entries 11-14). These results indicate
that Cs2CO3 is superior, as it has a better solubility than other
inorganic bases.[44]
Further experimental studies show that the reaction has a
broad scope (Scheme 2). The electronic and steric properties of
the parent aniline affected the optimal addition rate of Michael
acceptor 1. For example, with the standard rate of addition (4 h),
electron-rich ortho-substituted 3b was obtained in a ca 50 % yield,
which was improved to 88 % by a slower addition of 1 (over 6 h).
This indicates that ortho-substitution retards the reaction rate due
to steric hindrance. Strongly electron withdrawing substituents (3f
and 3g) necessitated a very slow addition of 1 (over 12 h),
regardless of substitution at the ortho or para-position, suggesting
a lower concentration of the forming carbamate ion due to
electronic destabilization. Medicinally relevant heterocylic
aminopyridine 2l and -thiazole 2m gave high yields (3l 78 %, 3m
63 %). The methodology was successfully extended to aliphatic
Entry
Deviation from above
Yield of 3a
(%)a
1
2
None
99
89
90
90
91
43
44
<5
85
46
29
64
18
tBuTMG, instead of TMG
DBU, instead of TMG
TBD, instead of TMG
MTBD, instead of TMG
Et3N, instead of TMG
DMAP, instead of TMG
Ar, instead of CO2
3
4
5
6
7
8b
9b
10b
11b
12b
13b
No Cs2CO3, excess TMG (4.2 eq)
No TMG
K2CO3, instead of Cs2CO3
K3PO4, instead of Cs2CO3
K2CO3 and TBAI (4 eq), instead of
Cs2CO3
14b
K3PO4 and CsBr (4 eq), instead of
Cs2CO3
55
[a] Yield determined by GC-FID with mesitylene as an internal standard. [b]
Control experiment.
A major fraction of previous research within medicinal chemistry
has focused on the C-C and C-N coupling of flat aromatic
moieties.[14–16] Thus, there is an increasing interest in novel
syntheses of three-dimensional structures consisting of sp3
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hybridized carbons,[2] and the introduction of fluoroalkyl groups.[45]
In accordance to the above, we report nitrile 5a, amide 5b and
fluorinated esters 5c and 5d as viable Michael acceptors (Scheme
3A). The desired 2-oxazolidinones 6a-d formed in good yields
(51-86 %). Intriguingly, a diastereoselective cyclization reaction
was observed for 5d, leading preferentially to the syn-2-
oxazolidinone 6d-2.[46] The observed diastereoselectivity (19:60)
originated from the fluorine gauche effect, and was comparable to
the selectivities in a previously reported intramolecular aza-
Michael addition.[47] Consequently, our method is a novel example
of diastereoselective fixation of CO2 into a cyclic carbamate.[48]
Furthermore, our approach is well-suited for late stage organic
synthesis (Scheme 3B). Deacetyl linezolid 2s, an antibiotic
aliphatic amine,[10] yielded 3s smoothly (74 %) with full retention
of the original chiral configuration. Arylamine 2t reacted to form 3t
in a moderate yield (40 %), which was likely due to the strongly
electron-deficient character of the aromatic ring. Further
modification of 3t by Suzuki-coupling provided 7, a novel
derivative of anti-cancer drug buparlisb,[49] in good yield (60 %).
We propose a mechanism based on quantitative 13C NMR
experiments, an isolated acyclic carbamate, control experiments
and previous literature (Scheme 4). Initially, TMG reacts
reversibly with CO2 to form a zwitterionic intermediate A, as has
been previously established.[50–52] Then, A undergoes CO2
exchange with aniline 2a to provide the mixed carbamate B,[52–54]
as observed by quantitative 13C NMR studies (see SI).[55] In the
following step, the mixed carbamate B reacts with Michael
acceptor 1 by nucleophilic substitution of bromine to form the
acyclic O-alkyl carbamate C and TMG·HBr. Intermediate C was
identified by using N-methylaniline as a substrate, leading to the
isolation of acyclic carbamate 3r. Next, highly-soluble Cs2CO3
regenerates TMG by deprotonation. The equilibrium is driven by
precipitation of Cs salts, as was observed in control experiments
presented in Table 1 (entries 11-14). In transition state D, it is
shown how TMG catalyzes the cyclization by proton transfer[56]
and enolate stabilization.[57,58] Therefore, it is likely that the
carbamate N-H bond is broken by TMG, which also donates its
proximal proton (Hp) to the enolate. This simultaneously affords
the desired 2-oxazolidinone 3a and regenerates TMG. Other
strong bases such as tBuTMG, DBU and MTBD lack a proximal
proton, and are thus unable to stabilize the enolate, which results
in lower yields of 3a, as presented in Table 1 (entries 2-5). It is
unlikely that the distal proton of TBD can stabilize the enolate, as
this would create a larger ring, compared to TMG, which is
energetically unfavorable.
the method readily tolerates various substrates including
heteroaromatics, anilines with different functional groups,
aliphatic amines, and phenylhydrazine as a substrate. γ-
Brominated α,β-unsaturated esters, amides and nitriles are viable
Michael acceptors. A slow addition of the Michael acceptor
prevents formation of N-alkylated by-products, resulting in good
yields. The reactions are conducted using simple reaction setups
at room temperature. The presented modular synthesis yields a
wide range of 3,4-disubstituted 2-oxazolidinones using CO2 as a
benign carbonyl source. Accordingly, this facilitates a direct
introduction of
a saturated heteroatom ring-structure to a
molecular scaffold.
In conclusion, we describe here a novel base-catalyzed
method for the synthesis of 3,4-disubstituted 2-oxazolidinones.
The catalytic pathway consists of three steps: carboxylation of the
aniline; generation of a corresponding O-alkyl carbamate; and
cyclization via an intramolecular aza-Michael addition. TMG as a
catalyst has two distinct roles in the synthesis. Firstly, TMG reacts
with (aryl)amines to form a mixed carbamate (R-NHCOO-
+
TMGH+), which reacts further to form an O-alkyl carbamate.
Secondly, free TMG catalyzes cyclization of the O-alkyl
carbamate by acting as a base, while simultaneously stabilizing
the forming enolate through hydrogen bonding. As shown here,
Scheme 2. Scope of the TMG-catalyzed synthesis of 3,4-disubstituted 2-
oxazolidinones.
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Scheme 3. Applicability of the TMG-catalyzed synthesis of 3,4-disubstituted 2-oxazolidinones.
Norway, Uppsala University, Stockholm University, KTH Royal
Institute of Technology, Aarhus University, University of Oslo,
University of Bergen, University of Helsinki, and University of
Iceland). J.K.M. gratefully acknowledges support from the
Magnus Ehrnrooth Foundation and the foundations of Nylands
Nation.
Conflict of interest
The authors declare no conflict of interest.
Keywords: carbon dioxide fixation • cyclization • heterocycles •
Michael addition • organocatalysis
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10.1002/chem.201902451
Chemistry - A European Journal
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One-step Synthesis of 3,4-
Disubstituted 2-Oxazolidinones via
Base-catalyzed CO2-Fixation and Aza-
Michael Addition
Base makes CO2 stick: 1,1,3,3-Tetramethylguanidine (TMG) catalyzes the one-
step synthesis of 3,4-disubstituted 2-oxazolidinones via an aza-Michael addition
using CO2 as a carbonyl source. The modular reaction occurs between a γ-
brominated Michael acceptor, CO2 and an arylamine, aliphatic amine or
phenylhydrazine. The method displays high yields (avg. 75 %) and enables late-
stage functionalization of complex drug-like molecules.
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